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Estimating the net contribution of interleukin‐28B variation to spontaneous hepatitis C virus clearance
Author(s) -
di Iulio Julia,
Ciuffi Angela,
Fitzmaurice Karen,
Kelleher Dermot,
Rotger Margalida,
Fellay Jacques,
Martinez Raquel,
Pulit Sara,
Furrer Hansjakob,
Günthard Huldrych F.,
Battegay Manuel,
Bernasconi Enos,
Schmid Patrick,
Hirschel Bernard,
Barnes Eleanor,
Klenerman Paul,
Telenti Amalio,
Rauch Andri
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24263
Subject(s) - interleukin 28b , linkage disequilibrium , genotyping , haplotype , single nucleotide polymorphism , biology , genetic variation , genetics , hepatitis c virus , genotype , virus , gene
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. (H EPATOLOGY 2011;)