Specific P-selectin and P-selectin glycoprotein ligand-1 genotypes/haplotypes are associated with risk of incident CHD and ischemic stroke: The Atherosclerosis Risk in Communities (ARIC) study

Volcik, Kelly A.; Ballantyne, Christie M.; Coresh, Josef; Folsom, Aaron R.; Boerwinkle, Eric

doi:10.1016/j.atherosclerosis.2007.03.007

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Volume 195, Issue 1 , Pages e76-e82, November 2007

Specific P-selectin and P-selectin glycoprotein ligand-1 genotypes/haplotypes are associated with risk of incident CHD and ischemic stroke: The Atherosclerosis Risk in Communities (ARIC) study

Kelly A. Volcik
- Human Genetics Center, University of Texas Health Science Center, Houston, TX, United States
- Corresponding author at: Human Genetics Center, University of Texas—Houston Health Science Center, 1200 Herman Pressler Dr., Houston, TX 77030, United States. Tel.: +1 713 500 9800; fax: +1 713 500 0900.
Christie M. Ballantyne
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
Josef Coresh
- Department of Epidemiology, John Hopkins University, Baltimore, MD, United States
Aaron R. Folsom
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, United States
Eric Boerwinkle
- Human Genetics Center, University of Texas Health Science Center, Houston, TX, United States

Received 10 January 2007; received in revised form 15 February 2007; accepted 6 March 2007. published online 11 April 2007.

Abstract

Objective

P-selectin (PSEL) and its ligand, P-selectin glycoprotein ligand-1 (PSGL-1), play key roles in both the inflammatory response and the atherosclerotic process, but there are conflicting results regarding the affect of PSEL and PSGL-1 gene variation on risk for cardiovascular and cerebrovascular disease. We tested the association of four PSEL and two PSGL-1 polymorphisms with incident coronary heart disease (CHD) and ischemic stroke among 13,875 participants in the prospective Atherosclerosis Risk in Communities (ARIC) study. We also tested common haplotypes in the PSEL and PSGL-1 genes to assess associations with incident CHD and ischemic stroke.

Methods and results

Incident ischemic stroke and CHD were identified through annual telephone calls and hospital and death certificate surveillance. Five hundred and twenty-five validated ischemic stroke and 1654 CHD events were identified. Allele frequencies for all PSEL and PSGL-1 polymorphisms were markedly different between whites and African Americans; therefore, all analyses were performed race-specific. Independent analyses showed the PSEL 290NN genotype to be a significant predictor of CHD in whites (HRR 1.30, 95%CI 1.00–1.70, P=0.05). PSGL-1 genotypes carrying the 62I allele were significantly protective for incident CHD (HRR 0.53, 95%CI 0.31–0.92, P=0.02) and ischemic stroke (HRR 0.73, 95%CI 0.55–0.97, P=0.03) in African Americans. Haplotype analyses showed the PSEL NNVP haplotype to be a significant predictor of incident CHD in whites (HRR 2.09, 95%CI 1.23–3.55, P=0.006). No significant haplotype findings were observed in African Americans.

Conclusions

PSEL S290N, in single polymorphism analysis and in the haplotypic background with T715P, was associated with increased risk of incident CHD in whites. The PSGL-1 M62I polymorphism was associated with decreased risk of both incident CHD and stroke in African Americans. These findings illustrate the complex relationship between genetic variation and disease in different racial groups.

Keywords: Cell adhesion molecules, Coronary heart disease, Stroke, P-selectin, PSGL-1