Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct 28;18(1):288.
doi: 10.1186/s12916-020-01762-z.

Genetic architecture of cardiometabolic risks in people living with HIV

Affiliations

Genetic architecture of cardiometabolic risks in people living with HIV

Haoxiang Cheng et al. BMC Med. .

Erratum in

  • Correction to: Genetic architecture of cardiometabolic risks in people living with HIV.
    Cheng H, Sewda A, Marquez-Luna C, White SR, Whitney BM, Williams-Nguyen J, Nance RM, Lee WJ, Kitahata MM, Saag MS, Willig A, Eron JJ, Mathews WC, Hunt PW, Moore RD, Webel A, Mayer KH, Delaney JA, Crane PK, Crane HM, Hao K, Peter I. Cheng H, et al. BMC Med. 2021 May 5;19(1):114. doi: 10.1186/s12916-021-01976-9. BMC Med. 2021. PMID: 33947393 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
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
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
Fig. 3
Gene set enrichment analysis of HIV-specific susceptibility loci. Statistical overrepresentation of HIV-specific variants (GWASHIV p < 0.01, GWASGEN p > 0.05, and no overlap between 99% confidence intervals of the corresponding beta coefficients) from GWASHIV 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
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
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
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

Similar articles

Cited by

References

    1. Global HIV and AIDS statistics - 2018 fact sheet [http://www.unaids.org/en/resources/fact-sheet].
    1. Van Epps P, Kalayjian RC. Human immunodeficiency virus and aging in the era of effective antiretroviral therapy. Infect Dis Clin N Am. 2017;31(4):791–810. - PubMed
    1. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, Kowalska JD, de Wit S, Law M, el Sadr W, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:a:D): a multicohort collaboration. Lancet. 2014;384(9939):241–248. - PubMed
    1. Croxford S, Kitching A, Desai S, Kall M, Edelstein M, Skingsley A, Burns F, Copas A, Brown AE, Sullivan AK, et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort. Lancet Public Health. 2017;2(1):e35–e46. - PubMed
    1. Feinstein MJ, Bahiru E, Achenbach C, Longenecker CT, Hsue P, So-Armah K, Freiberg MS, Lloyd-Jones DM. Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013. Am J Cardiol. 2016;117(2):214–220. - PMC - PubMed

Publication types