Genome-Wide Association Study of Spontaneous Resolution of Hepatitis C Virus Infection: Data From Multiple Cohorts

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Duggal, Priya | Thio, Chloe | Wojcik, Genevieve | Goedert, James | Mangia, Alessandra | Latanich, Rachel | Kim, Arthur | Lauer, Georg | Chung, Raymond | Peters, Marion | Kirk, Gregory | Mehta, Shruti | Cox, Andrea | Khakoo, Salim | Alric, Laurent | Cramp, Matthew | Donfield, Sharyne | Edlin, Brian | Tobler, Leslie | Busch, Michael | Alexander, Graeme | Rosen, Hugo | Gao, Xiaojiang | Abdel-Hamid, Mohamed | Apps, Richard | Carrington, Mary | Thomas, David

Edité par CCSD ; American College of Physicians -

International audience. BackgroundHepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood.ObjectiveTo evaluate the host genetic basis for spontaneous resolution of HCV infection.DesignTwo-stage genome wide association study (GWAS).Setting13 international multicenter study sites.Patients919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence).MeasurementsFrequencies of 792,721 SNPs.ResultsDifferences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015).LimitationsEpigenetic effects were not studied.ConclusionsIL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.

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