Hepatology. 2011 May;53(5):1446-54. doi: 10.1002/hep.24263.
Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.
di Iulio J,
Ciuffi A,
Fitzmaurice K,
Kelleher D,
Rotger M,
Fellay J,
Martinez R,
Pulit S,
Furrer H,
Günthard HF,
Battegay M,
Bernasconi E,
Schmid P,
Hirschel B,
Barnes E,
Klenerman P,
Telenti A,
Rauch A;
Swiss HIV Cohort Study.
Battegay M, Bernasconi E, Boni J, Bucher HC, Burgisser P, Calmy A, Cattacin S, Cavassini M, Dubs R, Egger M, Elzi L, Fischer M, Flepp M, Fontana A, Francioli P, Furrer H, Fux C, Gorgievski M, Gu H, Hirsch H, Hirschel B, Ho I, Kahlert C, Kaiser L, Karrer U, Kind C, Klimkait T, Ledergerber B, Martinetti G, Martinez B, Mu N, Nadal D, Opravil M, Paccaud F, Pantaleo G, Rauch A, Regenass S, Rickenbach M, Rudin C, Schmid P, Schultze D, Schupbach J, Speck R, Taffe P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S.
Source
Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
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.
Copyright © 2011 American Association for the Study of Liver Diseases.
- PMID:
- 21360716
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3128709
Free PMC ArticleFig. 2
Primer pair optimization for the pre-amplification step. Because discordant results were obtained by genotyping and resequencing, several primer combinations were tested for the pre-amplification step preceding the genotyping. The arrows show the different PCR products amplified for the pre-amplification step. Arrows with dashed lines indicate discordant results for a given SNP (heterozygous by resequencing and homozygous by the TaqMan assay), whereas arrows with solid lines indicate concordant results for a given SNP (heterozygous by both resequencing and TaqMan assay). A primer combination containing a forward primer located upstream of position g.-520G yielded discordant results in up to 19.5% of the individuals (for rs8103142). The red triangles show the location of the four genotyped SNPs.
Hepatology. Hepatology;53(5):1446-1454.
Fig. 4
Linkage disequilibrium plot for the multiple-source cohort. The linkage disequilibrium between the four candidate causal SNPs (rs4803219, rs28416813, rs8103142, and rs4803217) and the two previously identified tagging SNPs is shown.
Hepatology. Hepatology;53(5):1446-1454.
Fig. 1
IL-28B genotyping and haplotype inference. (A) Two tagging SNPs (rs8099917 and rs12979860) and four candidate causal SNPs in IL-28B were genotyped in all study participants. Boxes 1 to 5 denote exons. (B) Haplotype inference identified 12 distinct haplotypes divided into two main families (types I and II). Arrowheads indicate the presence of the minor allele.
Hepatology. Hepatology;53(5):1446-1454.
Fig. 3
CNVs at the IL-28B locus. (A,B) CNV data from the 1000 Genomes Project (pilots 1 and 2) for 1 Mb upstream and downstream of the IL-28B locus (black, vertical lines) in chromosome 19. The y axis and the horizontal color lines represent individual observations of possible CNVs (orange, not yet confirmed; red, refuted/invalidated; green, confirmed/validated). (C,D) Close-ups of the locus. The gray, vertical lines indicate the chromosomal locations of IL-28B, IL-28A, and IL-29.
Hepatology. Hepatology;53(5):1446-1454.
Fig. 5
IL-28B haplotypes and spontaneous HCV clearance in the multiple- and single-source cohorts. The odds ratios were adjusted for IL-28B haplotypes, sex, and coinfection with hepatitis B. Abbreviation: HBsAg, hepatitis B surface antigen.
Hepatology. Hepatology;53(5):1446-1454.
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