Contribution of Genome-Wide Significant Single-Nucleotide Polymorphisms and Antiretroviral Therapy to Dyslipidemia in HIV-Infected Individuals

Abstract

the Swiss HIV Cohort StudyBackground-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 have reliably associated common SNPs to dyslipidemia in the general population. Methods and Results-We validated the contribution of 42 SNPs (33 identified in genome-wide association studies and 9 previously reported SNPs not included in genome-wide association study 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 (nϭ34 565 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 genome-wide association study estimates. SNPs explained up to 7.6% (non-high-density lipoprotein cholesterol), 6.2% (high-density lipoprotein cholesterol), and 6.8% (triglycerides) of lipid variation; ART explained 3.9% (non-high-density lipoprotein cholesterol), 1.5% (high-density lipoprotein cholesterol), and 6.2% (triglycerides). An individual with the most dyslipidemic antiretroviral and genetic background had an Ϸ3-to 5-fold increased risk of sustained dyslipidemia compared with 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. (Circ Cardiovasc Genet. 2009;2:621-628.)Key Words: cardiovascular diseases Ⅲ HIV infection Ⅲ genome-wide analysis Ⅲ genetics Ⅲ hypercholesterolemia H IV-infected individuals may have accelerated atherogenesis 1 , and a major long-term concern is an increased risk of metabolic complications, including myocardial infarction, 2,3 diabetes mellitus, 4,5 stroke, and peripheral vascular disease. 6 A substantial proportion of the myocardial infarction risk in large, observational studies was explained by dyslipidemia. 2,3 The prevalent view is that dyslipidemia in HIV-infected individuals is largely determined by environmental factors such as advanced immunosuppression, uncontrolled HIV viremia, 7,8 and most notably, the dyslipidemic effects of antiretroviral therapy (ART). 9,10 Genetic factors are also likely to be involved. [11][12][13][14][15] However, previous studies Clinical Perspective on p 628investigating common single-nucleotide polymorphisms (SNPs) for their contribution to dyslipidemia in the HIV The aim of this study was to evaluate th...

Differential Subcutaneous Adipose Tissue Gene Expression Patterns in a Randomized Clinical Trial of Efavirenz or Lopinavir-Ritonavir in Antiretroviral-Naive Patients

“…Studies of genetic polymorphisms may help to identify HIVinfected patients under antiretroviral therapy (ART) at higher risk for metabolic complications (12)(13)(14). Moreover, gene expression studies of subcutaneous adipose tissue may help us to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate ART.…”

Pharmacogenetics of the Metabolic Disturbances and Atherosclerosis Associated with Antiretroviral Therapy in HIV-Infected Patients

“…A study with the Swiss cohort assessed the contribution of 43 polymorphisms, 33 of which were identified through genome-wide association studies, to dyslipidemia in 745 HIV-infected patients on HAART. The results indicated that the host genetic variants assessed explained up to 7.6% variation in non HDL-C levels, up to 6.2% variation in HDL-C levels and up to 6.8% variation in TGC levels through the study [41]. These percentages were slightly greater than those resulting from the effect of antiretroviral treatment.…”

Pvuii Genetic Polymorphism of Low Density Lipoprotein Receptorin Human Immunodeficiency Virus Type 1-Infected Patients: Possible Association with Dyslipidemia

“…The complex polygenic trait of dyslipidemia among the HIV-1-infected individuals has been demonstrated by a genome-wide study association (GWSA) that evaluated the contribution of 42 different SNPs and other variables, such as HAART, underlying conditions, sex, age, ethnicity, and HIV-1 disease parameters to dyslipidemia in 745 HIV-infected participants [47]. The results showed that the genetic background alone explained up to 7.6% of lipid variation in HIV-1-infected patients (7.6% non HDL-C, 6.2% HDL-C, and 6.8% TG), and HAART alone explained up to 6.2% of lipid variation (3.9% non HDL-C, 1.5% HDL-C, and 6.2% TG).…”