Abstract
BackgroundAdvances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown.MethodsWe screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH.ResultsWe confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI.ConclusionsOur findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.
Highlights
Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV
The final cohort consisted of 6284 PLWH with 3095 PLWHEA and 3189 PLWHAA; both sub-cohorts were predominantly male (89% and 69%, respectively), which is consistent with the HIV epidemic in the USA (Table 1)
PLWHAA had a higher prevalence of type 2 diabetes mellitus (T2D) (p < 0.0001, Table 1), but lower mean Low-density lipoprotein cholesterol (LDL) (p < 0.0001) and triglyceride (p < 0.0001) levels and higher mean High-density lipoprotein cholesterol (HDL) levels (p < 0.0001) than PLWHEA (Table 2)
Summary
Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. The number of people living with human immunodeficiency virus (HIV) infection (PLWH) worldwide has increased by 34.6% (from 27.4 million to 36.9 million) between 2000 and 2018, while acquired immune deficiency syndrome (AIDS)-related deaths have declined from 1.5 million to 940,000 annually [1]. These advances can be primarily attributed to therapeutic advances in antiretroviral therapy (ART) and improved access to ART, allowing PLWH to live longer. The possible causes of increased CVD risk among PLWH include inflammation and immune activation in response to HIV infection and viremia, adverse effects of ART, and lifestyle risk factors (e.g., smoking, alcohol, and illicit drug use). In randomized clinical trials, people with the highest burden of genetic risk demonstrated the most substantial clinical benefit from primary prevention (statin therapy) resulting in a roughly three-fold decrease in the number needed to treat to prevent one CAD event [22]
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