Genomics of Liver Fibrosis and Cirrhosis

• ABSTRACT
• GENETIC POLYMORPHISMS INFLUENCING LIVER FIBROSIS IN HUMANS
• Alcohol-Induced Liver Disease
• Chronic HCV Infection
• Nonalcoholic Steatohepatitis
• Hereditary Hemochromatosis
• Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and Autoimmune Hepatitis
• SUGGESTIONS FOR FUTURE ASSOCIATION STUDIES
• Selection of Candidate Genes
• Identification and Testing of Functional Genetic Variants
• Selection of Cases and Controls
• Molecular Biology Techniques
• Adequate Statistical Methods
• i ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Hepatic fibrosis is the response to chronic injury from viral, toxic, metabolic, cholestatic, or autoimmune liver injury. However, only a minority of affected individuals develop advanced fibrosis or cirrhosis, suggesting that modifiers determine the individual risk. Aside from well-established progression factors including gender, duration of exposure to the disease, and ethnicity, unknown host genetic factors are likely to influence disease progression and prognosis. Potential genetic susceptibility loci are single nucleotide polymorphisms in fibrosis-associated genes, point mutations, microsatellites, and haplotype blocks composed of genes pivotal for fibrosis development. However, the study of complex polygenetic diseases poses numerous pitfalls in contrast to the elucidation of monogenetic (i.e., Mendelian) diseases. Many publications on the role of certain genetic variants in modulating the progression of hepatic fibrosis have been limited by inadequate study design and low statistical power. At present, powerful research strategies are being developed that allow the application of knowledge derived from the successful sequencing of the human genome that will help to translate our newly acquired insight into practical improvements for research activities and medical practice.

Liver fibrosis is the result of an generalized wound-healing response of hepatic tissue toward repeated injury resulting in the formation of scar tissue instead of normal parenchyma.[1] Increased matrix formation (i.e., fibrogenesis) occurs in parallel to decreased matrix degradation (i.e., fibrolysis). A landmark finding was the identification of activated hepatic stellate cells (HSCs) and myofibroblasts as the major collagen-producing cells, which, upon activation by profibrogenic cytokines, including transforming growth factor β1 (TGF-β1) and angiotensin II (ATII), acquire a profibrogenic phenotype and start to synthesize extracellular matrix that replaces parenchymal tissue. Apart from collagens, a multitude of other matrix components including noncollagenous gycoproteins, proteoglycans, and glycosaminoglycans have been characterized in detail and their interaction and regulation elucidated.[2] Collagens type I and III represent more than 80% of fibrotic tissue. Progression of fibrosis results in the development of cirrhosis, chronic liver failure, portal hypertension, and hepatocellular carcinoma (HCC).[3] [4]

The natural history of liver fibrosis is influenced by several environmental and certain host genetic factors that act in concert. The former are not sufficient to explain the wide variety of phenotypes among individuals subjected to profibrogenic insults, and the latter are largely unknown. Hepatic fibrosis does not evolve in everyone exposed to the same profibrogenic trigger and does not progress at a uniform pace. For example, advanced fibrosis develops in only a proportion of patients infected with the hepatitis C virus[5] [6] [7] and progresses at highly variable pace.[8] The majority of individuals with excessive alcohol intake do not develop cirrhosis,[9] and only a minor fraction of patients with genetic defects in the hemochromatosis gene (HFE) show evidence for iron overload, let alone relevant liver disease.[10] [11] This common clinical observation and convincing evidence from human cohort and twin studies indicate that genetic factors account for a substantial proportion of individual susceptibility to develop cirrhosis.[12] [13] [14] [15]

Most liver diseases are polygenic and represent “complex traits.” Mendelian diseases with a dominant pattern of inheritance require only a single, usually rare, trait-causing allele to precipitate the corresponding disease phenotype, whereas complex diseases result from a variable interaction between several highly prevalent genotypes and certain environmental factors. Briefly, Mendelian disorders derive from a single gene alteration with high penetrance but low prevalence, whereas complex diseases relate to weaker effects of several genetic variants (for example, single nucleotide polymorphisms [SNPs]) with a high prevalence in a reference population. With regard to liver fibrosis, an array of modulators of fibrosis may be subject to genetic variation within their corresponding genes. Particularly, functional SNPs of genes involved in the pathogenesis of cirrhosis, such as genes coding for profibrogenic cytokines, or those coding for fibrolytic collagenases or necroinflammatory modulators were investigated.

However, our knowledge about the role of genetic factors in complex diseases such as hepatic fibrosis is still preliminary and even an avalanche of human studies on this topic in the last decade has not enhanced our understanding of the role of polymorphic variants of fibrosis-related genes.[16] [17] However, there is much optimism that novel genomic approaches will shed light on the role of inherited factors in the evolution of liver cirrhosis fueled by the publication of the sequence of the human genome as a result of the Human Genome Project in 2001, which provided the exact composition of the 3.2 billion nucleotides that form our genes.[18] [19] In particular, novel techniques using high-throughput automated assay systems such as genotyping platforms and gene chip arrays that assess gene expression and investigate gene-gene interactions are expected to drive the field of genomics from a purely descriptive discipline into a powerful analytic effort to understand how genes shape our diversity and contribute to disease. The Human Haplotype Map (HapMap) is providing access to SNPs and to identifying informative, cosegregated genetic clusters that are more likely to influence the course of or susceptibility to liver fibrosis than single genes.[20]

Genomics is a rapidly developing scientific field that seeks to understand how the genome orchestrates cell biology through differential expression of genes in response to other genes and external stimuli derived from the environment. The overall aim of genomic research is to identify the genetic components of a disease's pathophysiology to improve its prevention, diagnostic assessment, and the required therapeutic intervention.

Bearing in mind that only 2% of the whole human genome represents protein-coding genes (~30,000 genes), a large proportion of genetic variability is unlikely to affect biological processes and disease development because the relevant genes do not take part in transcription or its modification. Even in coding genes, it is pivotal where genetic variation exists because nucleotide variation with effects on promoter, initiator, or enhancer sequences are more likely to affect transcription or the generated protein. This holds particularly true for SNPs, the most common type of allelic variation. So far, more than 10 million SNPs have been reported of which ~5 million have been validated. SNPs are found throughout the human genome at a frequency of 1 per 1000 to 2000 base pairs (http://www.ncbi.nlm.nhi.gov/SNP). Most SNPs are situated in noncoding regions of genes and, therefore, have little or no direct impact on gene expression,[21] and the fraction of functionally relevant, coding SNPs is considered to be only around 50,000.[22]

We summarize and evaluate currently available studies and define quality criteria for future human candidate gene studies.

GENETIC POLYMORPHISMS INFLUENCING LIVER FIBROSIS IN HUMANS

Hepatic fibrosis can be viewed as a complex disease that results from interactions between behavioral, environmental, and genetic factors.[16] [17] [23] [24] Recently, numerous association studies have investigated the role of gene polymorphisms in several candidate genes on the progression of liver fibrosis or development of cirrhosis, or both, in patients with different types of chronic liver diseases (Table [1]).

Alcohol-Induced Liver Disease

Chronic alcohol consumption is the best established and studied toxin causing liver fibrosis. Although the amount of alcohol consumed is positively correlated with the degree of liver injury,[9] considerable individual variability exists and some subjects develop only macrovesicular steatosis whereas others with comparable ethanol consumption develop cirrhosis. Chronic hepatitis C virus infection and obesity have been identified as environmental factors affecting the degree of liver damage.[25] [26] However, these factors are not sufficient to explain the wide diversity of hepatic damage, suggesting a role for host factors. Further evidence comes from twin studies showing that the concordance for alcoholic cirrhosis is significantly greater in monozygotic than in dizygotic twins, leading to the conclusion that ~15% to 50% of the phenotypic variation of alcoholism can be attributed to genetic modifiers.[14] [27]

In alcoholic liver disease (ALD), genes encoding alcohol-metabolizing enzymes and proteins involved in liver toxicity represent primary candidates for genetic association studies.[28] Polymorphisms in genes encoding alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P450 have been studied extensively and have already been subjects of numerous review articles.[17]

Numerous lines of evidence point to a major role for oxidative stress in the hepatic toxicity of ethanol. Glutathione-S-transferases (GSTs) and superoxide dismutase are enzymes that counteracts oxidative stress. GSTs are sulfur-containing enzymes that inactivate reactive oxygen species (ROS) through conjugation with glutathione (GSH).[29] Most studies have focused on “null alleles” of the GSTM1 and GSTT1 genes that lack all enzyme activity, which should consequently increase the levels of toxic intermediates generated in the course of chronic alcohol consumption. These studies have revealed discrepant data.[30] [31] [32] [33] [34] [35] The largest study found a significant association of the GSTM1 null genotype with advanced ALD in heavy drinkers.[30] Combined carriage of GSTM1 and GSTT1 null genotypes has also been shown to increase the risk for ALD.[36] Manganese superoxide dismutase (MnSOD) detoxifies mitochondria-derived ROS into hydrogen peroxide and water.[37] An SNP of the MnSOD gene affects translocation into mitochondria[38] and has been suggested to be risk factor for severe ALD.[39] This polymorphism has also been shown to increases the risk for developing cirrhosis in patients with ALD and chronic hepatitis C virus (HCV) infection[40] and to be associated with the development of HCC and death related to cirrhosis.[41] However, studies from other groups with larger numbers of patients and controls have not been able to replicate or confirm these findings.[42] [43] [44]

Variations in genes encoding proinflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 1β [IL-1β], IL-10), a bacterial cell membrane receptor (CD14), and stimulatory cell surface receptor (CTLA-4) suggest an important role of the immune system in progression of ALD. ALD is a typically associated with excess TNF-α production. Therefore, genetic variation of the TNF-α gene causing variable TNF-α levels may influence the course of ALD. Two SNPs located in the promoter region of the TNF-α gene (-308G→A; -238G→A) are associated with increased cytokine expression. The rare TNFA-A allele at position -238 was found to be associated with more severe steatohepatitis and a higher risk to develop liver cirrhosis in patients with ALD.[45] [46] Three subsequent cohort studies also tested TNF-α variants but found no association.[44] [47] [48] The latter three studies also failed to replicate an association of genetic variations of the IL-10 gene with an increased risk of advanced ALD.[49]

IL-1 is a potent proinflammatory cytokine whose biological action is inhibited by IL-1 receptor antagonist (IL-1Ra) that prevents IL-1 from binding to its receptor. Two studies evaluated the impact of a microsatellite in the IL-1Ra gene that affects its expression[50] in patients with ALD. In a Spanish cohort this polymorphism increased the risk for alcoholism, but no relationship with ALD and alcoholic cirrhosis was observed.[51] In a Japanese study, heterozygosity for a certain allele tended to be more frequent in alcoholics with fibrosis than in those without.[52] However, this difference did not reach statistical significance. In a Chinese study another allele was reported to confer risk to more severe liver injury in the setting of chronic alcohol consumption,[53] making it more difficult to draw any conclusion from the available data. Takamatsu and colleagues also reported that the -511 IL-1β allele 2 is associated with cirrhosis in patients with ALD,[54] which was not confirmed in a Spanish cohort.[55]

In a Finnish cohort of patients with ALD, an SNP in the promoter region of the CD14 gene that results in increased protein synthesis conferred increased risk for developing alcohol-induced cirrhosis, which was later confirmed in a Spanish cohort.[56] [57] However, this association was not reproduced by others.[44] [58] Patients with polymorphism of in the cytotoxic T lymphocyte A4 (CTLA-4) gene are more susceptible to develop severe fibrosis,[59] which was also observed in patients with chronic HCV infection.[40] This might be explained by promotion of anti-CYP2E1 autoantibodies by this polymorphism that might contribute to alcohol-induced liver injury.[60] Two studies analyzing the contribution of several TGF-β1 polymorphisms that lead to elevated TGF-β1 expression could not find an association with alcoholic cirrhosis.[47] [61]

As with chronic hepatitis C, studies, evaluating the contribution of HFE gene mutations to the progression of ALD have revealed inconclusive results. Heterozygosity for the C282Y mutation of the HFE gene was suggested to confer risk for developing HCC in patients with alcoholic cirrhosis.[62] Others suggested that the H63D mutation is associated with the risk of developing advanced liver alcoholic disease.[63] Other groups have not been able to verify these findings.[64] [65]

Chronic HCV Infection

The natural history of patients with chronic hepatitis C is characterized by a highly variable disease progression[23] and cirrhosis may develop after an average of 30 years. In one third of patients, however, the rate of fibrosis progression is much faster and cirrhosis may develop in less than 20 years, and another third may develop cirrhosis only after 50 years. In this respect, “rapid fibrosers” and “slow fibrosers” with rapid or slow fibrosis progression per unit time were identified.[66] Although viral factors such as genotype or viral load do not influence disease progression, host factors such as duration of infection, gender, and alcohol consumption influence fibrosis progression and seem to play an important role.[23] A role for genetic susceptibility is suggested by the finding that patients with a positive family history for liver diseases are associated with developing cirrhosis at younger ages.[15] Genetic variations may affect susceptibility to chronic HCV infection, response to antiviral therapy, and progression to cirrhosis.

