Variants in Interferon-Alpha Pathway Genes and Response to Pegylated Interferon-Alpha2a Plus Ribavirin for Treatment of Chronic Hepatitis C Virus Infection in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial

被引：72

作者：

Welzel, Tania Mara ^{[1
]}

Morgan, Timothy R. ^{[2
,3
]}

Bonkovsky, Herbert L. ^{[4
,5
,6
]}

Naishadham, Deepa ^{[7
]}

Pfeiffer, Ruth M. ^{[1
]}

Wright, Elizabeth C. ^{[8
]}

Hutchinson, Amy A. ^{[10
]}

Crenshaw, Andrew T. ^{[10
]}

Bashirova, Arman ^{[11
]}

Carrington, Mary ^{[12
]}

Dotrang, Myhanh ^{[13
]}

Sterling, Richard K. ^{[14
]}

Lindsay, Karen L. ^{[15
]}

Fontana, Robert J. ^{[16
]}

Lee, William M. ^{[17
]}

Di Bisceglie, Adrian M. ^{[18
]}

Ghany, Marc G. ^{[9
]}

Gretch, David R. ^{[19
]}

Chanock, Stephen J. ^{[1
]}

Chung, Raymond T. ^{[20
,21
]}

O'Brien, Thomas R. ^{[1
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA

[2] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA

[3] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA

[4] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA

[5] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA

[6] Carolinas Med Ctr, Charlotte, NC 28203 USA

[7] New England Res Inst, Watertown, MA 02172 USA

[8] NIDDK, Off Director, NIH, Dept Hlth & Human Serv, Bethesda, MD USA

[9] NIDDK, Liver Dis Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA

[10] NCI, Core Genotyping Facil, Div Canc Epidemiol & Genet, Adv Technol Program,SAIC Frederick Inc, Frederick, MD 21701 USA

[11] Johns Hopkins Univ, Dept Med, Baltimore, MD USA

[12] NCI Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD USA

[13] Comp Sci Corp, Rockville, MD USA

[14] Virginia Commonwealth Univ, Med Ctr, Hepatol Sect, Richmond, VA USA

[15] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA

[16] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA

[17] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA

[18] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO USA

[19] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA

[20] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[21] Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA

来源：

HEPATOLOGY | 2009年 / 49卷 / 06期

基金：

美国国家卫生研究院;

关键词：

SINGLE NUCLEOTIDE POLYMORPHISM; PEGINTERFERON ALPHA-2A; VIRAL-INFECTION; PROTEIN-KINASE; THERAPY; PKR; MXA; ASSOCIATION; EXPRESSION; ROLES;

D O I：

10.1002/hep.22877

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Combination treatment with pegylated-interferon-alpha (PEG IFN-alpha) and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-alpha pathway may affect antiviral responses, we analyzed the relationship between variants in these genes and SVR among participants in the Hepatitis C Antiviral Long-Term treatment Against Cirrhosis (HALT-C) trial. Patients had advanced chronic hepatitis C that had previously failed to respond to interferon-based treatment. Participants were treated with peginterferonce-alpha 2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered nonresponders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-alpha pathway. This analysis compares genotypes for participants with an SVR to nonresponders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n = 131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVSI-22G (adjusted odds ratio, 0.57; P = 0.02); IFNAR2 Ex2-33C (adjusted odds ratio, 2.09; P = 0.02);JAK1 IVS22 + 112T (adjusted odds ratio, 1.66; P = 0.04); and ADAR Ex9 + 14A (adjusted odds ratio, 1.67; P = 0.03). For the TYK2-2256A promoter region variant, a borderline association was present among European American participants (OR, 1.51; P = 0.05) and a strong relationship among, African American patients; all 10 with SVR who were genotyped for TYK2-2256 carried the A variant compared with 68 of 120 (57%) nonresponders (P = 0.006). Conclusion. Genetic polymorphisms in the interferon-alpha pathway may affect responses to antiviral therapy of chronic hepatitis C. (HEPATOLOGY 2009;49:1847-1858.)

引用

页码：1847 / 1858

页数：12

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