icon-    folder.gif   Conference Reports for NATAP  
  17th CROI
Conference on Retroviruses
and Opportunistic Infections
San Francisco CA
February 16-19, 2010
Back grey_arrow_rt.gif
Association of IL28B Haplotypes with Chronic HCV Infection in HIV/HCV Co-infected Individuals
  Reported by Jules Levin
CROI 2010
Julia di Iulio*1, P-Y Bochud1, M Rotger1, H Furrer2, F Negro3, A Telenti1, A Rauch2, and Swiss HIV and HCV Cohort Studies 1Univ Hosp Lausanne and Univ of Lausanne, Switzerland; 2Univ Hosp Bern and Univ of Bern, Switzerland; and 3Univ Hosp Geneva, Switzerland
Background: In a genome-wide association study involving 347 individuals with spontaneous hepatitis C virus (HCV) clearance and 1015 with chronic hepatitis C, we identified a single nucleotide polymorphism (SNP), rs8099917, in the interferon lambda 3 (IL28B) locus significantly associated with chronic (versus spontaneously cleared) hepatitis C. To map the candidate causal variant or genetic region tagged by the risk allele rs8099917, we re-sequenced the IL28B gene.
Methods: To maximize the likelihood of identifying the causal region, we performed recombinant mapping on DNA from individuals selected for having concordant (homozygous risk allele/chronic infection, homozygous common allele/clearance) and discordant (homozygous risk allele/clearance, homozygous common allele/chronic infection) genotype-phenotype constellations. Fifteen individuals were selected per constellation, except for the rare coupling risk allele/clearance, where only 2 individuals were available for analysis. All individuals were HIV-HCV co-infected except 6 individuals with the common coupling risk allele/chronic infection who were HCV mono-infected. We performed re-sequencing of the promoter region (1491bp), exons and introns (1336bp) and the 3'UTR (1452bp).
Results: Re-sequencing of the IL28B locus identified 21 SNP. Haplotype inference led to the identification of 2 main haplotype families. The first family of haplotypes (Type I) included most individuals (90%) with HCV clearance phenotype who carried the favorable allele. The second family of haplotypes (Type II) carried most of the risk of chronicity: it was harbored by 97% of individuals homozygous for the risk allele and interestingly by 37% of "discordant" individuals that progressed to chronic infection despite absence of the risk allele. Five SNP enriched in Type II haplotypes were identified as candidates for being causal. These included 2 SNP in the promoter region (rs4803219 and rs28416813), an exonic SNP leading to a non-synonymous amino acid substitution (rs8103142), and 2 SNPs in the 3'UTR (rs4803217 and rs581930).
Conclusions: Re-sequencing of the IL28B locus identified distinct haplotypes associated with chronic hepatitis C and several specific SNP as candidates for being causal. This constitutes the first lead to the causal allele and mechanism of action of IL28B for the natural control of HCV infection.