Several candidate genes that are involved in connective tissue turnover have been tested in chronic hepatitis C (CHC). One of the first papers published on the contribution of host genetic factors to the evolvement of fibrosis in patients with CHC provided evidence that polymorphisms in the angiotensinogen gene as well as the TGF-β1 gene are major determinants of fibrosis progression.[67] Interestingly, this study showed an additive effect for these two mutations as one would expect for complex diseases. Polymorphisms in the promoter region of the angiotensinogen gene have also been shown to be associated with liver cirrhosis in patients with chronic hepatitis B.[68] However, another study focusing on genetic variations of genes of the renin-angiotensin system that also included the AT-6 polymorphism has not been able to confirm this finding.[69] Studies on TGF-β1 polymorphism also led to controversial results. Whereas Powell and colleagues reported that individuals homozygous for the arginine allele of the TGF-β1 gene polymorphism at codon 25 are more likely to have increased hepatic fibrosis, other studies suggested that the presence of proline at codon 25 predicts significantly faster progression to cirrhosis in patients with CHC.[70] [71] [72] In Caucasians, homozygous presence of the leucine allele at codon 10 is associated with slow progression to severe fibrosis.[70] [72] This finding was not confirmed in Japanese, Chinese, or Pakistan populations.[72] [73] [74] Genetic variations of matrix metalloproteinase genes (1, 3, and 9) affecting transcriptional activity have been suggested to account for some of the variability in the progression of HCV-related chronic liver diseases.[75] A polymorphism of the PDGF-B gene was reported to affect development and progression of hepatic fibrosis in patients with CHC after liver transplantation.[76]

Several studies have focused on polymorphisms in proinflammatory cytokines and chemokines as these might affect inflammation and fibrosis. Polymorphisms in the TNF-α promoter (-238 and -308A) were reported to be associated with advanced liver disease[77] [78] and with higher serum levels of type IV collagen as a surrogate marker for fibrosis[79] and risk for the development of HCC.[80] This might be explained by the increased promoter activity of these polymorphisms leading to insulin resistance and steatosis.[81] However, other groups have not been able to confirm these findings.[67] [74] [82] [83] [84] [85] [86] [87] [88] [89] [90] There is one report suggesting that polymorphisms in TNF-β (A/A allele) may affect the natural course of HCV infection.[82]

Genetic variations of other proinflammatory cytokines have also been suggested to affect progression to cirrhosis. In this respect, reports suggest that the C allele of the IL-12p40 gene[91] renders genetic protection against development of severe liver disease and polymorphisms of the IL-1β and IL-1Ra[90] and of the interferon-γ (IFN-γ) gene at position + 874[92] are associated with progression to cirrhosis. Other studies have not been able to replicate this finding for IFN-γ.[74] [85] [93]

Similar controversial results exist for genetic variations of the IL-10 promoter, an anti-inflammatory cytokine that is believed to be antifibrotic. Polymorphisms and certain haplotypes have been reported to influence not only outcome and treatment of HCV infection but also hepatic inflammation and fibrosis.[94] [95] In contrast to these two studies that found the G allele of the -1082 polymorphism to confer a lower risk of progression to cirrhosis, another study suggested that the GG genotype is associated with higher necroinflammatory activity and a tendency toward higher stages of fibrosis.[74] Other studies have not been able to confirm these results.[67] [79] [85] [93] A coding SNP of the IL-10 receptor 1 impairing signaling has also been reported to be associated with cirrhosis in chronic HCV-1 infection.[96]

Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine secreted by HSCs that regulates monocyte and macrophage trafficking. A polymorphism at position -2518 that results in increased production of MCP-1 was reported to be associated with advanced fibrosis and more severe inflammation.[97] However, three groups have not been able to confirm this association.[98] [99] [100] One study reported that a coding SNP of the MCP-2 gene is associated with more severe hepatic fibrosis.[98] This study also suggested that a 32 base pair deletion from the chemokine receptor-5 gene is associated with reduced portal inflammation and milder fibrosis, which was confirmed by one group.[40] Other groups, however, have not been able to confirm this finding.[101] [102] [103] [104] [105] [106] Two studies demonstrated that a polymorphism in the promoter of regulated upon activation, normal T-cell expressed, and secreted (RANTES), the most important CCR5 ligand, resulted in less hepatic inflammation,[98] [101] which was not confirmed by another study.[105]

Variations in genes involved in the immune response to HCV infection seem to influence disease progression. Chronic HCV infection evolves as HCV escapes surveillance of the human leukocyte antigen HLA-II-directed immune response to infect hepatocytes. In this respect, specific HLA-II alleles (DRB1*0405-DQB1*0401, DRB1*11, DRB1*13, DQB1*0301), which are also involved in host defense against viral infections, influence progression to cirrhosis.[107] [108] [109] [110] [111] Another study suggested only a weak contribution of class II HLA alleles to the severity of HCV liver disease.[112] HLA class I allelic diversity has been suggested to have only a minor influence on fibrosis progression rates. Heterozygosity at the B locus and homozygosity at the A locus predicted a higher median fibrosis progression rate.[113] Polymorphisms of other genes involved in the immune response such as mannose-binding lectin (MBL), transporter associated with antigen processing 2 (TAP2), and solute carrier family 11 member 1 (SLC11A1) have also been suggested to affect disease progression.[15] [78] [114] Variations of the low-density lipoprotein receptor are of special interest as this receptor has been shown to promote hepatitis C virus endocytosis, allowing entry into host cells. In this respect, a cSNP in exon 8 has been suggested to be associated with severity of fibrosis,[115] which was not replicated by others.[40]

Genetic variations of the apolipoprotein E (apoE) gene have been suggested to determine the severity of viral diseases. In this respect, carriage of an apoE-epsilon 4 allele may be protective against liver damage caused by HCV.[40] [116]

Genetic variation of the MTHFR gene causing hyperhomocysteinemia was reported to be associated with higher degree of steatosis, which in turn accelerates the progression of liver fibrosis in CHC.[117]

Other studies report that genetic variations of the complement factor 5 gene,[118] the carnitine palmitoyltransferase 1A, the DEAD box polypeptide 5 (DDX5) gene,[119] the S allele of the α₁-antitrypsin gene,[120] and the factor V Leiden polymorphism[121] account for some variation observed among patients with respect to progression to cirrhosis. Additional studies are needed to evaluate their impact.

Keratins have also been suggested as susceptibility genes for end-stage liver disease and progression of fibrosis during chronic hepatitis C infection.[122] [123]

Genetic variations in genes involved in the metabolism of ROS such as myeloperoxidase and microsomal epoxide hydrolase have also been suggested to affect progression to cirrhosis.[124] [125] The association of the A allele of the MPO promoter with advanced fibrosis has not been confirmed by another group.[40]

Richardson and colleagues used an interesting approach that may allow determination of a genetic profile predictive of rapid disease progression in HCV. They evaluated the role of nine polymorphisms in eight genes (HFE, MTP, APOE, CCR5, SOD2, CTLA4, LDLR, and MPO) that have been associated with fibrosis progression in some liver disease and confirmed the association of seven polymorphisms with more rapid fibrosis. They showed that the risk for more severe disease strongly increases with the number of polymorphisms in a given individual. Combing single polymorphisms with only modest effects identified patients with rapid or slow progressive disease. Using this approach, Richardson et al were able to classify correctly 80% of patients in this second cohort.[40]

Finally, studies have revealed contradictory results in assessing the role of HFE gene mutations in fibrosis in patients with CHC.[16] [126] [127] [128] [129] A large number of studies evaluated the role of HFE gene mutation in the evolution of fibrosis in patients with chronic HCV infection. These studies were based on the pathohistological observation of increased iron deposition in patients with chronic HCV infection, which could increase oxidative stress and subsequent liver damage and fibrosis. In addition, HFE gene mutations are common among Caucasians and have been demonstrated to be functional in terms of increased duodenal iron absorption and deposition, making it an attractive candidate gene. Indeed, the majority of reports suggest that heterozygosity for the C282Y mutation is associated with more severe iron deposition and more advanced fibrosis.[130] [131] [132] [133] [134] [135] Two reports also suggested that heterozygosity for the H63D variant of the HFE gene contributes to the faster fibrosis progression.[133] [134] Other studies have not been able to find a role for HFE mutation in the patients with chronic HCV infection.[136] [137] However, the more recent larger studies have demonstrated increased fibrosis in HCV patients who have the HFE C282Y allele.

Nonalcoholic Steatohepatitis

The worldwide epidemic of obesity has increased the prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD represents the hepatic manifestation of the metabolic syndrome and is believed to be the major reason for abnormal liver function and an increasing cause of liver cirrhosis in the Western world. NAFLD has a spectrum of liver manifestations ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis accompanied by the risk of end-stage liver disease. HCC is also a complication in an as yet unknown percentage of cases of NASH cirrhosis.[138] Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. Evidence for a contribution of genetic factors for the development of advanced fibrosis in NAFLD comes from family clustering studies showing that about one fifth of patients with NASH have an affected first-degree relative.[139] In another study, coexistence of NASH or cryptogenic cirrhosis, or both, was observed in seven out of eight families studied.[140] Interestingly, the prevalence of cryptogenic cirrhosis in Hispanic and African Americans was 3-fold higher and 4-fold lower, respectively, than in Americans of European origin although these groups share a similar prevalence of type 2 diabetes mellitus, suggesting that susceptibility to NAFLD may have genetic component.[141] Compared with chronic HCV infection and ALD, less is known about factors influencing fibrosis progression in patients with NAFLD.[24] Variations in genes affecting hepatic lipid metabolism, insulin resistance, hepatic fatty acid oxidation, ROS formation and degradation, cytokines, and endotoxin receptors are of special interest.[24]

A polymorphism of the microsomal triglyceride transfer protein (MTP) gene was reported to affect susceptibility to the development of NAFLD. In this respect, NASH patients displayed a higher incidence of the MTP gene G allele and of the G/G genotype compared with the controls. More severe steatosis and advanced stage of NASH were observed in patients with NASH and the G/G genotype compared with patients with genotype G/T.[142] The same study also suggested that the T/T genotype of the MnSOD gene is a susceptibility allele for the development of NAFLD. In a cohort of patients with type 2 diabetes, the -493 G/T MTP gene polymorphism was also associated with serum alanine aminotransferase (ALT) levels as biological surrogates of steatohepatitis.[143] Interestingly, MTP polymorphism was also reported to affect fibrosis progression in patients with chronic HCV infection.[40] Increased TNF-α levels caused by TNF-α polymorphisms favoring insulin resistance and impaired glucose tolerance were also suggested to affect susceptibility to and the progression of NAFLD as in chronic HCV infection.[144] Further evidence for the involvement of variations of proinflammatory cytokines comes from the observation that the IL-1β -511 T allele frequency and the T/T genotype frequency are significantly higher in NASH patients than in control subjects.[145] Similar to that in ALD,[56] the C(2159)T polymorphism in the promoter region of the CD14 endotoxin receptor was suggested to confer increased risk in progression from NAFL to NASH.[146] In accordance with findings in patients with chronic HCV infection[67] the combination of high angiotensinogen and TGF-β1 producing polymorphisms is associated with advanced hepatic fibrosis in obese patients with NAFLD.[147] As with ALD and chronic HCV infection, discrepant data concerning the contribution of HFE gene mutation to the severity of NAFLD exist. Whereas two studies showed that heterozygosity for the C282Y mutation is associated with more severe hepatic fibrosis,[148] [149] three subsequent studies have not been able to confirm these results.[138] [150] [151] Genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH. In this respect, genetic variations of the β2 and 3 adrenergic receptor genes were reported to be associated with NASH in Japanese patients.[145] [152] A polymorphism of the phosphatidylethanolamine N-methyltransferase (PEMT) gene, whose disruption in mice causes fatty liver disease, was reported to confer susceptibility to NAFLD.[153]

However, most of these reports have not been evaluated and replicated in larger well-designed studies, and they are likely to be subject to type I errors and represent chance findings.

Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC) is the most common genetic disease in populations of European ancestry, usually caused by mutations of the HFE gene. An unknown proportion of individuals, however, may not develop symptomatic disease at all.[10] [11] [128] Chronic alcohol abuse[154] and chronic viral hepatitis[155] have been reported to contribute to this phenotypic heterogeneity. Involvement of genetic factors is supported by the observation of greater concordance between clinical manifestations and biochemical markers of iron within families than between families.[156] ROS generated in the course of continuous iron deposition are believed to be a major factor causing liver injury in patients with HHC. Genetic variations of enzymes involved in generation and degradation of ROS are therefore of special interest. In this respect, polymorphisms of MPO and GSTP1 contribute to the progression to cirrhosis in patients with HHC.[157] [158] Polymorphisms of the TNF-α gene are of special interest as both TNF-α and the HFE gene are located on the short arm of chromosome 6, raising the possibility of linked inheritance. In addition, TNF-α is implicated in iron metabolism. Promoter polymorphisms at positions -238 and 308 were suggested to modulate the severity of liver damage in patients with HHC by affecting the grade of siderosis and serum ALT levels.[159] Curiously, a recent study found a completely opposite association between the -308 polymorphism and iron deposition.[160] However, others have not been able to find any contribution of TNF-α polymorphisms to the clinical presentation of patients with HHC.[161] [162] Any contribution of the TGF-β1 codon 25 polymorphism to the progression to cirrhosis as we have recently suggested has to be evaluated in a larger cohort of patients.[161]

Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and Autoimmune Hepatitis

Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune disease of the liver characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. PBC is believed to occur in a genetically susceptible individual triggered by an environmental factor leading to progressive immune cell-mediated destruction of bile ducts.[163] Considerable heterogeneity is observed among patients. Histological changes occur at different rates and with varying degrees of severity in different patients. Whereas some patients have persistent minor histological changes, others may progress to cirrhosis. Twin and family studies suggest a genetic predisposition to PBC.[164] [165] In this respect, 1% to 6% of patients have at least one affected family member[166] and monozygotic twins display a concordance rate of 63%.[167] Genetic variations of immunoregulatory and proinflammatory genes, such as HLA-II,[168] CTLA-4,[169] [170] vitamin D receptor,[171] TNF-α,[172] and IL-1β[173] have been suggested to affect susceptibility to PBC. Other studies have not been able to replicate these findings.[173] [174] [175] [176] In conclusion, there are no clear genetic influences on the occurrence of PBC.[177] Concerning the contribution of TNF-α polymorphism to disease progression, conflicting results exist as opposite alleles have been reported to be associated with advanced disease and other groups could not find any contribution at all.[172] [174] [175] [176] [178] Genetic variations of the IL-1β, IL-1 RA, and HLA class II genes have also been suggested to affect disease progression,[173] which with regard to HLA class II variants has not been observed in Brazilian PBC patients.[175]

Little is known about the impact of genetic variants influencing disease progression in primary sclerosis cholangitis. Disease susceptibility has been linked to certain HLA alleles[179] and a TNF-α variant.[180] An association between the MMP-3 genotype 5A/5A and the progression of liver damage in patients with primary sclerosing cholangitis has been reported.[181]

Finally, isolated reports suggest that in addition to gender, certain HLA-II alleles and genetic variations of TNF-α influence both susceptibility and disease progression in type 1 autoimmune hepatitis.[182] [183]

SUGGESTIONS FOR FUTURE ASSOCIATION STUDIES

Recently, many genotype-phenotype studies evaluating the role of genetic polymorphisms in liver diseases have been conducted. However, although initial studies based on exciting hypotheses often yielded very promising results, subsequent reports usually failed to replicate and validate observations (Table [1]). It is clear that genetic variations between patients account for some heterogeneity with respect to progression to cirrhosis in most or all liver diseases. However, no definite conclusion can be drawn with respect to many polymorphisms and their impact on the evolution of fibrosis. Interestingly, variations of genes that play a central role in the pathogenesis of liver cirrhosis irrespective of etiology and the underlying cause of liver disease such as TGF-β1 or angiotensinogen have also revealed contradictory results (Table [1]).

