MANUSCRIPT ID: CIRCULATIONAHA/2009/874412 Contribution of genome-wide significant single nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals - a longitudinal study

Background: HIV-infected individuals have an increased risk of myocardial infarction. Antiretroviral therapy (ART) is regarded as a major determinant of dyslipidemia in HIV-infected individuals. Previous genetic studies have been limited by the validity of the single nucleotide polymorphisms (SNPs) interrogated and by cross-sectional design. Recent genome-wide association studies (GWAS) have reliably associated common SNPs to dyslipidemia in the general population. Methods and Results: We validated the contribution of 42 SNPs (33 identified in GWAS and 9 previously reported SNPs not included in GWAS chips) and of longitudinally measured key nongenetic variables (ART, underlying conditions, sex, age, ethnicity and HIV disease parameters) to dyslipidemia in 745 HIV-infected study participants (n=34565 lipid measurements; median follow-up, 7.6 years). The relative impact of SNPs and ART to lipid variation in the study population, and their cumulative influence on sustained dyslipidemia at the level of the individual were calculated. SNPs were associated with lipid changes consistent with GWAS estimates. SNPs explained up to 7.6% (nonHDL cholesterol), 6.2% (HDL cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-HDL cholesterol), 1.5% (HDL cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an approximately 3-5 fold increased risk of sustained dyslipidemia, compared to an individual with the least dyslipidemic therapy and genetic background. Conclusions: In the HIV-infected population treated with ART, the weight of the contribution of common SNPs and ART to dyslipidemia was similar. When selecting an ART regimen, genetic information should be considered in addition to the dyslipidemic effects of ART agents.