Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan

Peter Durda; Jeremy Sabourin; Ethan M Lange; Mike A Nalls; Josyf C Mychaleckyj; Nancy Swords Jenny; Jin Li; Jeremy Walston; Tamara B Harris; Bruce M Psaty; William Valdar; Yongmei Liu; Mary Cushman; Alex P Reiner; Russell P Tracy; Leslie A Lange

doi:10.1161/ATVBAHA.115.305289

Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan

Arterioscler Thromb Vasc Biol. 2015 Oct;35(10):2246-53. doi: 10.1161/ATVBAHA.115.305289. Epub 2015 Aug 20.

Authors

Affiliations

¹ From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.).
² From the Departments of Pathology (P.D., N.S.J., M.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont College of Medicine, Burlington; Departments of Genetics (J.S., E.M.L., J.L., W.V., L.A.L.), Biostatistics (E.M.L., W.V.), Lineberger Comprehensive Cancer Center, School of Medicine (J.S., E.M.L., W.V.), University of North Carolina, Chapel Hill; Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, National Institute of Health, Bethesda, MD (M.A.N.); Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville (J.C.M.); Johns Hopkins Medical Institutions, Department of Medicine Geriatrics, Johns Hopkins University, John R. Burton Pavilion, Baltimore, MD (J.D.W.); Geriatric Epidemiology Section, National Institute on Aging, National Institute of Health, Bethesda, MD (T.B.H.); Cardiovascular Health Research Unit (B.M.P.), Departments of Medicine (B.M.P.) and Epidemiology (B.M.P., A.P.R.), University of Washington, Seattle; Group Health Research Institute, Division of Cardiology, Group Health Cooperative, Seattle, WA (B.M.P.); and Wake Forest University School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, NC (Y.L.). russell.tracy@med.uvm.edu.

Abstract

Objective: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

Approach and results: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

Conclusions: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

Keywords: atherosclerosis; genome-wide association study; heart failure; inflammation; interleukin-2 receptor subunit α.

Publication types

Comparative Study
Research Support, N.I.H., Extramural

MeSH terms

Adult
Age Distribution
Aged
Black or African American / genetics*
Cardiovascular Diseases / blood
Cardiovascular Diseases / ethnology
Cardiovascular Diseases / genetics
Cohort Studies
Coronary Artery Disease / blood
Coronary Artery Disease / ethnology
Coronary Artery Disease / genetics*
Coronary Artery Disease / mortality*
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Incidence
Interleukin-2 Receptor alpha Subunit / genetics*
Interleukin-2 Receptor alpha Subunit / metabolism
Kaplan-Meier Estimate
Male
Middle Aged
Polymorphism, Single Nucleotide
Proportional Hazards Models
Prospective Studies
Risk Assessment
Sex Distribution
Survival Analysis

Substances

Interleukin-2 Receptor alpha Subunit

Abstract

Publication types

MeSH terms

Substances

Grants and funding