Most of the controversy among currently available studies can be attributed to limitations in study design. We provide some guidelines to design high-quality association studies in the future.

Selection of Candidate Genes

Candidate genes for case-control studies should be selected on the basis of their biological plausibility as such as chosen genes play a putative role in the pathogenesis of the disease of interest.[184] Genetically modified animals have substantially improved our understanding of the pathogenesis of liver fibrogenesis. In this respect, knockout mice deficient for a particular gene or, conversely, transgenic mice overexpressing a certain genes have been studied in different models of liver fibrosis revealing their anti- or profibrogenic properties.[16] These identified genes represent ideal candidates to be studied further in human cohorts. However, the role of polymorphisms of some of these key genes involved in experimental fibrosis derived from studies using knockout or transgenic mice has not been evaluated in humans so far.

Identification and Testing of Functional Genetic Variants

Only genetic variants with functional significance (altered gene transcription, RNA stability, amino acid sequence) are likely to affect protein function and modulate disease progression and therefore should be studied. The functional implications of an SNP or a haplotype should be characterized through in vitro and in vivo experiments prior to their testing in association studies. If possible, multiple polymorphisms within a given gene should be studied. Furthermore, genes with similar function (TGF-β1, angiotensinogen, PDGF) or belonging to the same pathway (IL-10 and IL-10 receptor, angiotensinogen, AT1 receptor, and ACE) should be investigated together.

Selection of Cases and Controls

Adequate population stratification represents one of the most challenging problems in genotype-phenotype studies and most likely represents one of the reasons for the observed inconsistency of published reports.[185]

Usually, patients are recruited from a single center (tertiary hospital), where individuals suffer from more advanced diseases compared with primary centers. This might lead to an overrepresentation of severe cases and a selection bias to a subgroup of patients with advanced disease. Population stratification can affect genotype-phenotype studies if the studied gene displays variation in allele frequency across subgroups of the population with a different baseline risk for the disease.[186] [187]

Cases and controls need to be defined accurately, requiring a concrete definition of the phenotype of interest, that is, stage of fibrosis or cirrhosis. Different staging systems for fibrosis used by different researchers may represent one of the reasons for the discrepancy observed among published reports. Even though liver biopsy represents the “gold standard” for evaluating fibrosis, this method is susceptible to sampling error. This might have an impact on studies that evaluate the contribution of a certain polymorphism to different stages of fibrosis. Dividing the study cohort into two groups (cases and controls) is the usual way. Most of the reports compare patients with cirrhosis with patients without cirrhosis, who serve as controls. It would also make sense to compare patients with mild fibrosis (stages 1-2) and those with advanced fibrosis (stages 3-4). This, however, would be limited to interobserver variance among pathologist grading fibrosis stage 2 and 3 and intermediate stages and by sampling error of liver biopsies. The best would definitely be to compare rapid versus slow fibrosers. This, however, requires knowledge about the duration of disease, which in diseases such as ALD or chronic HCV infection sometimes can only be roughly estimated.

Other factors that need to be considered in hepatic fibrogenesis are ethnicity, history of alcohol abuse, and a quantification of amount, age, gender, menopausal status, comorbidities, and comedication. Cases and controls should be carefully evaluated and well matched for these variables to avoid any confounding effect.

Molecular Biology Techniques

Molecular biology techniques used to detect the variations in genes of interest should be validated before genotyping patients' DNA. Positive and negative controls should be included in every analysis, and the person performing genotyping should be “blinded” to the identity of the patients and the group to which a given sample belongs.

Adequate Statistical Methods

Statistical issues have become increasingly complex in genetic studies and, particularly, statistical power is important because it reflects the probability that a statistical test (i.e., genotype-phenotype study) will reject a false null hypothesis (cases and controls do not differ with respect to a particular polymorphism) or in other words that it will not make a type II error (false negative association). As power increases, the chances of a type II error decrease, and vice versa. The probability of a type II error is referred to as β and power is equal to 1 - β. Currently, a power of 0.8 for genetic association studies is generally accepted, which translates into an 80% chance of detecting a true association and a 20% chance of detecting a false negative association. The power of a study is influenced by several factors but mostly by sample size.[188] In underpowered studies because of a low sample size, type I errors (false positive associations = chance findings) may also occur, leading to misinterpretation of data. Many of the initial reports of positive associations conducted in small cohorts of patients are likely to be subject to type I errors, explaining why larger studies failed to replicate them.[185] [189] [190] Failure to replicate previous positive reports may be subject to type II errors attributed to small underpowered studies. Consequently, not only were results published that could not be reproduced because of lack of a true association with the studied disease but also some investigations may have missed an association because of an insufficient approach. The obvious solution is to study larger sample sizes.[191] A sample size of ≥ 150 has been defined as a critical threshold for the replication validity of genetic association studies.[189] In addition, an a priori power calculation should become an integral part of the planning of any candidate gene association study to recruit a significant number of patients. As recruitment of a significant number of patients with liver fibrosis may not be accomplished within a single institution, networking of different research centers is especially needed when studying rather rare diseases such as PBC, hemochromatosis, and autoimmune hepatitis. Adequate statistical data analysis requires adjustment for all potential cofactors (see earlier). This can be achieved by applying multiple logistic regression analysis, which allows correction of quantitative and qualitative covariates as predictors of the disease outcome. In addition, statistically significant differences should be adjusted by multiple correction tests. If all these prerequisites are taken into account, large numbers of patients and controls are usually necessary to give a study sufficient power to detect a significant effect.[185]

ACKNOWLEDGMENTS

Christoph H. Österreicher is supported by an Erwin Schroedinger research fellowship kindly provided by the Austrian Science Fund (FWF). David A. Brenner is supported by grants from the NIH.

