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

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.

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 10 Pg. 2246-53 (Oct 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 26293465 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Interleukin-2 Receptor alpha Subunit

Topics

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