Genetic architecture of cardiometabolic risks in people living with HIV

Abstract

Background: 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. 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.

Methods: We 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.

Results: We 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.

Conclusions: Our 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.

Keywords: Genome-wide association study; HIV; Lipoprotein; Myocardial infarction; Polygenic risk score; Triglyceride; Type 2 diabetes.

Fig. 1

Multi-phenotype, mirrored Manhattan plot of genome-wide association analysis of lipid traits in Willer et al. [31] (top) and the CNICS European American (bottom) cohorts. HDL, high-density lipoproteins, LDL, low-density lipoproteins. In the top panel, gene names are listed for loci with association p < E−5 in both cohorts. In the bottom panel, gene names are listed for loci if p < 0.01 in the CNICS cohort and p > 0.05 in the Willer et al. cohort and there is no overlap between 99% confidence intervals for the corresponding beta coefficients

Fig. 2

Multi-phenotype, mirrored Manhattan plot of genome-wide association analysis of lipid traits in Willer et al. [31] (top) and the CNICS African American (bottom) cohorts. HDL, high-density lipoproteins, LDL, low-density lipoproteins. In the top panel, gene names are listed for loci with association p < E−5 in both cohorts. In the bottom panel, gene names are listed for loci if p < 0.01 in the CNICS cohort and p > 0.05 in the Willer et al. cohort and there is no overlap between 99% confidence intervals for the corresponding beta coefficients

Fig. 3

Gene set enrichment analysis of HIV-specific susceptibility loci. Statistical overrepresentation of HIV-specific variants (GWAS_HIV p < 0.01, GWAS_GEN p > 0.05, and no overlap between 99% confidence intervals of the corresponding beta coefficients) from GWAS_HIV of HDL, LDL, and triglycerides was tested among numerous phenotype terms in the UK Biobank GWAS (version 1) gene set library. The y-axis is the negative log₁₀ of the adjusted p values for each enriched gene set term. The adjusted p values were calculated using the Benjamini-Hochberg method for correction for multiple hypotheses testing

Fig. 4

Heat map of polygenic risk scores in the CNICS HIV cohort (European American and African American sub-cohorts combined). The scores were generated using various p value cutoffs and SNP-level effect estimates from previously published genome-wide association analyses for each trait/disease phenotype and genotyped and imputed data from the CNICS HIV cohort. The associations marked with “▲” are significant at 10% false discovery rate

Fig. 5

Scatter plot comparing mean variance explained (R²) by polygenic risk scores (PRS) for lipid traits in African American and European American people living with HIV. y-axis: multiethnic PRS derived in HIV cohort. x-axis: PRS derived in the general population of European ancestry [31]. a European American PLWH. b African American PLWH. HDL, high-density lipoproteins; LDL, low-density lipoproteins; Trig, triglycerides

Fig. 6

Risk stratification for various polygenic risk score thresholds in European American and African American people living with HIV. OR, odds ratio. PRS-EUR, polygenic risk score derived based on the regression coefficients estimated in a European ancestry population [31]. PRS-Multi, multiethnic PRS. T2D, type 2 diabetes. MI, myocardial infarction. Asterisks denote ORs with false discovery rate-adjusted p < 0.05