ABBREVIATIONS

• ALD alcoholic liver disease

• ALT alanine aminotransferase

• apoE apolipoprotein E

• ATII angiotensin II

• CHC chronic hepatitis C

• GST glutathione-S-transferase

• HCC hepatocellular carcinoma

• HCV hepatitis C virus

• HHC hereditary hemochromatosis

• HLA human leukocyte antigen

• HSC hepatic stellate cell

• IFN-γ interferon-γ

• IL-1Ra interleukin 1 receptor antagonist

• IL-10 interleukin 10

• MCP-1 monocyte chemotactic protein-1

• MnSOD manganese superoxide dismutase

• NAFLD nonalcoholic fatty liver disease

• NASH nonalcoholic steatohepatitis

• PBC primary biliary cirrhosis

• ROS reactive oxygen species

• SNP single nucleotide polymorphism

• TGF-β1 transforming growth factor β1

• TNF-α tumor necrosis factor α

REFERENCES

• 1 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115 209-218
  CrossrefPubMedSearch in Google Scholar
• 2 Schuppan D, Ruehl M, Somasundaram R, Hahn E G. Matrix as a modulator of hepatic fibrogenesis.  Semin Liver Dis. 2001;  21 351-372
  Thieme ConnectPubMedSearch in Google Scholar
• 3 Albanis E, Friedman S L. Hepatic fibrosis: pathogenesis and principles of therapy.  Clin Liver Dis. 2001;  5 315-334
  CrossrefPubMedSearch in Google Scholar
• 4 Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites.  N Engl J Med. 2004;  350 1646-1654
  CrossrefPubMedSearch in Google Scholar
• 5 Forns X, Ampurdanes S, Sanchez-Tapias J M et al.. Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center.  J Hepatol. 2001;  35 265-271
  CrossrefPubMedSearch in Google Scholar
• 6 Niederau C, Lange S, Heintges T et al.. Prognosis of chronic hepatitis C: results of a large, prospective cohort study.  Hepatology. 1998;  28 1687-1695
  CrossrefPubMedSearch in Google Scholar
• 7 Sangiovanni A, Prati G M, Fasani P et al.. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients.  Hepatology. 2006;  43 1303-1310
  CrossrefPubMedSearch in Google Scholar
• 8 Massard J, Ratziu V, Thabut D et al.. Natural history and predictors of disease severity in chronic hepatitis C.  J Hepatol. 2006;  44(suppl) S19-S24
  PubMedSearch in Google Scholar
• 9 Bellentani S, Saccoccio G, Costa G et al.. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group.  Gut. 1997;  41 845-850
  CrossrefPubMedSearch in Google Scholar
• 10 Olynyk J K, Cullen D J, Aquilia S et al.. A population-based study of the clinical expression of the hemochromatosis gene.  N Engl J Med. 1999;  341 718-724
  CrossrefPubMedSearch in Google Scholar
• 11 Beutler E, Felitti V J, Koziol J A, Ho N J, Gelbart T. Penetrance of 845G→ A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet. 2002;  359 211-218
  CrossrefPubMedSearch in Google Scholar
• 12 Poynard T, Ratziu V, Charlotte F et al.. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c.  J Hepatol. 2001;  34 730-739
  CrossrefPubMedSearch in Google Scholar
• 13 Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin M E. Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology.  Semin Liver Dis. 2005;  25 265-280
  Thieme ConnectPubMedSearch in Google Scholar
• 14 Reed T, Page W F, Viken R J, Christian J C. Genetic predisposition to organ-specific endpoints of alcoholism.  Alcohol Clin Exp Res. 1996;  20 1528-1533
  CrossrefPubMedSearch in Google Scholar
• 15 Akuta N, Chayama K, Suzuki F et al.. Risk factors of hepatitis C virus-related liver cirrhosis in young adults: positive family history of liver disease and transporter associated with antigen processing 2(TAP2)*0201 allele.  J Med Virol. 2001;  64 109-116
  CrossrefPubMedSearch in Google Scholar
• 16 Bataller R, North K E, Brenner D A. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.  Hepatology. 2003;  37 493-503
  CrossrefPubMedSearch in Google Scholar
• 17 Stickel F, Osterreicher C H. The role of genetic polymorphisms in alcoholic liver disease.  Alcohol Alcohol. 2006;  41 209-224
  CrossrefPubMedSearch in Google Scholar
• 18 Lander E S, Linton L M, Birren B et al.. Initial sequencing and analysis of the human genome.  Nature. 2001;  409 860-921
  CrossrefPubMedSearch in Google Scholar
• 19 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
  CrossrefPubMedSearch in Google Scholar
• 20 Lazaridis K N, Juran B D. American Gastroenterological Association future trends committee report: the application of genomic and proteomic technologies to digestive disease diagnosis and treatment and their likely impact on gastroenterology clinical practice.  Gastroenterology. 2005;  129 1720-1752
  CrossrefPubMedSearch in Google Scholar
• 21 Tabor H K, Risch N J, Myers R M. Opinion: candidate-gene approaches for studying complex genetic traits-practical considerations.  Nat Rev Genet. 2002;  3 391-397
  PubMedSearch in Google Scholar
• 22 Kruglyak L, Nickerson D A. Variation is the spice of life.  Nat Genet. 2001;  27 234-236
  CrossrefPubMedSearch in Google Scholar
• 23 Feld J J, Liang T J. Hepatitis C-identifying patients with progressive liver injury.  Hepatology. 2006;  43(suppl 1) S194-S206
  CrossrefPubMedSearch in Google Scholar
• 24 Day C P. Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.  Liver Int. 2006;  26 1021-1028
  CrossrefPubMedSearch in Google Scholar
• 25 Wiley T E, McCarthy M, Breidi L, McCarthy M, Layden T J. Impact of alcohol on the histological and clinical progression of hepatitis C infection.  Hepatology. 1998;  28 805-809
  CrossrefPubMedSearch in Google Scholar
• 26 Raynard B, Balian A, Fallik D et al.. Risk factors of fibrosis in alcohol-induced liver disease.  Hepatology. 2002;  35 635-638
  CrossrefPubMedSearch in Google Scholar
• 27 Hrubec Z, Omenn G S. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans.  Alcohol Clin Exp Res. 1981;  5 207-215
  CrossrefPubMedSearch in Google Scholar
• 28 Agarwal D P. Genetic polymorphisms of alcohol metabolizing enzymes.  Pathol Biol (Paris). 2001;  49 703-709
  CrossrefPubMedSearch in Google Scholar
• 29 Armstrong R N. Structure, catalytic mechanism, and evolution of the glutathione transferases.  Chem Res Toxicol. 1997;  10 2-18
  CrossrefPubMedSearch in Google Scholar
• 30 Savolainen V T, Pjarinen J, Perola M, Penttila A, Karhunen P J. Glutathione-S-transferase GST M1 “null” genotype and the risk of alcoholic liver disease.  Alcohol Clin Exp Res. 1996;  20 1340-1345
  CrossrefPubMedSearch in Google Scholar
• 31 Rodrigo L, Alvarez V, Rodriguez M et al.. N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study.  Scand J Gastroenterol. 1999;  34 303-307
  CrossrefPubMedSearch in Google Scholar
• 32 Frenzer A, Butler W J, Norton I D et al.. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis.  J Gastroenterol Hepatol. 2002;  17 177-182
  CrossrefPubMedSearch in Google Scholar
• 33 Burim R V, Canalle R, Martinelli Ade L, Takahashi C S. Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics.  Mutagenesis. 2004;  19 291-298
  CrossrefPubMedSearch in Google Scholar
• 34 Hayes J D, Flanagan J U, Jowsey I R. Glutathione transferases.  Annu Rev Pharmacol Toxicol. 2005;  45 51-88
  CrossrefPubMedSearch in Google Scholar
• 35 Groppi A, Coutelle C, Fleury B et al.. Glutathione S-transferase class mu in French alcoholic cirrhotic patients.  Hum Genet. 1991;  87 628-630
  PubMedSearch in Google Scholar
• 36 Ladero J M, Martinez C, Garcia-Martin E et al.. Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease.  Scand J Gastroenterol. 2005;  40 348-353
  CrossrefPubMedSearch in Google Scholar
• 37 Wallace D C. Mitochondrial diseases in man and mouse.  Science. 1999;  283 1482-1488
  CrossrefPubMedSearch in Google Scholar
• 38 Sutton A, Khoury H, Prip-Buus C et al.. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.  Pharmacogenetics. 2003;  13 145-157
  CrossrefPubMedSearch in Google Scholar
• 39 Degoul F, Sutton A, Mansouri A et al.. Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease.  Gastroenterology. 2001;  120 1468-1474
  CrossrefPubMedSearch in Google Scholar
• 40 Richardson M M, Powell E E, Barrie H D et al.. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C.  J Med Genet. 2005;  42 e45
  CrossrefPubMedSearch in Google Scholar
• 41 Nahon P, Sutton A, Pessayre D et al.. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death.  Clin Gastroenterol Hepatol. 2005;  3 292-298
  CrossrefPubMedSearch in Google Scholar
• 42 Stewart S F, Leathart J B, Chen Y et al.. Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis.  Hepatology. 2002;  36 1355-1360
  CrossrefPubMedSearch in Google Scholar
• 43 Brind A, Fryer A, Hurlstone A, Fisher N, Pirmohamed M. The role of polymorphism in manganese superoxide dismutase in susceptibility to alcoholic liver disease.  Gastroenterology. 2003;  124 2000-2002
  PubMedSearch in Google Scholar
• 44 Martins A, Cortez-Pinto H, Machado M et al.. Are genetic polymorphisms of tumour necrosis factor alpha, interleukin-10, CD14 endotoxin receptor or manganese superoxide dismutase associated with alcoholic liver disease?.  Eur J Gastroenterol Hepatol. 2005;  17 1099-1104
  CrossrefPubMedSearch in Google Scholar
• 45 Grove J, Daly A K, Bassendine M F, Day C P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis.  Hepatology. 1997;  26 143-146
  CrossrefPubMedSearch in Google Scholar
• 46 Pastor I J, Laso F J, Romero A, Gonzalez-Sarmiento R. -238 G> A polymorphism of tumor necrosis factor alpha gene (TNFA) is associated with alcoholic liver cirrhosis in alcoholic Spanish men.  Alcohol Clin Exp Res. 2005;  29 1928-1931
  CrossrefPubMedSearch in Google Scholar
• 47 Bathgate A J, Pravica V, Perrey C, Hayes P C, Hutchinson I V. Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease.  Eur J Gastroenterol Hepatol. 2000;  12 1329-1333
  PubMedSearch in Google Scholar
• 48 Ladero J M, Fernandez-Arquero M, Tudela J I et al.. Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease.  Liver. 2002;  22 245-251
  CrossrefPubMedSearch in Google Scholar
• 49 Grove J, Daly A K, Bassendine M F, Gilvarry E, Day C P. Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease.  Gut. 2000;  46 540-545
  CrossrefPubMedSearch in Google Scholar
• 50 Danis V A, Millington M, Hyland V J, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism.  Clin Exp Immunol. 1995;  99 303-310
  PubMedSearch in Google Scholar
• 51 Pastor I J, Laso F J, Avila J J, Rodriguez R E, Gonzalez-Sarmiento R. Polymorphism in the interleukin-1 receptor antagonist gene is associated with alcoholism in Spanish men.  Alcohol Clin Exp Res. 2000;  24 1479-1482
  CrossrefPubMedSearch in Google Scholar
• 52 Takamatsu M, Yamauchi M, Maezawa Y et al.. Correlation of a polymorphism in the interleukin-1 receptor antagonist gene with hepatic fibrosis in Japanese alcoholics.  Alcohol Clin Exp Res. 1998;  22(suppl) 141S-144S
  PubMedSearch in Google Scholar
• 53 Chen W X, Xu G Y, Yu C H et al.. Correlation of polymorphism in the interleukin-1 receptor antagonist gene intron 2 with alcoholic liver disease.  Hepatobiliary Pancreat Dis Int. 2005;  4 41-45
  PubMedSearch in Google Scholar
• 54 Takamatsu M, Yamauchi M, Maezawa Y et al.. Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients.  Am J Gastroenterol. 2000;  95 1305-1311
  PubMedSearch in Google Scholar
• 55 Pastor I J, Laso F J, Romero A, Gonzalez-Sarmiento R. Interleukin-1 gene cluster polymorphisms and alcoholism in Spanish men.  Alcohol Alcohol. 2005;  40 181-186
  PubMedSearch in Google Scholar
• 56 Jarvelainen H A, Orpana A, Perola M et al.. Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease.  Hepatology. 2001;  33 1148-1153
  CrossrefPubMedSearch in Google Scholar
• 57 Campos J, Gonzalez-Quintela A, Quinteiro C et al.. The -159C/T polymorphism in the promoter region of the CD14 gene is associated with advanced liver disease and higher serum levels of acute-phase proteins in heavy drinkers.  Alcohol Clin Exp Res. 2005;  29 1206-1213
  CrossrefPubMedSearch in Google Scholar
• 58 Meiler C, Muhlbauer M, Johann M et al.. Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection.  World J Gastroenterol. 2005;  11 6031-6037
  CrossrefPubMedSearch in Google Scholar
• 59 Valenti L, De Feo T, Fracanzani A L et al.. Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients.  Alcohol Alcohol. 2004;  39 276-280
  PubMedSearch in Google Scholar
• 60 Vidali M, Stewart S F, Rolla R et al.. Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease.  Hepatology. 2003;  37 410-419
  CrossrefPubMedSearch in Google Scholar
• 61 Oliver J, Agundez J A, Morales S et al.. Polymorphisms in the transforming growth factor-beta gene (TGF-beta) and the risk of advanced alcoholic liver disease.  Liver Int. 2005;  25 935-939
  CrossrefPubMedSearch in Google Scholar
• 62 Lauret E, Rodriguez M, Gonzalez S et al.. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma.  Am J Gastroenterol. 2002;  97 1016-1021
  CrossrefPubMedSearch in Google Scholar
• 63 Ropero Gradilla P, Villegas Martinez A, Fernandez Arquero M et al.. C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease.  Rev Esp Enferm Dig. 2001;  93 156-163
  PubMedSearch in Google Scholar
• 64 Gleeson D, Evans S, Bradley M et al.. HFE genotypes in decompensated alcoholic liver disease: phenotypic expression and comparison with heavy drinking and with normal controls.  Am J Gastroenterol. 2006;  101 304-310
  CrossrefPubMedSearch in Google Scholar
• 65 Grove J, Daly A K, Burt A D et al.. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease.  Gut. 1998;  43 262-266
  CrossrefPubMedSearch in Google Scholar
• 66 Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.  Lancet. 1997;  349 825-832
  CrossrefPubMedSearch in Google Scholar
• 67 Powell E E, Edwards-Smith C J, Hay J L et al.. Host genetic factors influence disease progression in chronic hepatitis C.  Hepatology. 2000;  31 828-833
  CrossrefPubMedSearch in Google Scholar
• 68 Xiao F, Wei H, Song S, Li G, Song C. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B.  J Gastroenterol Hepatol. 2006;  21 1488-1491
  PubMedSearch in Google Scholar
• 69 Forrest E H, Thorburn D, Spence E et al.. Polymorphisms of the renin-angiotensin system and the severity of fibrosis in chronic hepatitis C virus infection.  J Viral Hepat. 2005;  12 519-524
  CrossrefPubMedSearch in Google Scholar
• 70 Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner A M. Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis.  Clin Chim Acta. 2002;  316 83-94
  CrossrefPubMedSearch in Google Scholar
• 71 Tag C G, Mengsteab S, Hellerbrand C et al.. Analysis of the transforming growth factor-beta1 (TGF-beta1) codon 25 gene polymorphism by LightCycler-analysis in patients with chronic hepatitis C infection.  Cytokine. 2003;  24 173-181
  CrossrefPubMedSearch in Google Scholar
• 72 Wang H, Mengsteab S, Tag C G et al.. Transforming growth factor-beta1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection.  World J Gastroenterol. 2005;  11 1929-1936
  PubMedSearch in Google Scholar
• 73 Suzuki S, Tanaka Y, Orito E et al.. Transforming growth factor-beta-1 genetic polymorphism in Japanese patients with chronic hepatitis C virus infection.  J Gastroenterol Hepatol. 2003;  18 1139-1143
  CrossrefPubMedSearch in Google Scholar
• 74 Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3.  World J Gastroenterol. 2005;  11 6656-6661
  PubMedSearch in Google Scholar
• 75 Okamoto K, Mimura K, Murawaki Y, Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease.  J Gastroenterol Hepatol. 2005;  20 1102-1108
  PubMedSearch in Google Scholar
• 76 Ben-Ari Z, Tambur A R, Pappo O et al.. Platelet-derived growth factor gene polymorphism in recurrent hepatitis C infection after liver transplantation.  Transplantation. 2006;  81 392-397
  CrossrefPubMedSearch in Google Scholar
• 77 Yee L J, Tang J, Herrera J, Kaslow R A, van Leeuwen D J. Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection.  Genes Immun. 2000;  1 386-390
  CrossrefPubMedSearch in Google Scholar
• 78 Romero-Gomez M, Montes-Cano M A, Otero-Fernandez M A et al.. SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C.  Gut. 2004;  53 446-450
  CrossrefPubMedSearch in Google Scholar
• 79 Kusumoto K, Uto H, Hayashi K et al.. Interleukin-10 or tumor necrosis factor-alpha polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan.  Cytokine. 2006;  34 24-31
  CrossrefPubMedSearch in Google Scholar
• 80 Ho S Y, Wang Y J, Chen H L et al.. Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene.  Cancer Causes Control. 2004;  15 657-663
  CrossrefPubMedSearch in Google Scholar
• 81 Valenti L, Pulixi E, Fracanzani A L et al.. TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis.  J Hepatol. 2005;  43 944-950
  CrossrefPubMedSearch in Google Scholar
• 82 Goyal A, Kazim S N, Sakhuja P et al.. Association of TNF-beta polymorphism with disease severity among patients infected with hepatitis C virus.  J Med Virol. 2004;  72 60-65
  CrossrefPubMedSearch in Google Scholar
• 83 Sanchez-Munoz D, Romero-Gomez M, Gonzalez-Escribano M F et al.. Tumour necrosis factor alpha polymorphisms are not involved in the development of steatosis in chronic hepatitis C.  Eur J Gastroenterol Hepatol. 2004;  16 761-765
  CrossrefPubMedSearch in Google Scholar
• 84 Mangia A, Santoro R, Piattelli M et al.. IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection.  Cytokine. 2004;  25 103-109
  CrossrefPubMedSearch in Google Scholar
• 85 Barrett S, Collins M, Kenny C et al.. Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection.  J Med Virol. 2003;  71 212-218
  CrossrefPubMedSearch in Google Scholar
• 86 Tokushige K, Tsuchiya N, Hasegawa K et al.. Influence of TNF gene polymorphism and HLA-DRB1 haplotype in Japanese patients with chronic liver disease caused by HCV.  Am J Gastroenterol. 2003;  98 160-166
  CrossrefPubMedSearch in Google Scholar
• 87 Wang Y, Kato N, Hoshida Y et al.. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.  Hepatology. 2003;  37 65-71
  CrossrefPubMedSearch in Google Scholar
• 88 Rosen H R, McHutchison J G, Conrad A J et al.. Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C.  Am J Gastroenterol. 2002;  97 714-720
  CrossrefPubMedSearch in Google Scholar
• 89 Yu M L, Dai C Y, Chiu C C et al.. Tumor necrosis factor alpha promoter polymorphisms at position -308 in Taiwanese chronic hepatitis C patients treated with interferon-alpha.  Antiviral Res. 2003;  59 35-40
  CrossrefPubMedSearch in Google Scholar
• 90 Bahr M J, el Menuawy M, Boeker K H et al.. Cytokine gene polymorphisms and the susceptibility to liver cirrhosis in patients with chronic hepatitis C.  Liver Int. 2003;  23 420-425
  CrossrefPubMedSearch in Google Scholar
• 91 Suneetha P V, Goyal A, Hissar S S, Sarin S K. Studies on TAQ1 polymorphism in the 3′untranslated region of IL-12P40 gene in HCV patients infected predominantly with genotype 3.  J Med Virol. 2006;  78 1055-1060
