Estimating the net contribution of interleukin-28B... : Hepatology (original) (raw)

Viral Hepatitis

Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance

di Iulio, Julia1; Ciuffi, Angela1; Fitzmaurice, Karen2; Kelleher, Dermot3; Rotger, Margalida1; Fellay, Jacques1; Martinez, Raquel1; Pulit, Sara4; Furrer, Hansjakob5; Günthard, Huldrych F.6; Battegay, Manuel7; Bernasconi, Enos8; Schmid, Patrick9; Hirschel, Bernard10; Barnes, Eleanor2; Klenerman, Paul2; Telenti, Amalio1; Rauch, Andri5 and the Swiss HIV Cohort Study

1 Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland

2 Oxford National Institute for Health Research Biomedical Research Centre and Nuffield Department of Clinical Medicine, Oxford University, Oxford, United Kingdom

3 Institute of Molecular Medicine, University of Dublin, Dublin, Ireland

4 Brigham and Women's Hospital, Harvard Medical School, Boston, MA

5 University Clinic of Infectious Diseases, University Hospital Bern, University of Bern, Bern, Switzerland

6 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

7 Infectious Diseases and Infection Control Clinic, Department of Medicine, University Hospital Basel, Basel, Switzerland

8 Infectious Diseases Service, Regional Hospital, Lugano, Switzerland

9 Division of Infectious Diseases, Canton Hospital, St. Gallen, Switzerland

10 Division of Infectious Diseases, University Hospital, Geneva, Switzerland

University Clinic of Infectious Diseases, University Hospital Bern, University of Bern, Inselspital PKT2 B, CH-3010 Bern, Switzerland

Address reprint requests to: Institute of Microbiology, University Hospital Center, University of Lausanne, Bugnon 48, 1011 Lausanne, Switzerland

Email:[email protected]

Email:[email protected].

Received 17 December 2010; Accepted 16 February 2011

Potential conflict of interest: Andri Rauch and Jacques Fellay are co-applicants for patents (currently being evaluated) on the original finding of the interleukin-28B association with spontaneous and treatment-induced hepatitis C virus clearance.

The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation (grants 3345CO-100935 and 324700–112655 and Swiss HIV Cohort Study grant 543) and by the Swiss HIV Cohort Study Research Foundation. Genotyping in the Swiss HIV Cohort Study is supported by an unrestricted grant from the Novartis Research Foundation. Paul Klenerman and Karen Fitzmaurice are supported by the Wellcome Trust, the James Martin 21st Century School (Oxford, United Kingdom), and the National Institute for Health Research Biomedical Research Centre (Oxford, United Kingdom). The supporters had no role in the study design, collection, analysis, or interpretation of data.

Julia di Iulio, Amalio Telenti, and Andri Rauch designed the study, established phenotypes, contributed to statistical analyses, and wrote the article. Julia di Iulio, Margalida Rotger, and Angela Ciuffi performed the genotyping, which was supervised by Amalio Telenti. Jacques Fellay and Paul Klenerman contributed to the study design and writing. All other authors contributed to the data and sample collection at the different study centers, and all authors provided a critical review of the article.

The members of the Swiss HIV Cohort Study are M. Battegay, E. Bernasconi, J. Böni, H. C. Bucher, P. Bürgisser, A. Calmy, S. Cattacin, M. Cavassini, R. Dubs, M. Egger, L. Elzi, M. Fischer, M. Flepp, A. Fontana, P. Francioli (president of the Swiss HIV Cohort Study, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland), H. Furrer (chairman of the clinical and laboratory committee), C. Fux, M. Gorgievski, H. Günthard (chairman of the scientific board), H. Hirsch, B. Hirschel, I. Hösli, C. Kahlert, L. Kaiser, U. Karrer, C. Kind, T. Klimkait, B. Ledergerber, G. Martinetti, B. Martinez, N. Müller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach (head of the data center), C. Rudin (chairman of the mother and child substudy), P. Schmid, D. Schultze, J. Schüpbach, R. Speck, P. Taffé, A. Telenti, A. Trkola, P. Vernazza, R. Weber, and S. Yerly.

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Abstract

The identification of associations between interleukin-28B ( IL-28B ) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10−9). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6–3.0] and 3.9 (95% CI = 1.5–10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage ( r 2 = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. Conclusion: We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution. (Hepatology 2011;)