Pro-Inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated by Oxidized Phospholipids and Lipoprotein(a)

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:63

Article

Tsimikas, Sotirios¹  Duff, Gordon W.²  Berger, Peter B.³  Rogus, John⁴  Huttner, Kenneth⁴  Clopton, Paul⁵  Brilakis, Emmanuel⁶  Kornman, Kenneth S.⁴  Witztum, Joseph L.⁷ 

[1] Univ Calif San Diego, Div Cardiovasc Dis, La Jolla, CA 92093 USA

[2] Univ Sheffield, Div Genom Med, Sheffield, S Yorkshire, England

[3] Geisinger Hlth Syst, Dept Cardiol, Danville, PA USA

[4] Interleukin Genet Inc, Waltham, MA USA

[5] Vet Affairs Med Ctr, San Diego, CA 92161 USA

[6] Vet Affairs North Texas Healthcare Syst, Dallas, TX USA

[7] Univ Calif San Diego, Div Endocrinol & Metab, La Jolla, CA 92093 USA

关键词: atherosclerosis;    genetic risk stratification;    haplotype;    IL-1;    inflammation;    lipoprotein(a);    lipoproteins;    oxidation;    oxidized phospholipids;    polymorphism;   

DOI  :  10.1016/j.jacc.2013.12.030

来源: Elsevier

【 摘 要 】

Objectives The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a). Background OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators. Methods IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(-). Results Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age <= 60 years (OR: 7.03; p < 0.001). In IL-1(-) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(-) group in patients age <= 60 years but not in those age >60 years. In IL-1(+) patients age <= 60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006). Conclusions Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events. (C) 2014 by the American College of Cardiology Foundation

【 授权许可】

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