  CrossrefPubMedSearch in Google Scholar
• 92 Dai C Y, Chuang W L, Hsieh M Y et al.. Polymorphism of interferon-gamma gene at position + 874 and clinical characteristics of chronic hepatitis C.  Transl Res. 2006;  148 128-133
  PubMedSearch in Google Scholar
• 93 Abbott W G, Rigopoulou E, Haigh P et al.. Single nucleotide polymorphisms in the interferon-gamma and interleukin-10 genes do not influence chronic hepatitis C severity or T-cell reactivity to hepatitis C virus.  Liver Int. 2004;  24 90-97
  CrossrefPubMedSearch in Google Scholar
• 94 Knapp S, Hennig B J, Frodsham A J et al.. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection.  Immunogenetics. 2003;  55 362-369
  CrossrefPubMedSearch in Google Scholar
• 95 Paladino N, Fainboim H, Theiler G et al.. Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism.  J Virol. 2006;  80 9144-9150
  CrossrefPubMedSearch in Google Scholar
• 96 Hofer H, Neufeld J B, Oesterreicher C et al.. Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection.  Genes Immun. 2005;  6 242-247
  CrossrefPubMedSearch in Google Scholar
• 97 Muhlbauer M, Bosserhoff A K, Hartmann A et al.. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.  Gastroenterology. 2003;  125 1085-1093
  CrossrefPubMedSearch in Google Scholar
• 98 Hellier S, Frodsham A J, Hennig B J et al.. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection.  Hepatology. 2003;  38 1468-1476
  PubMedSearch in Google Scholar
• 99 Glas J, Torok H P, Tonenchi L, Schiemann U, Folwaczny C. The -2518 promotor polymorphism in the MCP-1 gene is not associated with liver cirrhosis in chronic hepatitis C virus infection.  Gastroenterology. 2004;  126 1930-1931 , author reply 1931-1932
  CrossrefPubMedSearch in Google Scholar
• 100 Bonkovsky H L, Salek J. No role of the -2518 promoter polymorphism of monocyte chemotactic protein-1 in chronic hepatitis C.  Gastroenterology. 2005;  129 1361-1362
  CrossrefPubMedSearch in Google Scholar
• 101 Promrat K, McDermott D H, Gonzalez C M et al.. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.  Gastroenterology. 2003;  124 352-360
  CrossrefPubMedSearch in Google Scholar
• 102 Wasmuth H E, Werth A, Mueller T et al.. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia.  J Mol Med. 2004;  82 64-69
  CrossrefPubMedSearch in Google Scholar
• 103 Mascheretti S, Hinrichsen H, Ross S et al.. Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients.  Clin Exp Immunol. 2004;  136 328-333
  CrossrefPubMedSearch in Google Scholar
• 104 Ruiz-Ferrer M, Barroso N, Antinolo G, Aguilar-Reina J. Analysis of CCR5-Delta 32 and CCR2-V64I polymorphisms in a cohort of Spanish HCV patients using real-time polymerase chain reaction and fluorescence resonance energy transfer technologies.  J Viral Hepat. 2004;  11 319-323
  CrossrefPubMedSearch in Google Scholar
• 105 Goulding C, McManus R, Murphy A et al.. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source.  Gut. 2005;  54 1157-1161
  CrossrefPubMedSearch in Google Scholar
• 106 Goyal A, Suneetha P V, Kumar G T et al.. CCR5Delta32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C.  World J Gastroenterol. 2006;  12 4721-4726
  PubMedSearch in Google Scholar
• 107 Aikawa T, Kojima M, Onishi H et al.. HLA DRB1 and DQB1 alleles and haplotypes influencing the progression of hepatitis C.  J Med Virol. 1996;  49 274-278
  CrossrefPubMedSearch in Google Scholar
• 108 Kuzushita N, Hayashi N, Moribe T et al.. Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus.  Hepatology. 1998;  27 240-244
  CrossrefPubMedSearch in Google Scholar
• 109 Renou C, Halfon P, Pol S et al.. Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels.  Gut. 2002;  51 585-590
  CrossrefPubMedSearch in Google Scholar
• 110 Kryczka W, Brojer E, Kalinska A, Urbaniak A, Zarebska-Michaluk D. DRB1 alleles in relation to severity of liver disease in patients with chronic hepatitis C.  Med Sci Monit. 2001;  7(suppl 1) 217-220
  PubMedSearch in Google Scholar
• 111 Alric L, Fort M, Izopet J et al.. Genes of the major histocompatibility complex class II influence the outcome of hepatitis C virus infection.  Gastroenterology. 1997;  113 1675-1681
  CrossrefPubMedSearch in Google Scholar
• 112 Hue S, Cacoub P, Renou C et al.. Human leukocyte antigen class II alleles may contribute to the severity of hepatitis C virus-related liver disease.  J Infect Dis. 2002;  186 106-109
  CrossrefPubMedSearch in Google Scholar
• 113 Patel K, Norris S, Lebeck L et al.. HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C.  Hepatology. 2006;  43 241-249
  CrossrefPubMedSearch in Google Scholar
• 114 Sasaki K, Tsutsumi A, Wakamiya N et al.. Mannose-binding lectin polymorphisms in patients with hepatitis C virus infection.  Scand J Gastroenterol. 2000;  35 960-965
  CrossrefPubMedSearch in Google Scholar
• 115 Hennig B J, Hellier S, Frodsham A J et al.. Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection.  Genes Immun. 2002;  3 359-367
  CrossrefPubMedSearch in Google Scholar
• 116 Wozniak M A, Itzhaki R F, Faragher E B et al.. Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus.  Hepatology. 2002;  36 456-463
  CrossrefPubMedSearch in Google Scholar
• 117 Adinolfi L E, Ingrosso D, Cesaro G et al.. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients.  Hepatology. 2005;  41 995-1003
  CrossrefPubMedSearch in Google Scholar
• 118 Hillebrandt S, Wasmuth H E, Weiskirchen R et al.. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.  Nat Genet. 2005;  37 835-843
  CrossrefPubMedSearch in Google Scholar
• 119 Huang H, Shiffman M L, Cheung R C et al.. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2006;  130 1679-1687
  CrossrefPubMedSearch in Google Scholar
• 120 Settin A, El-Bendary M, Abo-Al-Kassem R, El Baz R. Molecular analysis of A1AT (S and Z) and HFE (C282Y and H63D) gene mutations in Egyptian cases with HCV liver cirrhosis.  J Gastrointestin Liver Dis. 2006;  15 131-135
  PubMedSearch in Google Scholar
• 121 Wright M, Goldin R, Hellier S et al.. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection.  Gut. 2003;  52 1206-1210
  CrossrefPubMedSearch in Google Scholar
• 122 Ku N O, Lim J K, Krams S M et al.. Keratins as susceptibility genes for end-stage liver disease.  Gastroenterology. 2005;  129 885-893
  CrossrefPubMedSearch in Google Scholar
• 123 Strnad P, Lienau T C, Tao G Z et al.. Keratin variants associate with progression of fibrosis during chronic hepatitis C infection.  Hepatology. 2006;  43 1354-1363
  CrossrefPubMedSearch in Google Scholar
• 124 Reynolds W F, Patel K, Pianko S et al.. A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection.  Genes Immun. 2002;  3 345-349
  CrossrefPubMedSearch in Google Scholar
• 125 Sonzogni L, Silvestri L, De Silvestri A et al.. Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease.  Hepatology. 2002;  36 195-201
  CrossrefPubMedSearch in Google Scholar
• 126 Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection.  Gastroenterology. 2003;  124 1509-1523
  CrossrefPubMedSearch in Google Scholar
• 127 Gattoni A, Parlato A, Vangieri B et al.. Role of hemochromatosis genes in chronic hepatitis C.  Clin Ter. 2006;  157 61-68
  PubMedSearch in Google Scholar
• 128 Bacon B R. Hemochromatosis: diagnosis and management.  Gastroenterology. 2001;  120 718-725
  PubMedSearch in Google Scholar
• 129 Snover D C. Hepatitis C, iron, and hemochromatosis gene mutations: a meaningful relationship or simple cohabitation?.  Am J Clin Pathol. 2000;  113 475-478
  CrossrefPubMedSearch in Google Scholar
• 130 Smith B C, Gorve J, Guzail M A et al.. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C.  Hepatology. 1998;  27 1695-1699
  CrossrefPubMedSearch in Google Scholar
• 131 Martinelli A L, Franco R F, Villanova M G et al.. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection?.  Acta Haematol. 2000;  102 152-156
  PubMedSearch in Google Scholar
• 132 Bonkovsky H L, Troy N, McNeal K et al.. Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C.  J Hepatol. 2002;  37 848-854
  CrossrefPubMedSearch in Google Scholar
• 133 Tung B Y, Emond M J, Bronner M P et al.. Hepatitis C, iron status, and disease severity: relationship with HFE mutations.  Gastroenterology. 2003;  124 318-326
  CrossrefPubMedSearch in Google Scholar
• 134 Erhardt A, Maschner-Olberg A, Mellenthin C et al.. HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis.  J Hepatol. 2003;  38 335-342
  CrossrefPubMedSearch in Google Scholar
• 135 Gehrke S G, Stremmel W, Mathes I et al.. Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCV genotype.  J Mol Med. 2003;  81 780-787
  CrossrefPubMedSearch in Google Scholar
• 136 Hezode C, Cazeneuve C, Coue O et al.. Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions.  J Hepatol. 1999;  31 979-984
  CrossrefPubMedSearch in Google Scholar
• 137 Thorburn D, Curry G, Spooner R et al.. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C.  Gut. 2002;  50 248-252
  CrossrefPubMedSearch in Google Scholar
• 138 Bugianesi E, Leone N, Vanni E et al.. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.  Gastroenterology. 2002;  123 134-140
  CrossrefPubMedSearch in Google Scholar
• 139 Willner I R, Waters B, Patil S R et al.. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.  Am J Gastroenterol. 2001;  96 2957-2961
  CrossrefPubMedSearch in Google Scholar
• 140 Struben V M, Hespenheide E E, Caldwell S H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds.  Am J Med. 2000;  108 9-13
  PubMedSearch in Google Scholar
• 141 Browning J D, Kumar K S, Saboorian M H, Thiele D L. Ethnic differences in the prevalence of cryptogenic cirrhosis.  Am J Gastroenterol. 2004;  99 292-298
  CrossrefPubMedSearch in Google Scholar
• 142 Namikawa C, Shu-Ping Z, Vyselaar J R et al.. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis.  J Hepatol. 2004;  40 781-786
  CrossrefPubMedSearch in Google Scholar
• 143 Bernard S, Touzet S, Personne I et al.. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes.  Diabetologia. 2000;  43 995-999
  CrossrefPubMedSearch in Google Scholar
• 144 Valenti L, Fracanzani A L, Dongiovanni P et al.. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease.  Gastroenterology. 2002;  122 274-280
  CrossrefPubMedSearch in Google Scholar
• 145 Nozaki Y, Saibara T, Nemoto Y et al.. Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis.  Alcohol Clin Exp Res. 2004;  28(suppl) 106S-110S
  PubMedSearch in Google Scholar
• 146 Brun P, Castagliuolo I, Floreani A R et al.. Increased risk of NASH in patients carrying the C(-159)T polymorphism in the CD14 gene promoter region.  Gut. 2006;  55 1212
  PubMedSearch in Google Scholar
• 147 Dixon J B, Bhathal P S, Jonsson J R et al.. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese.  J Hepatol. 2003;  39 967-971
  CrossrefPubMedSearch in Google Scholar
• 148 George D K, Goldwurm S, MacDonald G A et al.. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology. 1998;  114 311-318
  CrossrefPubMedSearch in Google Scholar
• 149 Bonkovsky H L, Jawaid Q, Tortorelli K et al.. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 421-429
  CrossrefPubMedSearch in Google Scholar
• 150 Chitturi S, Weltman M, Farrell G C et al.. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity.  Hepatology. 2002;  36 142-149
  CrossrefPubMedSearch in Google Scholar
• 151 Deguti M M, Sipahi A M, Gayotto L C et al.. Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis.  Braz J Med Biol Res. 2003;  36 739-745
  PubMedSearch in Google Scholar
• 152 Iwamoto N, Ogawa Y, Kajihara S et al.. Gln27Glu beta2-adrenergic receptor variant is associated with hypertriglyceridemia and the development of fatty liver.  Clin Chim Acta. 2001;  314 85-91
  CrossrefPubMedSearch in Google Scholar
• 153 Song J, da Costa K A, Fischer L M et al.. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).  FASEB J. 2005;  19 1266-1271
  CrossrefPubMedSearch in Google Scholar
• 154 Fletcher L M, Dixon J L, Purdie D M, Powell L W, Crawford D H. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 281-289
  CrossrefPubMedSearch in Google Scholar
• 155 Piperno A, Fargion S, D'Alba R et al.. Liver damage in Italian patients with hereditary hemochromatosis is highly influenced by hepatitis B and C virus infection.  J Hepatol. 1992;  16 364-368
  CrossrefPubMedSearch in Google Scholar
• 156 Powell L W, Subramaniam V N, Yapp T R. Haemochromatosis in the new millennium.  J Hepatol. 2000;  32(suppl) 48-62
  PubMedSearch in Google Scholar
• 157 Osterreicher C H, Datz C, Stickel F et al.. Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis.  J Hepatol. 2005;  42 914-919
  CrossrefPubMedSearch in Google Scholar
• 158 Stickel F, Osterreicher C H, Datz C et al.. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis.  Arch Intern Med. 2005;  165 1835-1840
  CrossrefPubMedSearch in Google Scholar
• 159 Fargion S, Valenti L, Dongiovanni P et al.. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis.  Blood. 2001;  97 3707-3712
  CrossrefPubMedSearch in Google Scholar
• 160 Krayenbuehl P A, Maly F E, Hersberger M et al.. Tumor necrosis factor-alpha -308G> A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.  Clin Chem. 2006;  52 1552-1558
  CrossrefPubMedSearch in Google Scholar
• 161 Osterreicher C H, Datz C, Stickel F et al.. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis.  Cytokine. 2005;  31 142-148
  CrossrefPubMedSearch in Google Scholar
• 162 Distante S, Elmberg M, Foss Haug K B et al.. Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.  Scand J Gastroenterol. 2003;  38 871-877
  CrossrefPubMedSearch in Google Scholar
• 163 Kaplan M M, Gershwin M E. Primary biliary cirrhosis.  N Engl J Med. 2005;  353 1261-1273
  CrossrefPubMedSearch in Google Scholar
• 164 Brind A M, Bray G P, Portmann B C, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis.  Gut. 1995;  36 615-617
  CrossrefPubMedSearch in Google Scholar
• 165 Agarwal K, Jones D E, Bassendine M F. Genetic susceptibility to primary biliary cirrhosis.  Eur J Gastroenterol Hepatol. 1999;  11 603-606
  CrossrefPubMedSearch in Google Scholar
• 166 Bittencourt P L, Farias A Q, Abrantes-Lemos C P et al.. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2004;  19 873-878
  CrossrefPubMedSearch in Google Scholar
• 167 Selmi C, Mayo M J, Bach N et al.. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.  Gastroenterology. 2004;  127 485-492
  CrossrefPubMedSearch in Google Scholar
• 168 Invernizzi P, Battezzati P M, Crosignani A et al.. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis.  J Hepatol. 2003;  38 401-406
  CrossrefPubMedSearch in Google Scholar
• 169 Agarwal K, Jones D E, Daly A K et al.. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.  J Hepatol. 2000;  32 538-541
  CrossrefPubMedSearch in Google Scholar
• 170 Fan L Y, Tu X Q, Cheng Q B et al.. Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population.  World J Gastroenterol. 2004;  10 3056-3059
  PubMedSearch in Google Scholar
• 171 Vogel A, Strassburg C P, Manns M P. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.  Hepatology. 2002;  35 126-131
  CrossrefPubMedSearch in Google Scholar
• 172 Gordon M A, Oppenheim E, Camp N J et al.. Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region.  J Hepatol. 1999;  31 242-247
  CrossrefPubMedSearch in Google Scholar
• 173 Donaldson P, Agarwal K, Craggs A et al.. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility.  Gut. 2001;  48 397-402
  CrossrefPubMedSearch in Google Scholar
• 174 Jones D E, Watt F E, Grove J et al.. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.  J Hepatol. 1999;  30 232-236
  CrossrefPubMedSearch in Google Scholar
• 175 Bittencourt P L, Palacios S A, Farias A Q et al.. Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2003;  18 1061-1066
  CrossrefPubMedSearch in Google Scholar
• 176 Tanaka A, Quaranta S, Mattalia A et al.. The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis.  J Hepatol. 1999;  30 826-829
  CrossrefPubMedSearch in Google Scholar
• 177 Jones D E, Donaldson P T. Genetic factors in the pathogenesis of primary biliary cirrhosis.  Clin Liver Dis. 2003;  7 841-864
  CrossrefPubMedSearch in Google Scholar
• 178 Donaldson P T. TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal.  J Hepatol. 1999;  31 366-368
  CrossrefPubMedSearch in Google Scholar
• 179 Norris S, Kondeatis E, Collins R et al.. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism.  Gastroenterology. 2001;  120 1475-1482
  PubMedSearch in Google Scholar
• 180 Mitchell S A, Grove J, Spurkland A et al.. Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.  Gut. 2001;  49 288-294
  CrossrefPubMedSearch in Google Scholar
• 181 Satsangi J, Chapman R W, Haldar N et al.. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.  Gastroenterology. 2001;  121 124-130
  CrossrefPubMedSearch in Google Scholar
• 182 Czaja A J, Cookson S, Constantini P K et al.. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis.  Gastroenterology. 1999;  117 645-652
  PubMedSearch in Google Scholar
• 183 Czaja A J, Donaldson P T. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis.  Am J Gastroenterol. 2002;  97 2051-2057
  CrossrefPubMedSearch in Google Scholar
• 184 Hirschhorn J N, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies.  Genet Med. 2002;  4 45-61
  PubMedSearch in Google Scholar
• 185 Cardon L R, Bell J I. Association study designs for complex diseases.  Nat Rev Genet. 2001;  2 91-99
  CrossrefPubMedSearch in Google Scholar
• 186 Caporaso N. Selection of candidate genes for population studies.  IARC Sci Publ. 1999;  (148) 23-36
  PubMedSearch in Google Scholar
• 187 Cardon L R, Palmer L J. Population stratification and spurious allelic association.  Lancet. 2003;  361 598-604
  CrossrefPubMedSearch in Google Scholar
• 188 Thomas D C, Witte J S. Point: population stratification-a problem for case-control studies of candidate-gene associations?.  Cancer Epidemiol Biomarkers Prev. 2002;  11 505-512
  PubMedSearch in Google Scholar
• 189 Ioannidis J P, Ntzani E E, Trikalinos T A, Contopoulos-Ioannidis D G. Replication validity of genetic association studies.  Nat Genet. 2001;  29 306-309
  CrossrefPubMedSearch in Google Scholar
• 190 Ioannidis J P, Trikalinos T A, Ntzani E E, Contopoulos-Ioannidis D G. Genetic associations in large versus small studies: an empirical assessment.  Lancet. 2003;  361 567-571
  CrossrefPubMedSearch in Google Scholar
• 191 Millikan R. The changing face of epidemiology in the genomics era.  Epidemiology. 2002;  13 472-480
  CrossrefPubMedSearch in Google Scholar

