Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.
Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.
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DOI：
10.1161/atvbaha.115.305289
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Lange LA
中科院分区：
文献类型：
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作者：
Durda P;Sabourin J;Lange EM;Nalls MA;Mychaleckyj JC;Jenny NS;Li J;Walston J;Harris TB;Psaty BM;Valdar W;Liu Y;Cushman M;Reiner AP;Tracy RP;Lange LA
白细胞介素2受体α亚基（IL-2 R α）调节淋巴细胞活化，在动脉粥样硬化中起重要作用。可溶性IL-2 R α与心血管疾病（CVD）之间的关系尚未得到广泛研究，对sIL-2 R α水平的遗传决定因素知之甚少。我们测量了来自心血管健康研究（CHS）的4408名欧洲裔美国人（EA）和766名非洲裔美国人（AA）成人的基线sIL-2 R α水平，并检查了与基线CVD危险因素、亚临床CVD和偶发CVD事件的相关性。我们还对CHS患者（2964例EA和683例AA）的sIL-2 R α进行了全基因组关联研究（GWAS），并在荟萃分析中进一步将CHS EA结果与其他两个EA队列的结果相结合（N=4464例EA）。在年龄、性别和种族校正模型中，sIL-2 R α与当前吸烟、2型糖尿病、高血压、胰岛素、腰围、C-反应蛋白、白细胞介素-6、纤维蛋白原、颈内动脉壁厚度、全因死亡率、CVD死亡率以及CVD、卒中和心力衰竭事件呈正相关。当校正基线CVD风险因素和亚临床CVD时，EA和AA中全因死亡率、CVD死亡率和心力衰竭的相关性仍然显著。在EA GWAS分析中，我们在染色体10 p15 -14区域观察到52个单核苷酸多态性（SNP），其中包含IL 2 RA，IL 15 RA和RMB 17，达到全基因组显著性（p<5×10-8）。最显著的SNP是rs7911500（p=1.31×10-75）。EA荟萃分析结果与仅CHS结果高度一致。在AA中没有SNPs达到统计学显著性。这些结果支持sIL-2 R α在动脉粥样硬化中的作用，并为染色体10 p15 -14处的多个相关SNP提供了证据。
Interleukin-2 receptor subunit alpha (IL-2Rα) regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels. 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 (GWAS) 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, hypertension, insulin, waist circumference, C-reactive protein, interleukin-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 GWAS analysis, we observed 52 single nucleotide polymorphisms (SNPs) in the chromosome 10p15-14 region, which contains IL2RA, IL15RA and RMB17, that reached genome-wide significance (p<5×10-8). The most significant SNP was rs7911500 (p=1.31×10-75). The EA meta-analysis results were highly consistent with CHS-only results. No SNPs reached statistical significance in the AAs. These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple associated SNPs at chromosome 10p15-14.