Peter Durda1, Jeremy Sabourin1, Ethan M Lange1, Mike A Nalls1, Josyf C Mychaleckyj1, Nancy Swords Jenny1, Jin Li1, Jeremy Walston1, Tamara B Harris1, Bruce M Psaty1, William Valdar1, Yongmei Liu1, Mary Cushman1, Alex P Reiner1, Russell P Tracy2, Leslie A Lange1. 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.
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.
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