David A BrennerM.D. 

Columbia University Medical Center, College of Physicians and Surgeons

622 West 168th Street, PH 8E-105J, New York, NY 10032

REFERENCES

• 1 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115 209-218
  CrossrefPubMedSearch in Google Scholar
• 2 Schuppan D, Ruehl M, Somasundaram R, Hahn E G. Matrix as a modulator of hepatic fibrogenesis.  Semin Liver Dis. 2001;  21 351-372
  Thieme ConnectPubMedSearch in Google Scholar
• 3 Albanis E, Friedman S L. Hepatic fibrosis: pathogenesis and principles of therapy.  Clin Liver Dis. 2001;  5 315-334
  CrossrefPubMedSearch in Google Scholar
• 4 Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites.  N Engl J Med. 2004;  350 1646-1654
  CrossrefPubMedSearch in Google Scholar
• 5 Forns X, Ampurdanes S, Sanchez-Tapias J M et al.. Long-term follow-up of chronic hepatitis C in patients diagnosed at a tertiary-care center.  J Hepatol. 2001;  35 265-271
  CrossrefPubMedSearch in Google Scholar
• 6 Niederau C, Lange S, Heintges T et al.. Prognosis of chronic hepatitis C: results of a large, prospective cohort study.  Hepatology. 1998;  28 1687-1695
  CrossrefPubMedSearch in Google Scholar
• 7 Sangiovanni A, Prati G M, Fasani P et al.. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients.  Hepatology. 2006;  43 1303-1310
  CrossrefPubMedSearch in Google Scholar
• 8 Massard J, Ratziu V, Thabut D et al.. Natural history and predictors of disease severity in chronic hepatitis C.  J Hepatol. 2006;  44(suppl) S19-S24
  PubMedSearch in Google Scholar
• 9 Bellentani S, Saccoccio G, Costa G et al.. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group.  Gut. 1997;  41 845-850
  CrossrefPubMedSearch in Google Scholar
• 10 Olynyk J K, Cullen D J, Aquilia S et al.. A population-based study of the clinical expression of the hemochromatosis gene.  N Engl J Med. 1999;  341 718-724
  CrossrefPubMedSearch in Google Scholar
• 11 Beutler E, Felitti V J, Koziol J A, Ho N J, Gelbart T. Penetrance of 845G→ A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet. 2002;  359 211-218
  CrossrefPubMedSearch in Google Scholar
• 12 Poynard T, Ratziu V, Charlotte F et al.. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c.  J Hepatol. 2001;  34 730-739
  CrossrefPubMedSearch in Google Scholar
• 13 Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin M E. Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology.  Semin Liver Dis. 2005;  25 265-280
  Thieme ConnectPubMedSearch in Google Scholar
• 14 Reed T, Page W F, Viken R J, Christian J C. Genetic predisposition to organ-specific endpoints of alcoholism.  Alcohol Clin Exp Res. 1996;  20 1528-1533
  CrossrefPubMedSearch in Google Scholar
• 15 Akuta N, Chayama K, Suzuki F et al.. Risk factors of hepatitis C virus-related liver cirrhosis in young adults: positive family history of liver disease and transporter associated with antigen processing 2(TAP2)*0201 allele.  J Med Virol. 2001;  64 109-116
  CrossrefPubMedSearch in Google Scholar
• 16 Bataller R, North K E, Brenner D A. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.  Hepatology. 2003;  37 493-503
  CrossrefPubMedSearch in Google Scholar
• 17 Stickel F, Osterreicher C H. The role of genetic polymorphisms in alcoholic liver disease.  Alcohol Alcohol. 2006;  41 209-224
  CrossrefPubMedSearch in Google Scholar
• 18 Lander E S, Linton L M, Birren B et al.. Initial sequencing and analysis of the human genome.  Nature. 2001;  409 860-921
  CrossrefPubMedSearch in Google Scholar
• 19 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
  CrossrefPubMedSearch in Google Scholar
• 20 Lazaridis K N, Juran B D. American Gastroenterological Association future trends committee report: the application of genomic and proteomic technologies to digestive disease diagnosis and treatment and their likely impact on gastroenterology clinical practice.  Gastroenterology. 2005;  129 1720-1752
  CrossrefPubMedSearch in Google Scholar
• 21 Tabor H K, Risch N J, Myers R M. Opinion: candidate-gene approaches for studying complex genetic traits-practical considerations.  Nat Rev Genet. 2002;  3 391-397
  PubMedSearch in Google Scholar
• 22 Kruglyak L, Nickerson D A. Variation is the spice of life.  Nat Genet. 2001;  27 234-236
  CrossrefPubMedSearch in Google Scholar
• 23 Feld J J, Liang T J. Hepatitis C-identifying patients with progressive liver injury.  Hepatology. 2006;  43(suppl 1) S194-S206
  CrossrefPubMedSearch in Google Scholar
• 24 Day C P. Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.  Liver Int. 2006;  26 1021-1028
  CrossrefPubMedSearch in Google Scholar
• 25 Wiley T E, McCarthy M, Breidi L, McCarthy M, Layden T J. Impact of alcohol on the histological and clinical progression of hepatitis C infection.  Hepatology. 1998;  28 805-809
  CrossrefPubMedSearch in Google Scholar
• 26 Raynard B, Balian A, Fallik D et al.. Risk factors of fibrosis in alcohol-induced liver disease.  Hepatology. 2002;  35 635-638
  CrossrefPubMedSearch in Google Scholar
• 27 Hrubec Z, Omenn G S. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans.  Alcohol Clin Exp Res. 1981;  5 207-215
  CrossrefPubMedSearch in Google Scholar
• 28 Agarwal D P. Genetic polymorphisms of alcohol metabolizing enzymes.  Pathol Biol (Paris). 2001;  49 703-709
  CrossrefPubMedSearch in Google Scholar
• 29 Armstrong R N. Structure, catalytic mechanism, and evolution of the glutathione transferases.  Chem Res Toxicol. 1997;  10 2-18
  CrossrefPubMedSearch in Google Scholar
• 30 Savolainen V T, Pjarinen J, Perola M, Penttila A, Karhunen P J. Glutathione-S-transferase GST M1 “null” genotype and the risk of alcoholic liver disease.  Alcohol Clin Exp Res. 1996;  20 1340-1345
  CrossrefPubMedSearch in Google Scholar
• 31 Rodrigo L, Alvarez V, Rodriguez M et al.. N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study.  Scand J Gastroenterol. 1999;  34 303-307
  CrossrefPubMedSearch in Google Scholar
• 32 Frenzer A, Butler W J, Norton I D et al.. Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis.  J Gastroenterol Hepatol. 2002;  17 177-182
  CrossrefPubMedSearch in Google Scholar
• 33 Burim R V, Canalle R, Martinelli Ade L, Takahashi C S. Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics.  Mutagenesis. 2004;  19 291-298
  CrossrefPubMedSearch in Google Scholar
• 34 Hayes J D, Flanagan J U, Jowsey I R. Glutathione transferases.  Annu Rev Pharmacol Toxicol. 2005;  45 51-88
  CrossrefPubMedSearch in Google Scholar
• 35 Groppi A, Coutelle C, Fleury B et al.. Glutathione S-transferase class mu in French alcoholic cirrhotic patients.  Hum Genet. 1991;  87 628-630
  PubMedSearch in Google Scholar
• 36 Ladero J M, Martinez C, Garcia-Martin E et al.. Polymorphisms of the glutathione S-transferases mu-1 (GSTM1) and theta-1 (GSTT1) and the risk of advanced alcoholic liver disease.  Scand J Gastroenterol. 2005;  40 348-353
  CrossrefPubMedSearch in Google Scholar
• 37 Wallace D C. Mitochondrial diseases in man and mouse.  Science. 1999;  283 1482-1488
  CrossrefPubMedSearch in Google Scholar
• 38 Sutton A, Khoury H, Prip-Buus C et al.. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.  Pharmacogenetics. 2003;  13 145-157
  CrossrefPubMedSearch in Google Scholar
• 39 Degoul F, Sutton A, Mansouri A et al.. Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease.  Gastroenterology. 2001;  120 1468-1474
  CrossrefPubMedSearch in Google Scholar
• 40 Richardson M M, Powell E E, Barrie H D et al.. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C.  J Med Genet. 2005;  42 e45
  CrossrefPubMedSearch in Google Scholar
• 41 Nahon P, Sutton A, Pessayre D et al.. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death.  Clin Gastroenterol Hepatol. 2005;  3 292-298
  CrossrefPubMedSearch in Google Scholar
• 42 Stewart S F, Leathart J B, Chen Y et al.. Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis.  Hepatology. 2002;  36 1355-1360
  CrossrefPubMedSearch in Google Scholar
• 43 Brind A, Fryer A, Hurlstone A, Fisher N, Pirmohamed M. The role of polymorphism in manganese superoxide dismutase in susceptibility to alcoholic liver disease.  Gastroenterology. 2003;  124 2000-2002
  PubMedSearch in Google Scholar
• 44 Martins A, Cortez-Pinto H, Machado M et al.. Are genetic polymorphisms of tumour necrosis factor alpha, interleukin-10, CD14 endotoxin receptor or manganese superoxide dismutase associated with alcoholic liver disease?.  Eur J Gastroenterol Hepatol. 2005;  17 1099-1104
  CrossrefPubMedSearch in Google Scholar
• 45 Grove J, Daly A K, Bassendine M F, Day C P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis.  Hepatology. 1997;  26 143-146
  CrossrefPubMedSearch in Google Scholar
• 46 Pastor I J, Laso F J, Romero A, Gonzalez-Sarmiento R. -238 G> A polymorphism of tumor necrosis factor alpha gene (TNFA) is associated with alcoholic liver cirrhosis in alcoholic Spanish men.  Alcohol Clin Exp Res. 2005;  29 1928-1931
  CrossrefPubMedSearch in Google Scholar
• 47 Bathgate A J, Pravica V, Perrey C, Hayes P C, Hutchinson I V. Polymorphisms in tumour necrosis factor alpha, interleukin-10 and transforming growth factor beta1 genes and end-stage liver disease.  Eur J Gastroenterol Hepatol. 2000;  12 1329-1333
  PubMedSearch in Google Scholar
• 48 Ladero J M, Fernandez-Arquero M, Tudela J I et al.. Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease.  Liver. 2002;  22 245-251
  CrossrefPubMedSearch in Google Scholar
• 49 Grove J, Daly A K, Bassendine M F, Gilvarry E, Day C P. Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease.  Gut. 2000;  46 540-545
  CrossrefPubMedSearch in Google Scholar
• 50 Danis V A, Millington M, Hyland V J, Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism.  Clin Exp Immunol. 1995;  99 303-310
  PubMedSearch in Google Scholar
• 51 Pastor I J, Laso F J, Avila J J, Rodriguez R E, Gonzalez-Sarmiento R. Polymorphism in the interleukin-1 receptor antagonist gene is associated with alcoholism in Spanish men.  Alcohol Clin Exp Res. 2000;  24 1479-1482
  CrossrefPubMedSearch in Google Scholar
• 52 Takamatsu M, Yamauchi M, Maezawa Y et al.. Correlation of a polymorphism in the interleukin-1 receptor antagonist gene with hepatic fibrosis in Japanese alcoholics.  Alcohol Clin Exp Res. 1998;  22(suppl) 141S-144S
  PubMedSearch in Google Scholar
• 53 Chen W X, Xu G Y, Yu C H et al.. Correlation of polymorphism in the interleukin-1 receptor antagonist gene intron 2 with alcoholic liver disease.  Hepatobiliary Pancreat Dis Int. 2005;  4 41-45
  PubMedSearch in Google Scholar
• 54 Takamatsu M, Yamauchi M, Maezawa Y et al.. Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients.  Am J Gastroenterol. 2000;  95 1305-1311
  PubMedSearch in Google Scholar
• 55 Pastor I J, Laso F J, Romero A, Gonzalez-Sarmiento R. Interleukin-1 gene cluster polymorphisms and alcoholism in Spanish men.  Alcohol Alcohol. 2005;  40 181-186
  PubMedSearch in Google Scholar
• 56 Jarvelainen H A, Orpana A, Perola M et al.. Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease.  Hepatology. 2001;  33 1148-1153
  CrossrefPubMedSearch in Google Scholar
• 57 Campos J, Gonzalez-Quintela A, Quinteiro C et al.. The -159C/T polymorphism in the promoter region of the CD14 gene is associated with advanced liver disease and higher serum levels of acute-phase proteins in heavy drinkers.  Alcohol Clin Exp Res. 2005;  29 1206-1213
  CrossrefPubMedSearch in Google Scholar
• 58 Meiler C, Muhlbauer M, Johann M et al.. Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection.  World J Gastroenterol. 2005;  11 6031-6037
  CrossrefPubMedSearch in Google Scholar
• 59 Valenti L, De Feo T, Fracanzani A L et al.. Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients.  Alcohol Alcohol. 2004;  39 276-280
  PubMedSearch in Google Scholar
• 60 Vidali M, Stewart S F, Rolla R et al.. Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease.  Hepatology. 2003;  37 410-419
  CrossrefPubMedSearch in Google Scholar
• 61 Oliver J, Agundez J A, Morales S et al.. Polymorphisms in the transforming growth factor-beta gene (TGF-beta) and the risk of advanced alcoholic liver disease.  Liver Int. 2005;  25 935-939
  CrossrefPubMedSearch in Google Scholar
• 62 Lauret E, Rodriguez M, Gonzalez S et al.. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma.  Am J Gastroenterol. 2002;  97 1016-1021
  CrossrefPubMedSearch in Google Scholar
• 63 Ropero Gradilla P, Villegas Martinez A, Fernandez Arquero M et al.. C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease.  Rev Esp Enferm Dig. 2001;  93 156-163
  PubMedSearch in Google Scholar
