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 D Walston, Tamara B. Harris, Bruce M. Psaty, William Valdar, Yongmei Liu, Mary Cushman, Alex P. Reiner, Russell P. Tracy, Leslie A. Lange

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)2246-2253
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume35
Issue number10
DOIs
StatePublished - Oct 25 2015

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Interleukin-2 Receptors
Genome-Wide Association Study
Cardiovascular Diseases
Single Nucleotide Polymorphism
Chromosomes, Human, Pair 14
Mortality
Health
Atherosclerosis
Heart Failure
Interleukins
Waist Circumference
Lymphocyte Activation
African Americans
C-Reactive Protein
Fibrinogen
Type 2 Diabetes Mellitus
Meta-Analysis
Interleukin-6
Smoking
Myocardial Infarction

Keywords

  • Atherosclerosis
  • Genome-wide association study
  • Heart failure
  • Inflammation
  • Interleukin-2 receptor subunit α

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Plasma levels of soluble interleukin-2 receptor α associations with clinical cardiovascular events and genome-wide association scan. / Durda, Peter; Sabourin, Jeremy; Lange, Ethan M.; Nalls, Mike A.; Mychaleckyj, Josyf C.; Jenny, Nancy Swords; Li, Jin; Walston, Jeremy D; Harris, Tamara B.; Psaty, Bruce M.; Valdar, William; Liu, Yongmei; Cushman, Mary; Reiner, Alex P.; Tracy, Russell P.; Lange, Leslie A.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, No. 10, 25.10.2015, p. 2246-2253.

Research output: Contribution to journalArticle

Durda, P, Sabourin, J, Lange, EM, Nalls, MA, Mychaleckyj, JC, Jenny, NS, Li, J, Walston, JD, Harris, TB, Psaty, BM, Valdar, W, Liu, Y, Cushman, M, Reiner, AP, Tracy, RP & Lange, LA 2015, 'Plasma levels of soluble interleukin-2 receptor α associations with clinical cardiovascular events and genome-wide association scan', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 10, pp. 2246-2253. https://doi.org/10.1161/ATVBAHA.115.305289
Durda, Peter ; Sabourin, Jeremy ; Lange, Ethan M. ; Nalls, Mike A. ; Mychaleckyj, Josyf C. ; Jenny, Nancy Swords ; Li, Jin ; Walston, Jeremy D ; Harris, Tamara B. ; Psaty, Bruce M. ; Valdar, William ; Liu, Yongmei ; Cushman, Mary ; Reiner, Alex P. ; Tracy, Russell P. ; Lange, Leslie A. / Plasma levels of soluble interleukin-2 receptor α associations with clinical cardiovascular events and genome-wide association scan. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2015 ; Vol. 35, No. 10. pp. 2246-2253.
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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 D

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.

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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.

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