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African Americans coinfected with HIV and hepatitis C virus ( HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/ HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study ( WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+ AA hazards ratios [( HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+ AC ( HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity ( HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants ( HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/ HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality. [ABSTRACT FROM AUTHOR]

Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 ( CLDN1) could play a role in HCV infection, we conducted a ‘whole gene association study’ among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV ( n = 658) to those in IDUs who had cleared HCV ( n = 199) or remained HCV-uninfected ( n = 68). Analyses were controlled for racial ancestry (African-American or European-American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs −15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00–2.94; P = 0.048] , −7153A (OR, 2.13; 95% CI, 1.25–3.62; P = 0.006) and − 5414C (OR, 1.78; 95% CI, 1.06–3.00; P = 0.03). HCV-uninfected participants less often carried CLDN1 IVS1−2983C (OR, 0.55; 95% CI, 0.31–0.97; P = 0.04), which lies in intron 1. CLDN1 −15312C, −7153A and − 5414C formed a haplotype in both the African-American and European-American participants and a haplotype analysis supported the association of CLDN1 −7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection. [ABSTRACT FROM AUTHOR]