TY - JOUR
T1 - Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a)
AU - Tsimikas, Sotirios
AU - Duff, Gordon W.
AU - Berger, Peter B.
AU - Rogus, John
AU - Huttner, Kenneth
AU - Clopton, Paul
AU - Brilakis, Emmanuel
AU - Kornman, Kenneth S.
AU - Witztum, Joseph L.
N1 - Funding Information:
This study was supported by National Institutes of Health grants HL055798 and HL088093 and a grant from Interleukin Genetics Inc. to the Mayo Clinic Foundation. Drs. Tsimikas and Witztum are co-inventors of patents owned by the University of California San Diego, on the clinical use of oxidation-specific antibodies and interleukin genotypes. Dr. Tsimikas has received honoraria for consulting for Isis Pharmaceuticals, Inc., Quest Diagnostics Inc., The Sanofi-Aventis Group, and Genzyme Corporation. Dr. Duff has been a member of the scientific advisory board for, has received honoraria for consulting for, and is a stockholder of, Interleukin Genetics Inc. Drs. Rogus and Huttner are former employees of Interleukin Genetics Inc. Dr. Rogus has received honoraria for consulting for Interleukin Genetics Inc. Dr. Brilakis has received honoraria for serving on the speaker's bureaus of and/or consulting for The Sanofi-Aventis Group, Janssen Pharmaceuticals, Inc, St. Jude Medical, Inc., Terumo Medical Corporation, Asahi Kasei Medical Co., Ltd., Abbott Vascular, and Boston Scientific; has received a research grant from Guerbet LLC ; and is the spouse of an employee of Medtronic, Inc. Dr. Kornman is an officer and shareholder of Interleukin Genetics Inc., which holds patents covering the use of IL-1 genetic variations in multiple diseases. Dr. Witztum has received honoraria for consulting for Isis Pharmaceuticals, Inc., Quest Diagnostics Inc., and Regulus Therapeutics Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Kausik K. Ray, MD, MPhil, served as Guest Editor for this paper.
PY - 2014/5/6
Y1 - 2014/5/6
N2 - 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.
AB - 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.
KW - IL-1
KW - atherosclerosis
KW - genetic risk stratification
KW - haplotype
KW - inflammation
KW - lipoprotein(a)
KW - lipoproteins
KW - oxidation
KW - oxidized phospholipids
KW - polymorphism
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U2 - 10.1016/j.jacc.2013.12.030
DO - 10.1016/j.jacc.2013.12.030
M3 - Article
C2 - 24530664
AN - SCOPUS:84899659288
SN - 0735-1097
VL - 63
SP - 1724
EP - 1734
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 17
ER -