Dyslipidemia in HIV-infected Individuals: From Pharmacogenetics to Pharmacogenomics

Philip E Tarr; Margalida Rotger; Amalio Telenti

Disclosures

Pharmacogenomics. 2010;11(4):587-594. 

In This Article

Abstract and Introduction

Abstract

HIV-infected individuals may have accelerated atherogenesis and an increased risk for premature coronary artery disease. Dyslipidemia represents a key pro-atherogenic mechanism. In HIV-infected patients, dyslipidemia is typically attributed to the adverse effects of antiretroviral therapy. Nine recent genome-wide association studies have afforded a comprehensive, unbiased inventory of common SNPs at 36 genetic loci that are reproducibly associated with dyslipidemia in the general population. Genome-wide association study-validated SNPs have now been demonstrated to contribute to dyslipidemia in the setting of HIV infection and antiretroviral therapy. In a Swiss HIV-infected study population, a similar proportion of serum lipid variability was explained by antiretroviral therapy and by genetic background. In the individual patient, both antiretroviral therapy and the cumulative effect of SNPs contribute to the risk of high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol and hypertriglyceridemia. Genetic variants presumably contribute to additional major metabolic complications in HIV-infected individuals, including diabetes mellitus and coronary artery disease. In an effort to explain an increasing proportion of the heritability of complex metabolic traits, ongoing large-scale gene resequencing studies are focusing on the effects of rare SNPs and structural genetic variants.

Introduction

Large observational studies have shown that HIV-infected individuals have accelerated atherogenesis. They are experiencing coronary artery disease (CAD), peripheral vascular disease and stroke events at an earlier age and increased rates than would be expected from the HIV-seronegative, general population.[1–6] The pathogenesis of these 'metabolic' complications in HIV-infected persons is likely to be multifactorial. Important atherogenic mechanisms among HIV-infected individuals may include chronic inflammation and procoagulant changes associated with HIV-related immunosuppression and uncontrolled HIV viremia,[7–9] direct adverse endothelial or procoagulant effects of HIV-infection and certain antiretroviral therapy (ART) agents, most notably certain protease inhibitors,[10–12] an increased incidence of diabetes mellitus,[13,14] and a high prevalence of smoking and drug use, cocaine in particular. A key additional pro-atherogenic mechanism is dyslipidemia, which explained approximately 50% of the increased incidence of myocardial infarction associated with protease inhibitor use in the large Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study.[2,3,15]

The prevalent view is that dyslipidemia in HIV-infected individuals is largely determined by the dyslipidemic effects of ART.[16–18] Long-term cholesterol increases after ART initiation may also partially reflect the expected age-associated increases that occur with normal aging. In addition, the occurrence of dyslipidemia (decreased levels of high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, total cholesterol, and elevated triglyceride levels) is well recorded in HIV-infected persons even prior to antiretroviral treatment, particularly with advanced HIV infection.[19,20] Within months of ART initiation, total and HDL cholesterol typically increase, irrespective of the ART regimen used. This suggests that the hypercholesterolemia observed following ART may in part represent a return of cholesterol levels (that were reduced because of HIV infection) to preinfection levels.[20]

Ever since the introduction of ART in 1995, a heritable component in the pathogenesis of dyslipidema has been suspected, but the precise genetic mechanisms predisposing to dyslipidemia were initially not well understood.[21] The aims of this review are to summarize the published literature on the pharmacogenetics of dyslipidemia in HIV-infected persons, and to highlight the shift from pharmacogenetics to pharmacogenomics that has taken place in the field, following the publication of the human HapMap in 2005[22] and an escalating number of genome-wide association studies (GWAS) of metabolic diseases in the general population.[23,24] We will also outline an approach to studying genetic mechanisms relevant to CAD in HIV-infected individuals. This is a dynamic field in which knowledge regarding additional genetic variants is accumulating rapidly.

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