• 64 Gleeson D, Evans S, Bradley M et al.. HFE genotypes in decompensated alcoholic liver disease: phenotypic expression and comparison with heavy drinking and with normal controls.  Am J Gastroenterol. 2006;  101 304-310
  CrossrefPubMedSearch in Google Scholar
• 65 Grove J, Daly A K, Burt A D et al.. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease.  Gut. 1998;  43 262-266
  CrossrefPubMedSearch in Google Scholar
• 66 Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.  Lancet. 1997;  349 825-832
  CrossrefPubMedSearch in Google Scholar
• 67 Powell E E, Edwards-Smith C J, Hay J L et al.. Host genetic factors influence disease progression in chronic hepatitis C.  Hepatology. 2000;  31 828-833
  CrossrefPubMedSearch in Google Scholar
• 68 Xiao F, Wei H, Song S, Li G, Song C. Polymorphisms in the promoter region of the angiotensinogen gene are associated with liver cirrhosis in patients with chronic hepatitis B.  J Gastroenterol Hepatol. 2006;  21 1488-1491
  PubMedSearch in Google Scholar
• 69 Forrest E H, Thorburn D, Spence E et al.. Polymorphisms of the renin-angiotensin system and the severity of fibrosis in chronic hepatitis C virus infection.  J Viral Hepat. 2005;  12 519-524
  CrossrefPubMedSearch in Google Scholar
• 70 Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner A M. Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis.  Clin Chim Acta. 2002;  316 83-94
  CrossrefPubMedSearch in Google Scholar
• 71 Tag C G, Mengsteab S, Hellerbrand C et al.. Analysis of the transforming growth factor-beta1 (TGF-beta1) codon 25 gene polymorphism by LightCycler-analysis in patients with chronic hepatitis C infection.  Cytokine. 2003;  24 173-181
  CrossrefPubMedSearch in Google Scholar
• 72 Wang H, Mengsteab S, Tag C G et al.. Transforming growth factor-beta1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection.  World J Gastroenterol. 2005;  11 1929-1936
  PubMedSearch in Google Scholar
• 73 Suzuki S, Tanaka Y, Orito E et al.. Transforming growth factor-beta-1 genetic polymorphism in Japanese patients with chronic hepatitis C virus infection.  J Gastroenterol Hepatol. 2003;  18 1139-1143
  CrossrefPubMedSearch in Google Scholar
• 74 Abbas Z, Moatter T, Hussainy A, Jafri W. Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3.  World J Gastroenterol. 2005;  11 6656-6661
  PubMedSearch in Google Scholar
• 75 Okamoto K, Mimura K, Murawaki Y, Yuasa I. Association of functional gene polymorphisms of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 with the progression of chronic liver disease.  J Gastroenterol Hepatol. 2005;  20 1102-1108
  PubMedSearch in Google Scholar
• 76 Ben-Ari Z, Tambur A R, Pappo O et al.. Platelet-derived growth factor gene polymorphism in recurrent hepatitis C infection after liver transplantation.  Transplantation. 2006;  81 392-397
  CrossrefPubMedSearch in Google Scholar
• 77 Yee L J, Tang J, Herrera J, Kaslow R A, van Leeuwen D J. Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection.  Genes Immun. 2000;  1 386-390
  CrossrefPubMedSearch in Google Scholar
• 78 Romero-Gomez M, Montes-Cano M A, Otero-Fernandez M A et al.. SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C.  Gut. 2004;  53 446-450
  CrossrefPubMedSearch in Google Scholar
• 79 Kusumoto K, Uto H, Hayashi K et al.. Interleukin-10 or tumor necrosis factor-alpha polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan.  Cytokine. 2006;  34 24-31
  CrossrefPubMedSearch in Google Scholar
• 80 Ho S Y, Wang Y J, Chen H L et al.. Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene.  Cancer Causes Control. 2004;  15 657-663
  CrossrefPubMedSearch in Google Scholar
• 81 Valenti L, Pulixi E, Fracanzani A L et al.. TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis.  J Hepatol. 2005;  43 944-950
  CrossrefPubMedSearch in Google Scholar
• 82 Goyal A, Kazim S N, Sakhuja P et al.. Association of TNF-beta polymorphism with disease severity among patients infected with hepatitis C virus.  J Med Virol. 2004;  72 60-65
  CrossrefPubMedSearch in Google Scholar
• 83 Sanchez-Munoz D, Romero-Gomez M, Gonzalez-Escribano M F et al.. Tumour necrosis factor alpha polymorphisms are not involved in the development of steatosis in chronic hepatitis C.  Eur J Gastroenterol Hepatol. 2004;  16 761-765
  CrossrefPubMedSearch in Google Scholar
• 84 Mangia A, Santoro R, Piattelli M et al.. IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection.  Cytokine. 2004;  25 103-109
  CrossrefPubMedSearch in Google Scholar
• 85 Barrett S, Collins M, Kenny C et al.. Polymorphisms in tumour necrosis factor-alpha, transforming growth factor-beta, interleukin-10, interleukin-6, interferon-gamma, and outcome of hepatitis C virus infection.  J Med Virol. 2003;  71 212-218
  CrossrefPubMedSearch in Google Scholar
• 86 Tokushige K, Tsuchiya N, Hasegawa K et al.. Influence of TNF gene polymorphism and HLA-DRB1 haplotype in Japanese patients with chronic liver disease caused by HCV.  Am J Gastroenterol. 2003;  98 160-166
  CrossrefPubMedSearch in Google Scholar
• 87 Wang Y, Kato N, Hoshida Y et al.. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.  Hepatology. 2003;  37 65-71
  CrossrefPubMedSearch in Google Scholar
• 88 Rosen H R, McHutchison J G, Conrad A J et al.. Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C.  Am J Gastroenterol. 2002;  97 714-720
  CrossrefPubMedSearch in Google Scholar
• 89 Yu M L, Dai C Y, Chiu C C et al.. Tumor necrosis factor alpha promoter polymorphisms at position -308 in Taiwanese chronic hepatitis C patients treated with interferon-alpha.  Antiviral Res. 2003;  59 35-40
  CrossrefPubMedSearch in Google Scholar
• 90 Bahr M J, el Menuawy M, Boeker K H et al.. Cytokine gene polymorphisms and the susceptibility to liver cirrhosis in patients with chronic hepatitis C.  Liver Int. 2003;  23 420-425
  CrossrefPubMedSearch in Google Scholar
• 91 Suneetha P V, Goyal A, Hissar S S, Sarin S K. Studies on TAQ1 polymorphism in the 3′untranslated region of IL-12P40 gene in HCV patients infected predominantly with genotype 3.  J Med Virol. 2006;  78 1055-1060
  CrossrefPubMedSearch in Google Scholar
• 92 Dai C Y, Chuang W L, Hsieh M Y et al.. Polymorphism of interferon-gamma gene at position + 874 and clinical characteristics of chronic hepatitis C.  Transl Res. 2006;  148 128-133
  PubMedSearch in Google Scholar
• 93 Abbott W G, Rigopoulou E, Haigh P et al.. Single nucleotide polymorphisms in the interferon-gamma and interleukin-10 genes do not influence chronic hepatitis C severity or T-cell reactivity to hepatitis C virus.  Liver Int. 2004;  24 90-97
  CrossrefPubMedSearch in Google Scholar
• 94 Knapp S, Hennig B J, Frodsham A J et al.. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection.  Immunogenetics. 2003;  55 362-369
  CrossrefPubMedSearch in Google Scholar
• 95 Paladino N, Fainboim H, Theiler G et al.. Gender susceptibility to chronic hepatitis C virus infection associated with interleukin 10 promoter polymorphism.  J Virol. 2006;  80 9144-9150
  CrossrefPubMedSearch in Google Scholar
• 96 Hofer H, Neufeld J B, Oesterreicher C et al.. Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection.  Genes Immun. 2005;  6 242-247
  CrossrefPubMedSearch in Google Scholar
• 97 Muhlbauer M, Bosserhoff A K, Hartmann A et al.. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease.  Gastroenterology. 2003;  125 1085-1093
  CrossrefPubMedSearch in Google Scholar
• 98 Hellier S, Frodsham A J, Hennig B J et al.. Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection.  Hepatology. 2003;  38 1468-1476
  PubMedSearch in Google Scholar
• 99 Glas J, Torok H P, Tonenchi L, Schiemann U, Folwaczny C. The -2518 promotor polymorphism in the MCP-1 gene is not associated with liver cirrhosis in chronic hepatitis C virus infection.  Gastroenterology. 2004;  126 1930-1931 , author reply 1931-1932
  CrossrefPubMedSearch in Google Scholar
• 100 Bonkovsky H L, Salek J. No role of the -2518 promoter polymorphism of monocyte chemotactic protein-1 in chronic hepatitis C.  Gastroenterology. 2005;  129 1361-1362
  CrossrefPubMedSearch in Google Scholar
• 101 Promrat K, McDermott D H, Gonzalez C M et al.. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.  Gastroenterology. 2003;  124 352-360
  CrossrefPubMedSearch in Google Scholar
• 102 Wasmuth H E, Werth A, Mueller T et al.. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia.  J Mol Med. 2004;  82 64-69
  CrossrefPubMedSearch in Google Scholar
• 103 Mascheretti S, Hinrichsen H, Ross S et al.. Genetic variants in the CCR gene cluster and spontaneous viral elimination in hepatitis C-infected patients.  Clin Exp Immunol. 2004;  136 328-333
  CrossrefPubMedSearch in Google Scholar
• 104 Ruiz-Ferrer M, Barroso N, Antinolo G, Aguilar-Reina J. Analysis of CCR5-Delta 32 and CCR2-V64I polymorphisms in a cohort of Spanish HCV patients using real-time polymerase chain reaction and fluorescence resonance energy transfer technologies.  J Viral Hepat. 2004;  11 319-323
  CrossrefPubMedSearch in Google Scholar
• 105 Goulding C, McManus R, Murphy A et al.. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source.  Gut. 2005;  54 1157-1161
  CrossrefPubMedSearch in Google Scholar
• 106 Goyal A, Suneetha P V, Kumar G T et al.. CCR5Delta32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C.  World J Gastroenterol. 2006;  12 4721-4726
  PubMedSearch in Google Scholar
• 107 Aikawa T, Kojima M, Onishi H et al.. HLA DRB1 and DQB1 alleles and haplotypes influencing the progression of hepatitis C.  J Med Virol. 1996;  49 274-278
  CrossrefPubMedSearch in Google Scholar
• 108 Kuzushita N, Hayashi N, Moribe T et al.. Influence of HLA haplotypes on the clinical courses of individuals infected with hepatitis C virus.  Hepatology. 1998;  27 240-244
  CrossrefPubMedSearch in Google Scholar
• 109 Renou C, Halfon P, Pol S et al.. Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels.  Gut. 2002;  51 585-590
  CrossrefPubMedSearch in Google Scholar
• 110 Kryczka W, Brojer E, Kalinska A, Urbaniak A, Zarebska-Michaluk D. DRB1 alleles in relation to severity of liver disease in patients with chronic hepatitis C.  Med Sci Monit. 2001;  7(suppl 1) 217-220
  PubMedSearch in Google Scholar
• 111 Alric L, Fort M, Izopet J et al.. Genes of the major histocompatibility complex class II influence the outcome of hepatitis C virus infection.  Gastroenterology. 1997;  113 1675-1681
  CrossrefPubMedSearch in Google Scholar
• 112 Hue S, Cacoub P, Renou C et al.. Human leukocyte antigen class II alleles may contribute to the severity of hepatitis C virus-related liver disease.  J Infect Dis. 2002;  186 106-109
  CrossrefPubMedSearch in Google Scholar
• 113 Patel K, Norris S, Lebeck L et al.. HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C.  Hepatology. 2006;  43 241-249
  CrossrefPubMedSearch in Google Scholar
• 114 Sasaki K, Tsutsumi A, Wakamiya N et al.. Mannose-binding lectin polymorphisms in patients with hepatitis C virus infection.  Scand J Gastroenterol. 2000;  35 960-965
  CrossrefPubMedSearch in Google Scholar
• 115 Hennig B J, Hellier S, Frodsham A J et al.. Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection.  Genes Immun. 2002;  3 359-367
  CrossrefPubMedSearch in Google Scholar
• 116 Wozniak M A, Itzhaki R F, Faragher E B et al.. Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus.  Hepatology. 2002;  36 456-463
  CrossrefPubMedSearch in Google Scholar
• 117 Adinolfi L E, Ingrosso D, Cesaro G et al.. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients.  Hepatology. 2005;  41 995-1003
  CrossrefPubMedSearch in Google Scholar
• 118 Hillebrandt S, Wasmuth H E, Weiskirchen R et al.. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.  Nat Genet. 2005;  37 835-843
  CrossrefPubMedSearch in Google Scholar
• 119 Huang H, Shiffman M L, Cheung R C et al.. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2006;  130 1679-1687
  CrossrefPubMedSearch in Google Scholar
• 120 Settin A, El-Bendary M, Abo-Al-Kassem R, El Baz R. Molecular analysis of A1AT (S and Z) and HFE (C282Y and H63D) gene mutations in Egyptian cases with HCV liver cirrhosis.  J Gastrointestin Liver Dis. 2006;  15 131-135
  PubMedSearch in Google Scholar
• 121 Wright M, Goldin R, Hellier S et al.. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection.  Gut. 2003;  52 1206-1210
  CrossrefPubMedSearch in Google Scholar
• 122 Ku N O, Lim J K, Krams S M et al.. Keratins as susceptibility genes for end-stage liver disease.  Gastroenterology. 2005;  129 885-893
  CrossrefPubMedSearch in Google Scholar
