Antiretroviral therapy modifies the genetic effect of known type 2 diabetes-associated risk variants in HIV-infected women

OBJECTIVE:: Type 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). METHODS:: The WomenÊ1/4s 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 WomenÊ1/4s 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. RESULTS:: In non-African Americans, heterogeneity across cART regimen was observed for nine of the 14 polymorphisms (phet<0.05). One polymorphism was statistically significantly inversely associated with diabetes mellitus risk among women taking two nucleotide reverse transcriptase inhibitors (NRTIs) + non-nucleotide reverse transcriptase inhibitor (NNRTI). Five polymorphisms were statistically significantly associated with diabetes mellitus among women treated with at least two NRTIs+at least one protease inhibitor and one polymorphism was associated with diabetes mellitus among those treated with at least three NRTIs±NNRTI. The hazard ratio per risk allele for IGF2BP2 rs1470579 was 2.67 (95% confidence interval 1.67-4.31) for women taking cART with at least two NRTIs+at least one protease inhibitor and 2.45 (95% confidence interval 1.08-5.53) in women taking at least three NRTIs±NNRTI (phet=2.50×10). No such associations were observed in the African Americans. CONCLUSIONS:: Genetic susceptibility to diabetes mellitus, based on the variants studied, is substantially elevated among HIV-infected women using cART containing three or more NRTI/protease inhibitor components. A personalized medicine approach to cART selection may be indicated for HIV-infected persons carrying these diabetes mellitus-risk variants.