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

di Iulio, Julia and Ciuffi, Angela and Fitzmaurice, Karen and Kelleher, Dermot and Rotger, Margalida and Fellay, Jacques and Martinez, Raquel and Pulit, Sara and Furrer, Hansjakob and Günthard, Huldrych F. and Battegay, Manuel and Bernasconi, Enos and Schmid, Patrick and Hirschel, Bernard and Barnes, Eleanor and Klenerman, Paul and Telenti, Amalio and Rauch, Andri and Swiss HIV Cohort Study, . (2011) Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance. Hepatology, Vol. 53, No. 5. pp. 1446-1454.

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Official URL: http://edoc.unibas.ch/dok/A6004770

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Infection Biology (Khanna)
UniBasel Contributors:Battegay, Manuel E.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Saunders
ISSN:0270-9139
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Aug 2013 07:34
Deposited On:16 Aug 2013 07:32

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