Combinatorial use of single nucleotide polymorphisms to help predict liver fibrosis in patients with hepatitis C infections

Expert Opinion on Medical Diagnostics

Volumn 3, Issue 4, 2009, Pages 355-370

  Minisini, Rosalba ^a   Fabris, Carlo ^b   Toniutto, Pierluigi ^b   Pirisi, Mario ^a  

^a UNIVERSITY OF EASTERN PIEDMONT   (Italy)

^b UNIVERSITY OF UDINE   (Italy)

Author keywords

Cirrhosis; Hepatitis C virus; Natural history; Outcome; Single nucleotide polymorphism

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); ABC TRANSPORTER; ANGIOTENSIN; ANGIOTENSINOGEN; APOLIPOPROTEIN E; BLOOD CLOTTING FACTOR 5 LEIDEN; BLOOD CLOTTING FACTOR 7; CHEMOKINE RECEPTOR CX3CR1; CHITINASE; COMPLEMENT COMPONENT C5; CYTOCHROME P450; EPOXIDE HYDROLASE; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 10 RECEPTOR ALPHA; INTERLEUKIN 12; INTERLEUKIN 12P40; LOW DENSITY LIPOPROTEIN RECEPTOR; MATRIX METALLOPROTEINASE; MICROSOME ENZYME; MONOCYTE CHEMOTACTIC PROTEIN 1; MONOCYTE CHEMOTACTIC PROTEIN 2; MYELOPEROXIDASE; PROTEIN KINASE; PROTEIN KINASE R; PROTEINASE ACTIVATED RECEPTOR 1; RANTES; TOLL LIKE RECEPTOR 7; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR;

DRUG METABOLISM; FIBROGENESIS; GENE FREQUENCY; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HEMOCHROMATOSIS; HEPATITIS C; HEREDITY; HUMAN; INFLAMMATION; INFORMATION RETRIEVAL; LIVER FIBROSIS; MAJOR HISTOCOMPATIBILITY COMPLEX; MEDLINE; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; VIRUS ENTRY; VIRUS REPLICATION;

EID: 77953458981     PISSN: 17530059     EISSN: 17530067     Source Type: Journal    
DOI: 10.1517/17530050902893311     Document Type: Review

References (136)

1. Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006;10(1):76-99
2. Awad MR, El-Gamel A, Hasleton P, et al. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 1998;66(8):1014-20
3. Powell EE, Edwards-Smith CJ, Hay JL, et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000;31(4):828-33
4. Gewaltig J, Mangasser-Stephan K, Gartung C, etal. 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(1-2):83-94
5. Tag CG, 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(5):173-81
6. Ben-Ari Z, Pappo O, Druzd T, et al. Role of cytokine gene polymorphism and hepatic transforming growth factor beta1 expression in recurrent hepatitis C after liver transplantation. Cytokine 2004;27(1):7-14
7. 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(2):212-8
8. 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(10):1139-43
9. Wang H, Mengsteab S, Tag CG, 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(13):1929-36
10. Yee LJ, Tang YM, Kleiner DE, et al. Myxovirus-1 and protein kinase haplotypes and fibrosis in chronic hepatitis C virus. Hepatology 2007;46(1):74-83
11. Wolf G. Novel aspects of the renin-angiotensin-aldosterone-system. Front Biosci 2008;13:4993-5005
12. Ramos SG, Montenegro AP, Goissis G, et al. Captopril reduces collagen and mast cell and eosinophil accumulation in pig serum-induced rat liver fibrosis. Pathol Int 1994;44(9):655-61
13. Wei HS, Li DG, Lu HM, etal. Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4). World J Gastroenterol 2000;6(4):540-45
14. Wei HS, Lu HM, Li DG, et al. The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis:effects of RAS inhibitors on hepatic fibrosis induced by CCl(4). World J Gastroenterol 2000;6(6):824-28
15. Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001;34(4 Pt 1):745-50
16. Tuncer I, Ozbek H, Ugras S, et al. Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat. The effect of AT1-R blocker on the hepatic fibrosis. Exp Toxicol Pathol 2003;55(2-3):159-66
17. Castano GO, Sookoian SC. Angiotensin II type 1 receptor blockade in early cirrhosis. J Hepatol 2007;47(3):426-7
18. Forrest EH, 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(5):519-24
19. Marra F, Romanelli RG, Giannini C, et al. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology 1999;29(1):140-8
20. Zamara E, Galastri S, Aleffi S, et al. Prevention of severe toxic liver injury and oxidative stress in MCP-1-deficient mice. J Hepatol 2007;46(2):230-8
21. Muhlbauer M, Bosserhoff AK, Hartmann A, etal. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Gastroenterology 2003;125(4):1085-1093
22. Glas J, Torok HP, Tonenchi L, et al. The -2518 promotor polymorphism in the MCP-1 gene is not associated with liver cirrhosis in chronic hepatitis C virus infection. Gastroenterology 2004;126(7):1930-1; author reply 31-32 (Pubitemid 38736363)
23. Bonkovsky HL, Salek J. No role of the -2518 promoter polymorphism of monocyte chemotactic protein-1 in chronic hepatitis C. Gastroenterology 2005;129(4):1361-1362 (Pubitemid 41446880)
24. Cui J, Eitzman DT, Westrick RJ, et al. Spontaneous thrombosis in mice carrying the factor V Leiden mutation. Blood 2000;96(13):4222-4226
25. 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(8):1206-1210 (Pubitemid 36877437)
26. Poujol-Robert A, Boelle PY, Poupon R, et al. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology 2004;39(4):1174-1175 (Pubitemid 38428958)
27. Matthews RG. Methylenetetrahydrofolate reductase: a common human polymorphism and its biochemical implications. Chem Rec 2002;2(1):4-12 (Pubitemid 44127755)
28. Adinolfi LE, Ingrosso D, Cesaro G, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology 2005;41(5):995-1003 (Pubitemid 40593907)
29. Toniutto P, Fabris C, Falleti E, et al. Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver Int 2008;28(2):257-263 (Pubitemid 351201039)
30. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69(3):562-573 (Pubitemid 43139720)
31. Yan C, Boyd DD. Regulation of matrix metalloproteinase gene expression. J Cell Physiol 2007;211(1):19-26 (Pubitemid 46363892)
32. Abilleira S, Bevan S, Markus HS. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet 2006;43(12):897-901 (Pubitemid 46080185)
33. Peters DG, Kassam A, St Jean PL, et al. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke 1999;30(12):2612-2616
34. Decock J, Paridaens R, Ye S. Genetic polymorphisms of matrix metalloproteinases in lung, breast and colorectal cancer. Clin Genet 2008;73(3):197-211 (Pubitemid 351228503)
35. Okamoto K, Mimura K, Murawaki Y, et al. 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(7):1102-1108 (Pubitemid 40961235)
36. Wasmuth HE, Tag CG, Van de Leur E, et al. The marburg I variant (G534E) of the factor VII-activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet-derived growth factor BB. Hepatology 2008;49(3):775-780
37. Berres ML, Papen S, Pauels K, etal. A functional variation in CHI3L1 is associated with severity of liver fibrosis and YKL-40 serum levels in chronic hepatitis C infection. J Hepatol 2009;50(2):370-376
