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Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a).
J Am Coll Cardiol. 2014 May 06; 63(17):1724-34.JACC

Abstract

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.

Authors+Show Affiliations

Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California. Electronic address: stsimikas@ucsd.edu.Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom.Department of Cardiology, Geisinger Health System, Danville, Pennsylvania.Interleukin Genetics, Inc., Waltham, Massachusetts.Interleukin Genetics, Inc., Waltham, Massachusetts.Veterans Affairs Medical Center, San Diego, California.Veterans Affairs North Texas Healthcare System, Dallas, Texas.Interleukin Genetics, Inc., Waltham, Massachusetts.Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24530664

Citation

Tsimikas, Sotirios, et al. "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, vol. 63, no. 17, 2014, pp. 1724-34.
Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol. 2014;63(17):1724-34.
Tsimikas, S., Duff, G. W., Berger, P. B., Rogus, J., Huttner, K., Clopton, P., Brilakis, E., Kornman, K. S., & Witztum, J. L. (2014). 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, 63(17), 1724-34. https://doi.org/10.1016/j.jacc.2013.12.030
Tsimikas S, et al. Pro-inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated By Oxidized Phospholipids and Lipoprotein(a). J Am Coll Cardiol. 2014 May 6;63(17):1724-34. PubMed PMID: 24530664.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2014/02/12/ PY - 2013/08/15/received PY - 2013/12/03/revised PY - 2013/12/04/accepted PY - 2014/2/18/entrez PY - 2014/2/18/pubmed PY - 2014/6/25/medline 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 SP - 1724 EP - 34 JF - Journal of the American College of Cardiology JO - J. Am. Coll. Cardiol. VL - 63 IS - 17 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. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/24530664/Pro_inflammatory_interleukin_1_genotypes_potentiate_the_risk_of_coronary_artery_disease_and_cardiovascular_events_mediated_by_oxidized_phospholipids_and_lipoprotein_a__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(14)00332-5 DB - PRIME DP - Unbound Medicine ER -