Elsevier

Atherosclerosis

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

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

https://doi.org/10.1016/j.atherosclerosis.2007.03.007Get rights and content

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.

Introduction

The pathogenesis of atherosclerosis is known to contain an important inflammatory component, involving the recruitment and adhesion of circulating leukocytes to the vascular endothelium [1], [2]. P-selectin (PSEL), a member of the selectin family of adhesion molecules, initiates leukocyte rolling and mediates interactions of leukocytes with the endothelium, platelets with the endothelium, and leukocytes with platelets [3], [4], [5]. Multiple studies provide evidence supporting a key role for PSEL in atherosclerotic lesion formation, thrombosis and arterial wall changes [3], [5], [6], [7], [8], [9], [10], [11]. Leukocyte–endothelium and leukocyte–platelet interactions require the presence of a counter-ligand on the leukocyte surface, P-selectin glycoprotein ligand-1 (PSGL-1) [12], [13], [14]. By acting as the primary ligand for PSEL, PSGL-1 plays a pivotal role in both the inflammatory response and the atherosclerotic process [15], [16], [17], [18].

Several studies have investigated associations between genetic variation in the PSEL and PSGL-1 genes and cardiovascular disease, but results of these studies have been inconsistent [14], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. All of these studies have focused on independent associations with single genetic variants, with only one examining PSEL haplotypes and one examining PSGL-1 haplotypes [14], [23]. The most commonly studied PSEL polymorphism is T715P in relation to CHD, with two studies showing no association with CHD [19], [20], three studies showing a protective effect of the 715P allele against CHD [21], [22], [23], and one study showing the 715P allele to be associated with increased risk of CHD [24]. Each of these was a case-control study comprised of European populations. The most commonly studied genetic variation in the PSGL-1 gene with regards to cardiovascular disease is a VNTR located in the coding region of the gene [14], [25], [26], [27]. Studies investigating the PSGL-1 VNTR have been limited to Spanish and German populations, with results showing this polymorphism to have no association with CHD [14], [25], [26], to be associated with decreased risk of CHD [27], or to be associated with decreased risk of cerebrovascular disease [25]. We have genotyped the large prospective Atherosclerosis Risk in Communities (ARIC) cohort, comprised of both whites and African Americans, for six polymorphisms in the PSEL and PSGL-1 genes and analyzed their association, both independently and as haplotypes, with incident coronary heart disease (CHD) and ischemic stroke.

Section snippets

The ARIC study

Study participants were selected from the ARIC study, a prospective investigation of atherosclerosis and its clinical sequelae involving 15,792 individuals aged 45–64 years at recruitment (1987–1989). Institutional review boards approved the ARIC study, and all participants provided their written informed consent. A detailed description of the ARIC study design and methods, as well as details on quality assurance for ascertainment and classification of CHD and stroke events, have been published

Results

The ARIC cohort was genotyped for six polymorphisms in the PSEL gene and three polymorphisms in the PSGL-1 gene. PSEL V168M and T233I, as well as PSGL-1 P236S, had a very low allele frequency in both whites and African Americans, did not have different frequencies between cases and non-cases, and were observed to be “tagged” by another polymorphism presented in the current study. Therefore, no additional analyses were conducted for these three polymorphisms; the current study presents results

Discussion

In separate analyses of each PSEL polymorphism, we found the 290NN homozygous genotype to be a significant predictor of CHD in whites, but not in African Americans. No significant findings were observed for ischemic stroke in either whites or African Americans. PSEL haplotype analyses in whites resulted in eight common haplotypes that accounted for 99.8% of all haplotypes observed. The NNVP haplotype was associated with increased risk of incident CHD in whites. No significant haplotype findings

Acknowledgements

The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions.

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