• 123 Strnad P, Lienau T C, Tao G Z et al.. Keratin variants associate with progression of fibrosis during chronic hepatitis C infection.  Hepatology. 2006;  43 1354-1363
  CrossrefPubMedSearch in Google Scholar
• 124 Reynolds W F, Patel K, Pianko S et al.. A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection.  Genes Immun. 2002;  3 345-349
  CrossrefPubMedSearch in Google Scholar
• 125 Sonzogni L, Silvestri L, De Silvestri A et al.. Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease.  Hepatology. 2002;  36 195-201
  CrossrefPubMedSearch in Google Scholar
• 126 Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection.  Gastroenterology. 2003;  124 1509-1523
  CrossrefPubMedSearch in Google Scholar
• 127 Gattoni A, Parlato A, Vangieri B et al.. Role of hemochromatosis genes in chronic hepatitis C.  Clin Ter. 2006;  157 61-68
  PubMedSearch in Google Scholar
• 128 Bacon B R. Hemochromatosis: diagnosis and management.  Gastroenterology. 2001;  120 718-725
  PubMedSearch in Google Scholar
• 129 Snover D C. Hepatitis C, iron, and hemochromatosis gene mutations: a meaningful relationship or simple cohabitation?.  Am J Clin Pathol. 2000;  113 475-478
  CrossrefPubMedSearch in Google Scholar
• 130 Smith B C, Gorve J, Guzail M A et al.. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C.  Hepatology. 1998;  27 1695-1699
  CrossrefPubMedSearch in Google Scholar
• 131 Martinelli A L, Franco R F, Villanova M G et al.. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection?.  Acta Haematol. 2000;  102 152-156
  PubMedSearch in Google Scholar
• 132 Bonkovsky H L, Troy N, McNeal K et al.. Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C.  J Hepatol. 2002;  37 848-854
  CrossrefPubMedSearch in Google Scholar
• 133 Tung B Y, Emond M J, Bronner M P et al.. Hepatitis C, iron status, and disease severity: relationship with HFE mutations.  Gastroenterology. 2003;  124 318-326
  CrossrefPubMedSearch in Google Scholar
• 134 Erhardt A, Maschner-Olberg A, Mellenthin C et al.. HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis.  J Hepatol. 2003;  38 335-342
  CrossrefPubMedSearch in Google Scholar
• 135 Gehrke S G, Stremmel W, Mathes I et al.. Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCV genotype.  J Mol Med. 2003;  81 780-787
  CrossrefPubMedSearch in Google Scholar
• 136 Hezode C, Cazeneuve C, Coue O et al.. Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions.  J Hepatol. 1999;  31 979-984
  CrossrefPubMedSearch in Google Scholar
• 137 Thorburn D, Curry G, Spooner R et al.. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C.  Gut. 2002;  50 248-252
  CrossrefPubMedSearch in Google Scholar
• 138 Bugianesi E, Leone N, Vanni E et al.. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.  Gastroenterology. 2002;  123 134-140
  CrossrefPubMedSearch in Google Scholar
• 139 Willner I R, Waters B, Patil S R et al.. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.  Am J Gastroenterol. 2001;  96 2957-2961
  CrossrefPubMedSearch in Google Scholar
• 140 Struben V M, Hespenheide E E, Caldwell S H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds.  Am J Med. 2000;  108 9-13
  PubMedSearch in Google Scholar
• 141 Browning J D, Kumar K S, Saboorian M H, Thiele D L. Ethnic differences in the prevalence of cryptogenic cirrhosis.  Am J Gastroenterol. 2004;  99 292-298
  CrossrefPubMedSearch in Google Scholar
• 142 Namikawa C, Shu-Ping Z, Vyselaar J R et al.. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis.  J Hepatol. 2004;  40 781-786
  CrossrefPubMedSearch in Google Scholar
• 143 Bernard S, Touzet S, Personne I et al.. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes.  Diabetologia. 2000;  43 995-999
  CrossrefPubMedSearch in Google Scholar
• 144 Valenti L, Fracanzani A L, Dongiovanni P et al.. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease.  Gastroenterology. 2002;  122 274-280
  CrossrefPubMedSearch in Google Scholar
• 145 Nozaki Y, Saibara T, Nemoto Y et al.. Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis.  Alcohol Clin Exp Res. 2004;  28(suppl) 106S-110S
  PubMedSearch in Google Scholar
• 146 Brun P, Castagliuolo I, Floreani A R et al.. Increased risk of NASH in patients carrying the C(-159)T polymorphism in the CD14 gene promoter region.  Gut. 2006;  55 1212
  PubMedSearch in Google Scholar
• 147 Dixon J B, Bhathal P S, Jonsson J R et al.. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese.  J Hepatol. 2003;  39 967-971
  CrossrefPubMedSearch in Google Scholar
• 148 George D K, Goldwurm S, MacDonald G A et al.. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology. 1998;  114 311-318
  CrossrefPubMedSearch in Google Scholar
• 149 Bonkovsky H L, Jawaid Q, Tortorelli K et al.. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 421-429
  CrossrefPubMedSearch in Google Scholar
• 150 Chitturi S, Weltman M, Farrell G C et al.. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity.  Hepatology. 2002;  36 142-149
  CrossrefPubMedSearch in Google Scholar
• 151 Deguti M M, Sipahi A M, Gayotto L C et al.. Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis.  Braz J Med Biol Res. 2003;  36 739-745
  PubMedSearch in Google Scholar
• 152 Iwamoto N, Ogawa Y, Kajihara S et al.. Gln27Glu beta2-adrenergic receptor variant is associated with hypertriglyceridemia and the development of fatty liver.  Clin Chim Acta. 2001;  314 85-91
  CrossrefPubMedSearch in Google Scholar
• 153 Song J, da Costa K A, Fischer L M et al.. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD).  FASEB J. 2005;  19 1266-1271
  CrossrefPubMedSearch in Google Scholar
• 154 Fletcher L M, Dixon J L, Purdie D M, Powell L W, Crawford D H. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 281-289
  CrossrefPubMedSearch in Google Scholar
• 155 Piperno A, Fargion S, D'Alba R et al.. Liver damage in Italian patients with hereditary hemochromatosis is highly influenced by hepatitis B and C virus infection.  J Hepatol. 1992;  16 364-368
  CrossrefPubMedSearch in Google Scholar
• 156 Powell L W, Subramaniam V N, Yapp T R. Haemochromatosis in the new millennium.  J Hepatol. 2000;  32(suppl) 48-62
  PubMedSearch in Google Scholar
• 157 Osterreicher C H, Datz C, Stickel F et al.. Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis.  J Hepatol. 2005;  42 914-919
  CrossrefPubMedSearch in Google Scholar
• 158 Stickel F, Osterreicher C H, Datz C et al.. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis.  Arch Intern Med. 2005;  165 1835-1840
  CrossrefPubMedSearch in Google Scholar
• 159 Fargion S, Valenti L, Dongiovanni P et al.. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis.  Blood. 2001;  97 3707-3712
  CrossrefPubMedSearch in Google Scholar
• 160 Krayenbuehl P A, Maly F E, Hersberger M et al.. Tumor necrosis factor-alpha -308G> A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.  Clin Chem. 2006;  52 1552-1558
  CrossrefPubMedSearch in Google Scholar
• 161 Osterreicher C H, Datz C, Stickel F et al.. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis.  Cytokine. 2005;  31 142-148
  CrossrefPubMedSearch in Google Scholar
• 162 Distante S, Elmberg M, Foss Haug K B et al.. Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.  Scand J Gastroenterol. 2003;  38 871-877
  CrossrefPubMedSearch in Google Scholar
• 163 Kaplan M M, Gershwin M E. Primary biliary cirrhosis.  N Engl J Med. 2005;  353 1261-1273
  CrossrefPubMedSearch in Google Scholar
• 164 Brind A M, Bray G P, Portmann B C, Williams R. Prevalence and pattern of familial disease in primary biliary cirrhosis.  Gut. 1995;  36 615-617
  CrossrefPubMedSearch in Google Scholar
• 165 Agarwal K, Jones D E, Bassendine M F. Genetic susceptibility to primary biliary cirrhosis.  Eur J Gastroenterol Hepatol. 1999;  11 603-606
  CrossrefPubMedSearch in Google Scholar
• 166 Bittencourt P L, Farias A Q, Abrantes-Lemos C P et al.. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2004;  19 873-878
  CrossrefPubMedSearch in Google Scholar
• 167 Selmi C, Mayo M J, Bach N et al.. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.  Gastroenterology. 2004;  127 485-492
  CrossrefPubMedSearch in Google Scholar
• 168 Invernizzi P, Battezzati P M, Crosignani A et al.. Peculiar HLA polymorphisms in Italian patients with primary biliary cirrhosis.  J Hepatol. 2003;  38 401-406
  CrossrefPubMedSearch in Google Scholar
• 169 Agarwal K, Jones D E, Daly A K et al.. CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.  J Hepatol. 2000;  32 538-541
  CrossrefPubMedSearch in Google Scholar
• 170 Fan L Y, Tu X Q, Cheng Q B et al.. Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population.  World J Gastroenterol. 2004;  10 3056-3059
  PubMedSearch in Google Scholar
• 171 Vogel A, Strassburg C P, Manns M P. Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.  Hepatology. 2002;  35 126-131
  CrossrefPubMedSearch in Google Scholar
• 172 Gordon M A, Oppenheim E, Camp N J et al.. Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region.  J Hepatol. 1999;  31 242-247
  CrossrefPubMedSearch in Google Scholar
• 173 Donaldson P, Agarwal K, Craggs A et al.. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility.  Gut. 2001;  48 397-402
  CrossrefPubMedSearch in Google Scholar
• 174 Jones D E, Watt F E, Grove J et al.. Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.  J Hepatol. 1999;  30 232-236
  CrossrefPubMedSearch in Google Scholar
• 175 Bittencourt P L, Palacios S A, Farias A Q et al.. Analysis of major histocompatibility complex and CTLA-4 alleles in Brazilian patients with primary biliary cirrhosis.  J Gastroenterol Hepatol. 2003;  18 1061-1066
  CrossrefPubMedSearch in Google Scholar
• 176 Tanaka A, Quaranta S, Mattalia A et al.. The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis.  J Hepatol. 1999;  30 826-829
  CrossrefPubMedSearch in Google Scholar
• 177 Jones D E, Donaldson P T. Genetic factors in the pathogenesis of primary biliary cirrhosis.  Clin Liver Dis. 2003;  7 841-864
  CrossrefPubMedSearch in Google Scholar
• 178 Donaldson P T. TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal.  J Hepatol. 1999;  31 366-368
  CrossrefPubMedSearch in Google Scholar
• 179 Norris S, Kondeatis E, Collins R et al.. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism.  Gastroenterology. 2001;  120 1475-1482
  PubMedSearch in Google Scholar
• 180 Mitchell S A, Grove J, Spurkland A et al.. Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.  Gut. 2001;  49 288-294
  CrossrefPubMedSearch in Google Scholar
• 181 Satsangi J, Chapman R W, Haldar N et al.. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis.  Gastroenterology. 2001;  121 124-130
  CrossrefPubMedSearch in Google Scholar
• 182 Czaja A J, Cookson S, Constantini P K et al.. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis.  Gastroenterology. 1999;  117 645-652
  PubMedSearch in Google Scholar
• 183 Czaja A J, Donaldson P T. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis.  Am J Gastroenterol. 2002;  97 2051-2057
  CrossrefPubMedSearch in Google Scholar
• 184 Hirschhorn J N, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies.  Genet Med. 2002;  4 45-61
  PubMedSearch in Google Scholar
• 185 Cardon L R, Bell J I. Association study designs for complex diseases.  Nat Rev Genet. 2001;  2 91-99
  CrossrefPubMedSearch in Google Scholar
• 186 Caporaso N. Selection of candidate genes for population studies.  IARC Sci Publ. 1999;  (148) 23-36
  PubMedSearch in Google Scholar
• 187 Cardon L R, Palmer L J. Population stratification and spurious allelic association.  Lancet. 2003;  361 598-604
  CrossrefPubMedSearch in Google Scholar
• 188 Thomas D C, Witte J S. Point: population stratification-a problem for case-control studies of candidate-gene associations?.  Cancer Epidemiol Biomarkers Prev. 2002;  11 505-512
  PubMedSearch in Google Scholar
• 189 Ioannidis J P, Ntzani E E, Trikalinos T A, Contopoulos-Ioannidis D G. Replication validity of genetic association studies.  Nat Genet. 2001;  29 306-309
  CrossrefPubMedSearch in Google Scholar
• 190 Ioannidis J P, Trikalinos T A, Ntzani E E, Contopoulos-Ioannidis D G. Genetic associations in large versus small studies: an empirical assessment.  Lancet. 2003;  361 567-571
  CrossrefPubMedSearch in Google Scholar
• 191 Millikan R. The changing face of epidemiology in the genomics era.  Epidemiology. 2002;  13 472-480
  CrossrefPubMedSearch in Google Scholar

David A BrennerM.D. 

Columbia University Medical Center, College of Physicians and Surgeons

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