TY - JOUR
T1 - Plasma levels of soluble interleukin-2 receptor α associations with clinical cardiovascular events and genome-wide association scan
AU - Durda, Peter
AU - Sabourin, Jeremy
AU - Lange, Ethan M.
AU - Nalls, Mike A.
AU - Mychaleckyj, Josyf C.
AU - Jenny, Nancy Swords
AU - Li, Jin
AU - Walston, Jeremy
AU - Harris, Tamara B.
AU - Psaty, Bruce M.
AU - Valdar, William
AU - Liu, Yongmei
AU - Cushman, Mary
AU - Reiner, Alex P.
AU - Tracy, Russell P.
AU - Lange, Leslie A.
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/10/25
Y1 - 2015/10/25
N2 - 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 metaanalysis (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 genomewide significance (P5'~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.
AB - 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 metaanalysis (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 genomewide significance (P5'~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.
KW - Atherosclerosis
KW - Genome-wide association study
KW - Heart failure
KW - Inflammation
KW - Interleukin-2 receptor subunit α
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U2 - 10.1161/ATVBAHA.115.305289
DO - 10.1161/ATVBAHA.115.305289
M3 - Article
C2 - 26293465
AN - SCOPUS:84942248263
SN - 1079-5642
VL - 35
SP - 2246
EP - 2253
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 10
ER -