Genomics of Liver Fibrosis and Cirrhosis

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.

KEYWORDS

Fibrosis - cirrhosis - genomics - polymorphism - SNP

REFERENCES

• 1 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115 209-218
• 2 Schuppan D, Ruehl M, Somasundaram R, Hahn E G. Matrix as a modulator of hepatic fibrogenesis.  Semin Liver Dis. 2001;  21 351-372
• 3 Albanis E, Friedman S L. Hepatic fibrosis: pathogenesis and principles of therapy.  Clin Liver Dis. 2001;  5 315-334
• 4 Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites.  N Engl J Med. 2004;  350 1646-1654
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 17 Stickel F, Osterreicher C H. The role of genetic polymorphisms in alcoholic liver disease.  Alcohol Alcohol. 2006;  41 209-224
• 18 Lander E S, Linton L M, Birren B et al.. Initial sequencing and analysis of the human genome.  Nature. 2001;  409 860-921
• 19 Venter J C, Adams M D, Myers E W et al.. The sequence of the human genome.  Science. 2001;  291 1304-1351
• 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
• 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
• 22 Kruglyak L, Nickerson D A. Variation is the spice of life.  Nat Genet. 2001;  27 234-236
• 23 Feld J J, Liang T J. Hepatitis C-identifying patients with progressive liver injury.  Hepatology. 2006;  43(suppl 1) S194-S206
• 24 Day C P. Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.  Liver Int. 2006;  26 1021-1028
• 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
• 26 Raynard B, Balian A, Fallik D et al.. Risk factors of fibrosis in alcohol-induced liver disease.  Hepatology. 2002;  35 635-638
• 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
• 28 Agarwal D P. Genetic polymorphisms of alcohol metabolizing enzymes.  Pathol Biol (Paris). 2001;  49 703-709
• 29 Armstrong R N. Structure, catalytic mechanism, and evolution of the glutathione transferases.  Chem Res Toxicol. 1997;  10 2-18
• 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
• 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
• 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
• 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
• 34 Hayes J D, Flanagan J U, Jowsey I R. Glutathione transferases.  Annu Rev Pharmacol Toxicol. 2005;  45 51-88
• 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
• 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
• 37 Wallace D C. Mitochondrial diseases in man and mouse.  Science. 1999;  283 1482-1488
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 126 Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection.  Gastroenterology. 2003;  124 1509-1523
• 127 Gattoni A, Parlato A, Vangieri B et al.. Role of hemochromatosis genes in chronic hepatitis C.  Clin Ter. 2006;  157 61-68
• 128 Bacon B R. Hemochromatosis: diagnosis and management.  Gastroenterology. 2001;  120 718-725
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 140 Struben V M, Hespenheide E E, Caldwell S H. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds.  Am J Med. 2000;  108 9-13
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 156 Powell L W, Subramaniam V N, Yapp T R. Haemochromatosis in the new millennium.  J Hepatol. 2000;  32(suppl) 48-62
• 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
• 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
• 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
• 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
• 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
• 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
• 163 Kaplan M M, Gershwin M E. Primary biliary cirrhosis.  N Engl J Med. 2005;  353 1261-1273
• 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
• 165 Agarwal K, Jones D E, Bassendine M F. Genetic susceptibility to primary biliary cirrhosis.  Eur J Gastroenterol Hepatol. 1999;  11 603-606
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 177 Jones D E, Donaldson P T. Genetic factors in the pathogenesis of primary biliary cirrhosis.  Clin Liver Dis. 2003;  7 841-864
• 178 Donaldson P T. TNF gene polymorphisms in primary biliary cirrhosis: a critical appraisal.  J Hepatol. 1999;  31 366-368
• 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
• 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
• 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
• 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
• 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
• 184 Hirschhorn J N, Lohmueller K, Byrne E, Hirschhorn K. A comprehensive review of genetic association studies.  Genet Med. 2002;  4 45-61
• 185 Cardon L R, Bell J I. Association study designs for complex diseases.  Nat Rev Genet. 2001;  2 91-99
• 186 Caporaso N. Selection of candidate genes for population studies.  IARC Sci Publ. 1999;  (148) 23-36
• 187 Cardon L R, Palmer L J. Population stratification and spurious allelic association.  Lancet. 2003;  361 598-604
• 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
• 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
• 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
• 191 Millikan R. The changing face of epidemiology in the genomics era.  Epidemiology. 2002;  13 472-480