Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance

JOURNAL OF HEPATOLOGY

卷:63

Article

O'Brien, Thomas R.¹  Pfeiffer, Ruth M.¹  Paquin, Ashley²  Kuhs, Krystle A. Lang¹  Chen, Sabrina³  Bonkovsky, Herbert L.^4,5  Edlin, Brian R.^6,7  Howell, Charles D.⁸  Kirk, Gregory D.⁹  Kuniholm, Mark H.¹⁰  Morgan, Timothy R.¹¹  Strickler, Howard D.¹⁰  Thomas, David L.⁹  Prokunina-Olsson, Ludmila² 

[1] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[2] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[3] Informat Management Serv Inc, Calverton, MD USA

[4] Carolinas HealthCare Syst, Dept Med, Charlotte, NC USA

[5] Carolinas HealthCare Syst, Liver Biliary Pancreat Ctr, Charlotte, NC USA

[6] Natl Dev & Res Inst, New York, NY USA

[7] Weill Cornell Med Coll, New York, NY USA

[8] Howard Univ, Coll Med, Dept Med, Washington, DC USA

[9] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA

[10] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA

[11] VA Long Beach Healthcare Syst, Long Beach, CA USA

关键词: Genetics;    IL28B;    IFNL3;    IFNL4;    Innate immunity;    Interferon lambda;    Treatment;    Viral clearance;   

DOI  :  10.1016/j.jhep.2015.06.035

来源: Elsevier

【 摘 要 】

Background & Aims: Genetic polymorphisms within the interferon lambda (IFN-lambda) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-Delta G/TT (rs368234815) polymorphism, which controls the generation of IFN-lambda 4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. Methods: We compared IFNL4-Delta G/TT and rs4803217 for association with response to pegylated-IFN-alpha/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-Delta G/TT and rs4803217 genotypes by a bootstrap approach. Results: Among European Americans, linkage disequilibrium between IFNL4-Delta G/TT and rs4803217 was strong (r(2) = 0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-Delta G/TT than rs4803217 (p = 0.003); the IFNL4-Delta G:rs48 03217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p = 0.03, comparison to IFNL4-Delta G:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-Delta G/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p = 0.03) and week 20 in HALT-C (p = 0.03), as well as for spontaneous HCV clearance (p = 0.048). Conclusion: IFNL4-Delta G/TT is the primary IFN-lambda region polymorphism for impaired HCV clearance. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

【 授权许可】

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