38. Martinelli A, Knapp S, Anstee Q, et al. Effect of a thrombin receptor (protease-activated receptor 1, PAR-1) gene polymorphism in chronic hepatitis C liver fibrosis. J Gastroenterol Hepatol 2008;23(9):1403-1409
39. Chen J, Liu X. The role of interferon gamma in regulation of CD4+ T-cells and its clinical implications. Cell Immunol 2009;254(2):85-90
40. Vandenbroeck K, Goris A. Cytokine gene polymorphisms in multifactorial diseases: gateways to novel targets for immunotherapy? Trends Pharmacol Sci 2003;24(6):284-289
41. Dai CY, Chuang WL, Hsieh MY, et al. Polymorphism of interferon-gamma gene at position +874 and clinical characteristics of chronic hepatitis C. Transl Res 2006;148(3):128-133 (Pubitemid 44287635)
42. Abbott WG, 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(2):90-97 (Pubitemid 38584993)
43. Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 2005;115(1):1-20 (Pubitemid 40598088)
44. Sheikh MY, Choi J, Qadri I, et al. Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology 2008;47(6):2127-2133 (Pubitemid 351945577)
45. Kota RS, Ramana CV, Tenorio FA, et al. Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. J Biol Chem 2005;280(35):31076-31084 (Pubitemid 41291842)
46. Yee LJ, Tang J, Herrera J, et al. Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection. Genes Immun 2000;1(6):386-390
47. Dai CY, Chuang WL, Lee LP, et al. Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C. J Viral Hepat 2006;13(11):770-774 (Pubitemid 44583503)
48. Valenti L, Pulixi E, Fracanzani AL, et al. TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis. J Hepatol 2005;43(6):944-950 (Pubitemid 41627978)
49. Bahr MJ, el Menuawy M, Boeker KH, et al. Cytokine gene polymorphisms and the susceptibility to liver cirrhosis in patients with chronic hepatitis C. Liver Int 2003;23(6):420-425
50. Mangia A, Santoro R, Piattelli M, et al. IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection. Cytokine 2004;25(3):103-109 (Pubitemid 38096267)
51. Yu ML, Dai CY, Chiu CC, 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(1):35-40 (Pubitemid 36773888)
52. Rosen HR, McHutchison JG, Conrad AJ, et al. Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C. Am J Gastroenterol 2002;97(3):714-720 (Pubitemid 34245903)
53. Knapp S, Hennig BJ, Frodsham AJ, et al. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics 2003;55(6):362-369 (Pubitemid 37255487)
54. Hennig BJ, Frodsham AJ, Hellier S, et al. Influence of IL-10RA and IL-22 polymorphisms on outcome of hepatitis C virus infection. Liver Int 2007;27(8):1134-1143 (Pubitemid 47399449)
55. Cooper AM, Khader SA. IL-12p40: an inherently agonistic cytokine. Trends Immunol 2007;28(1):33-38
56. Suneetha PV, Goyal A, Hissar SS, et al. 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(8):1055-1060
57. Eiserich JP, Baldus S, Brennan ML, et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002;296(5577):2391-2394
58. Hoy A, Tregouet D, Leininger-Muller B, et al. Serum myeloperoxidase concentration in a healthy population: biological variations, familial resemblance and new genetic polymorphisms. Eur J Hum Genet 2001;9(10):780-786 (Pubitemid 33014591)
59. Reynolds WF, Patel K, Pianko S, etal. A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection. Genes Immun 2002;3(6):345-349
60. Hillebrandt S, Wasmuth HE, Weiskirchen R, etal. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 2005;37(8):835-843
61. Halangk J, Sarrazin C, Neumann K, et al. Evaluation of complement factor 5 variants as genetic risk factors for the development of advanced fibrosis in chronic hepatitis C infection. J Hepatol 2008;49(3):339-345
62. McKiernan SM, Hagan R, Curry M, et al. The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C. Gastroenterology 2000;118(6):1124-1130 (Pubitemid 30346989)
63. Thursz M, Yallop R, Goldin R, et al. Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 1999;354(9196):2119-2124
64. Mangia A, Gentile R, Cascavilla I, et al. HLA class II favors clearance of HCV infection and progression of the chronic liver damage. J Hepatol 1999;30(6):984-989 (Pubitemid 29278740)
65. Barrett S, Ryan E, Crowe J. Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin. J Hepatol 1999;306):979-983 (Pubitemid 29278739)
66. Tillmann HL, Chen DF, Trautwein C, et al. Low frequency of HLA-DRB1*11 in hepatitis C virus induced end stage liver disease. Gut 2001;48(5):714-718 (Pubitemid 32378596)
67. 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(4):274-278 (Pubitemid 26301098)
68. Yenigun A, Durupinar B. Decreased frequency of the HLA-DRB1*11 allele in patients with chronic hepatitis C virus infection. J Virol 2002;76(4):1787-1789 (Pubitemid 34094626)
69. Asti M, Martinetti M, Zavaglia C, et al. Human leukocyte antigen class II and III alleles and severity of hepatitis C virus-related chronic liver disease. Hepatology 1999;29(4):1272-1279 (Pubitemid 29168765)
70. Hraber P, Kuiken C, Yusim K. Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection. Hepatology 2007;46(6):1713-1721
71. Patel K, Norris S, Lebeck L, etal. HLA class I allelic diversity and progression of fibrosis in patients with chronic hepatitis C. Hepatology 2006;43(2):241-249
