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||A multi-ancestry sex stratified genome-wide association study of spontaneous clearance of hepatitis C virus.
||Vergara C, Valencia A, Thio CL, Goedert JJ, Mangia A, Piazzolla V, Johnson E, Kral AH, O'Brien TR, Mehta SH, Kirk GD, Kim AY, Lauer GM, Chung RT, Cox AL, Peters MG, Khakoo SI, Alric L, Cramp ME, Donfield SM, Edlin BR, Busch MP, Alexander G, Rosen HR, Murphy EL, Wojcik GL, Taub MA, Thomas DL, Duggal P
||J Infect Dis
||2020 Oct 29
||BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 males, 1520 females) of European, African and Hispanic ancestry. We performed autosomal, and X-chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near ADP-ribosylation factor-like-5B gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have a chronic HCV infection compared to individuals with the T allele (ORMales=0.69,P-valueMales=1.98x10-07) and this was not seen in females. The ARL5B gene encodes an interferon stimulated gene that inhibits immune response to dsRNA viruses. We also identified suggestive associations near Septin6 and Ribosomal Protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared to the A allele (OR= 1.4, P-valueAll individuals=2.46 x 10-06). Septin6 facilitates HCV replication via interaction with the HCV NS5b protein and RPL39 acts as an HCV core interactor. CONCLUSION: These novel gene associations support differential mechanisms of HCV clearance between sexes and provide biologic targets for treatment or vaccine development.