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ObjectiveType 2 diabetes mellitus incidence is increased in HIV-infected persons. We examined the associations of diabetes mellitus with known diabetes mellitus-risk alleles from the general population in the context of HIV infection, and explored effect modification by combination antiretroviral therapy (cART).MethodsThe Women's Interagency HIV Study is a prospective cohort of HIV-infected women. Seventeen European-derived diabetes mellitus-risk polymorphisms were genotyped in the eligible participants of the Women's Interagency HIV Study. Analyses were run separately for non-African Americans (Whites, Hispanics, Asians, and other; n = 378, 49 with incident diabetes mellitus) and African Americans (n = 591, 49 with incident diabetes mellitus). Cox proportional-hazards models were fit to estimate hazard ratios for diabetes mellitus overall and within strata of cART.ResultsIn non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet

ObjectiveCYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.DesignThe effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.MethodsFive putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n = 91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.ResultsRs3745274 was significantly associated with virologic suppression [odds ratio = 3.61, 95% confidence interval (CI) 1.16-11.22, P trend = 0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend = 0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.ConclusionThe CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.