PPARγ Variant Influences Angiographic Outcome and 10-Year Cardiovascular Risk in Male Symptomatic Coronary Artery Disease Patients
- Jakub J. Regieli, MD1,2,
- J. Wouter Jukema, MD3,4,5,
- Pieter A. Doevendans, MD2,
- Aeilko H. Zwinderman, PHD6,
- Yolanda van der Graaf, MD1,
- John J. Kastelein, MD7 and
- Diederick E. Grobbee, MD1
- 1Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands;
- 2Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands;
- 3Department of Cardiology and Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands;
- 4Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands;
- 5Durrer Institute for Cardiogenetic Research, Amsterdam, the Netherlands;
- 6Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, the Netherlands;
- 7Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
- Corresponding author: Diederick E. Grobbee, d.e.grobbee{at}umcutrecht.nl
Abstract
OBJECTIVE Activation of peroxisome proliferator–activated receptor (PPAR)-γ signaling influences metabolic profiles and the propensity toward inflammation. Small-molecule stimulation of PPARγ is investigated for secondary prevention of cardiovascular disease. The common PPARγ Pro12Ala variant has functional and prognostic consequences. A protective effect of the 12Ala-allele carriership on diabetes and myocardial infarction in healthy populations has been suggested. The relevance of this pathway also needs exploration in patients with manifest vascular disease. We investigated the effects of carriership of the Pro12Ala variant on angiographic and cardiovascular event outcomes in male patients with symptomatic coronary artery disease (CAD).
RESEARCH DESIGN AND METHODS The Regression Growth Evaluation Statin Study (REGRESS) cohort was genotyped for the Pro12Ala variant (rs1801282). Ten-year follow-up was derived from nation-wide registries, and risks were estimated using proportional hazards. Quantitative coronary angiography measurements were obtained and relations with genotype estimated using a generalized linear model.
RESULTS Genotypes ascertained (n = 679) comprised 540 (80%) Pro/Pro, 126 (19%) Pro/Ala, and 13 (2%) Ala/Ala subjects. The 12Ala allele was associated with less extensive focal (P = 0.001) and diffuse (P = 0.002) atherosclerosis and lower 10-year cardiovascular risk. Hazard ratios were 0.10 (95% CI 0.01–0.70, P = 0.02) for ischemic heart disease and 0.24 (0.08–0.74, P = 0.013) for vascular death, per each added copy of 12Ala, respectively.
CONCLUSIONS Carriers of the 12Ala allele of PPARγ have less widespread CAD and are considerably protected against 10-year (cardio)vascular morbidity and mortality. These long-term findings in patients with manifest CAD support an important role of PPARγ in determining vascular risk.
Footnotes
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- Received October 5, 2008.
- Accepted February 7, 2009.
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- © 2009 by the American Diabetes Association.
