Genetic architecture of cardiometabolic risks in people living with HIV
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RESEARCH ARTICLE
Open Access
Genetic architecture of cardiometabolic risks in people living with HIV Haoxiang Chang1†, Anshuman Sewda1,2†, Carla Marquez-Luna3, Sierra R. White1, Bridget M. Whitney4, Jessica Williams-Nguyen4, Robin M. Nance1,5, Won Jun Lee1, Mari M. Kitahata5,6, Michael S. Saag7, Amanda Willig7, Joseph J. Eron8, W. Christopher Mathews9, Peter W. Hunt10, Richard D. Moore11,12, Allison Webel13, Kenneth H. Mayer14, Joseph A. Delaney4, Paul K. Crane5, Heidi M. Crane5,6, Ke Hao1† and Inga Peter1*†
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: HIV, Polygenic risk score, Lipoprotein, Triglyceride, Type 2 diabetes, Myocardial infarction, Genomewide association study
* Correspondence: [email protected] † Haoxiang Chang and Anshuman Sewda are first authors equally contributed to this work. † Ke Hao and Inga Peter are senior authors equally contributed to this work. 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States of America Full list of author information is available at the end of the arti
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