Soluble P-Selectin, SELP Polymorphisms, and Atherosclerotic Risk in European-American and African-African Young Adults

Abstract

Objective-To characterize the genetic and clinical correlates of soluble P-selectin, and the relationship of P-selectin to atherosclerotic risk, in young European-American (EA) and African-American (AA) adults. Methods and Results-We assessed the interrelationships between 25 common SELP polymorphisms, soluble P-selectin, and atherosclerotic risk in 1222 EA and 1072 AA from the longitudinal population-based CARDIA study. Male sex, smoking, blood pressure, and metabolic status were strong cross-sectional correlates of soluble P-selectin among CARDIA subjects aged 33 to 45 years, explaining 13% of the variance. Among EAs, higher soluble P-selectin predicted carotid intima-media thickness (IMT) measured 5 years later, even after accounting for traditional risk factors. Common SELP nucleotide sequence variants explained 11% and 5% of the interindividual variation in soluble P-selectin levels in EAs and AAs, respectively. Four distinct variants contributed to P-selectin phenotype in EAs, including a polymorphism of the 5Ј SELP haplotype block associated with carotid IMT. Half of the phenotypic variation attributable to SELP in EAs could be explained by the Thr715Pro polymorphism, whereas Val599Leu was more strongly associated with soluble P-selectin among AAs. Key Words: P-selectin Ⅲ carotid atherosclerosis Ⅲ haplotype P -selectin (CD62P) is a cell adhesion receptor expressed mainly at the surface of platelets and endothelial cells and plays an important role in the early stages of atherosclerosis. 1 A soluble form of P-selectin lacking the transmembrane domain circulates in plasma. Increased soluble P-selectin levels are associated with various cardiovascular risk factors and occurrence or severity of acute and chronic cardiovascular disorders, primarily among older adults. [1][2][3][4][5][6] In some 7 but not all 8 cohorts of apparently healthy individuals, higher soluble P-selectin levels predicted future clinical cardiovascular events. Cross-sectional studies suggest soluble 9 or platelet 10 P-selectin is significantly correlated with subclinical atherosclerosis, even after accounting for known risk factors. Prospective data on soluble P-selectin as a predictor of early atherosclerotic disease, however, have not been previously reported. Conclusions-CommonThe heritability of circulating P-selectin levels has been estimated between 45% and 70%. 4,5,11 The Thr715Pro polymorphism (rs6136) of the P-selectin gene (SELP) has been associated with lower soluble P-selectin levels, accounting for Ϸ10% to 20% of the variation in healthy EuropeanAmerican (EA) populations. [12][13][14][15][16] Other SELP polymorphisms, including Val599Leu (rs6133), appear to account for some of the residual variance in soluble P-selectin among EAs. 5,12,16 The Thr715Pro polymorphism is rare in people of African descent, 14,15 but little is known about determinants of soluble P-selectin among African-Americans (AA) or allelic heterogeneity of other SELP polymorphisms between population groups.Using data from a large well-characterized populati...

Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease

“…It is also important to note that the SELP SNP associated with increased risk for case status in our study (rs732314) is in strong linkage disequilibrium with rs2235302, a SNP shown to be signifi cantly associated with both soluble P-selectin and carotid intima-media thickness among EuropeanAmericans in CARDIA ( 44 ). Finally, in silico analysis demonstrated a functional prediction (transcription factor binding site) for rs732314 in SELP , suggesting that this SNP is functionally relevant.…”

Soluble P-Selectin Levels Are Associated with Cardiovascular Mortality and Sudden Cardiac Death in Male Dialysis Patients

“…In mouse models of atherosclerosis, P-selectin gene knockout slowed development of atherosclerotic lesions [13,14], and overexpression led to increased plaque burden [15]. In humans, higher soluble P-selectin levels have been associated with greater atherosclerotic plaque burden [16,17] and myocardial infarction [18]. In this study, we detected a marginal association between soluble P-selectin levels and aggregate ASCVD events among males after adjustment for demographics and cardiovascular risk factors, but the association did not persist after the adjustment for other inflammatory markers.…”

An evolutionary history of the selectin gene cluster in humans

“…The derived 640Leu allele, which is common in populations of African descent, has previously been associated with atopy, thrombo-embolic stroke and systemic lupus erythematosus, suggesting that it might affect some properties of SELP, which are relevant to immunologic/inflammatory functions (Bourgain et al, 2003;Zee et al, 2004;Morris et al, 2009). The variant has also been shown to modulate circulating levels of soluble P-selectin in some studies but not in others (Reiner et al, 2008;Barbalic et al, 2010). As for the two subclades within A group haplotypes, all variants separating the two branches are non-coding, suggesting that the selection target might be represented by one or more regulatory variants.…”

“…The circulating amount of P-selectin and ICAM1 is influenced by polymorphisms located at their respective loci, and by variants in ABO (Miller et al, 2004;Reiner et al, 2008;Barbalic et al, 2010).…”