72. Thio CL, Thomas DL, Goedert JJ, et al. Racial differences in HLA class II associations with hepatitis C virus outcomes. J Infect Dis 2001;184(1):16-21 (Pubitemid 32568495)
73. Sugimoto K, Stadanlick J, Ikeda F, et al. Influence of ethnicity in the outcome of hepatitis C virus infection and cellular immune response. Hepatology 2003;37(3):590-599 (Pubitemid 36258781)
74. Harris RA, Sugimoto K, Kaplan DE, et al. Human leukocyte antigen class II associations with hepatitis C virus clearance and virus-specific CD4 T cell response among Caucasians and African Americans. Hepatology 2008;48(1):70-79 (Pubitemid 351975532)
75. Kuzushita N, Hayashi N, Kanto T, et al. Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection. Gastroenterology 1999;116(5):1149-1154 (Pubitemid 29203025)
76. 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(2):109-116 (Pubitemid 32405398)
77. Hellier S, Frodsham AJ, Hennig BJ, 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(6):1468-1476 (Pubitemid 37466973)
78. 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(8):1157-1161 (Pubitemid 41025913)
79. Promrat K, McDermott DH, Gonzalez CM, etal. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology 2003;124(2):352-360
80. Wasmuth HE, Zaldivar MM, Berres ML, et al. The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection. J Hepatol 2008;48(2):208-215
81. Kaisho T, Akira S. Toll-like receptors as adjuvant receptors. Biochim Biophys Acta 2002;1589(1):1-13
82. Schott E, Witt H, Neumann K, et al. A Toll-like receptor 7 single nucleotide polymorphism protects from advanced inflammation and fibrosis in male patients with chronic HCV-infection. J Hepatol 2007;47(2):203-211 (Pubitemid 47021254)
83. Agnello V, Abel G, Elfahal M, et al. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci USA 1999;96(22):12766-12771 (Pubitemid 29513577)
84. Hennig BJ, Hellier S, Frodsham AJ, et al. Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection. Genes Immun 2002;3(6):359-367 (Pubitemid 38967564)
85. Lopez-Miranda J, Williams C, Lairon D. Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism. Br J Nutr 2007;98(3):458-473 (Pubitemid 47272862)
86. Wozniak MA, Itzhaki RF, Faragher EB, et al. Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology 2002;36(2):456-463 (Pubitemid 34810367)
87. Toniutto P, Fabris C, Fumo E, et al. Carriage of the apolipoprotein E-epsilon4 allele and histologic outcome of recurrent hepatitis C after antiviral treatment. Am J Clin Pathol 2004;122(3):428-433 (Pubitemid 39145549)
88. Gale MJ Jr, Korth MJ, Tang NM, et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997;230(2):217-227 (Pubitemid 27211852)
89. Taylor MW, Tsukahara T, Brodsky L, et al. Changes in gene expression during pegylated interferon and ribavirin therapy of chronic hepatitis C virus distinguish responders from nonresponders to antiviral therapy. J Virol 2007;81(7):3391-3401 (Pubitemid 46456648)
90. Sermasathanasawadi R, Kato N, Muroyama R, etal. Association of interferon regulatory factor-7 gene polymorphism with liver cirrhosis in chronic hepatitis C patients. Liver Int 2008;28(6):798-806 • Excellent review of the relationship between iron metabolism and viruses, including HCV and human immunodeficiency virus.
91. Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol 2008;6(7):541-552
92. Bonkovsky HL, Naishadham D, Lambrecht RW, etal. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006;131(5):1440-1451
93. Bonkovsky HL, 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(6):848-854 (Pubitemid 35404226)
94. Corengia C, Galimberti S, Bovo G, et al. Iron accumulation in chronic hepatitis C: relation of hepatic iron distribution, HFE genotype, and disease course. Am J Clin Pathol 2005;124(6):846-853 (Pubitemid 41740184)
95. Erhardt A, Maschner-Olberg A, Mellenthin C, etal. HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. J Hepatol 2003;38(3):335-342 (Pubitemid 36286547)
96. Gehrke SG, 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(12):780-787 (Pubitemid 38058160)
97. Geier A, Reugels M, Weiskirchen R, et al. Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C. Liver Int 2004;24(4):285-294 (Pubitemid 39162068)
98. 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(6):979-984
99. Kazemi-Shirazi L, Datz C, Maier-Dobersberger T, etal. The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. Gastroenterology 1999;116(1):127-134
100. Knöll A, Kreuzpaintner B, Kreuzpaintner E, etal. Hemochromatosis mutation in hepatitis C: histopathology. Gastroenterology 1998;115(5):1307-1309
101. Mah YH, Kao JH, Liu CJ, et al. Prevalence and clinical implications of HFE gene mutations (C282Y and H63D) in patients with chronic hepatitis B and C in Taiwan. Liver Int 2005;25(2):214-219 (Pubitemid 40500551)
102. Martinelli AL, Franco RF, Villanova MG, et al. Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection? Acta Haematol 2000;102(3):152-156
103. Negro F, Samii K, Rubbia-Brandt L, et al. Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis. J Med Virol 2000;60(1):21-27
104. Pirisi M, Scott CA, Avellini C, et al. Iron deposition and progression of disease in chronic hepatitis C. Role of interface hepatitis, portal inflammation, and HFE missense mutations. Am J Clin Pathol 2000;113(4):546-554 (Pubitemid 30217364)
105. Smith BC, Gorve J, Guzail MA, et al. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 1998;27(6):1695-1699 (Pubitemid 28264696)
106. 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(2):248-252 (Pubitemid 34087940)
107. Tung BY, Emond MJ, Bronner MP, et al. Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 2003;124(2):318-326 (Pubitemid 36169248)
108. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G-> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211-218
109. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002;360(9340):1155-1162
110. Lu LG, Zeng MD, Li JQ, et al. Study on the role of free fatty acids in proliferation of rat hepatic stellate cells (II). World J Gastroenterol 1998;4(6):500-502 (Pubitemid 128620222)
111. 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(5):730-739 (Pubitemid 32488789)
112. Fishman S, Lurie Y, Peretz H, et al. Role of CYP2D6 polymorphism in predicting liver fibrosis progression rate in Caucasian patients with chronic hepatitis C. Liver Int 2006;26(3):279-284 (Pubitemid 43349316)
113. Fretland AJ, Omiecinski CJ. Epoxide hydrolases: biochemistry and molecular biology. Chem Biol Interact 2000;129(1-2):41-59 (Pubitemid 32061053)
114. 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(1):195-201 (Pubitemid 34700778)
115. Pearson TA, Manolio TA. How to interpret a genome-wide association study. JAMA 2008;299(11):1335-44 •• Excellent review for clinicians and scientists concerning design, interpretation, application and limitations of genome-wide association studies.
116. Huang H, Shiffman ML, Cheung RC, et al. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C. Gastroenterology 2006;130(6):1679-87 •• A gene-centric association study investigating host genetic factors of fibrosis in chronic hepatitis C with a multistage design, starting from the evaluation in 24,832 functional SNPs.
117. Liu ZR. p68 RNA helicase is an essential human splicing factor that acts at the U1 snRNA-5′ splice site duplex. Mol Cell Biol 2002;22(15):5443-5450 (Pubitemid 34755755)
118. Ioannidis JP. Genetic associations: false or true? Trends Mol Med 2003;9(4):135-138
119. Richardson MM, Powell EE, Barrie HD, et al. A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C. J Med Genet 2005;42(7):e45
120. Huang H, Shiffman ML, Friedman S, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007;46(2):297-306 •• An important paper showing that predicting hepatitis C course by a relatively simple gene signature may be feasible; it descends from scanning genetic variation by the wide approach reported above (see [116]).
121. Celera Corp. Available from: https://www.celera.com/celera/in-dev- genetics [Last accessed on 9 April 2009]
122. Grünhage F, Mueller T, Günther R, et al. Re-evaluation of the genetic cirrhosis risk score in patients with chronic hepatitis C virus infection. Hepatology 2008;48(4 Suppl):1095A
123. 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(9055):825-32 • First study to identify major predictors of natural history in chronic hepatitis C.
124. Thein HH, Yi Q, Dore GJ, et al. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS 2008;22(15):1979-1991
125. Gane EJ. The natural history of recurrent hepatitis C and what influences this. Liver Transpl 2008;14(Suppl 2):S36-44
126. Ortiz V, Berenguer M, Rayon JM, et al. Contribution of obesity to hepatitis C-related fibrosis progression. Am J Gastroenterol 2002;97(9):2408-2414 (Pubitemid 35052063)
127. Rodger AJ, Roberts S, Lanigan A, et al. Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975. Hepatology 2000;32(3):582-587
128. Wright M, Goldin R, Fabre A, et al. Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study. Gut 2003;52(4):574-579 (Pubitemid 36363414)
129. Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003;37(3):493-503 (Pubitemid 36258768)
130. Jonsson JR, Purdie DM, Clouston AD, et al. Recognition of genetic factors influencing the progression of hepatitis C: potential for personalized therapy. Mol Diagn Ther 2008;12(4):209-218
131. Osterreicher CH, Stickel F, Brenner DA. Genomics of liver fibrosis and cirrhosis. Semin Liver Dis 2007;27(1):28-43
132. Available from: http://department.obg.cuhk.edu.hk/researchsupport/ statmenu.asp, [Last accessed on 9 April 2009]
133. Barnes C, Plagnol V, Fitzgerald T, et al. A robust statistical method for case-control association testing with copy number variation. Nat Genet 2008;40(10):1245-1252
134. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy - a genomewide study. N Engl J Med 2008;359(8):789-799
135. National Centre for Biotechnology Information. Available from: http://www.ncbi.nlm.nih.gov/SNP/
136. Allele Frequency Database (ALFRED). Available from: http://alfred.med. yale.edu/alfred/entity.asp?condition=alphaloci