A novel variant in the platelet endothelial aggregation receptor-1 gene is associated with increased platelet aggregability

Abstract

Objective: Platelet endothelial aggregation receptor-1 (PEAR1) is a recently identified platelet transmembrane protein that becomes activated by platelet contact. We looked for novel genetic variants in PEAR1 and studied their association with agonist-induced native platelet aggregation and with the inhibitory effect of aspirin on platelets.

Methods and results: We genotyped PEAR1 for 10 single nucleotide polymorphisms (SNPs), selected for optimal gene coverage at a density of 4 kb, in 1486 apparently healthy individuals from two generations of families with premature CAD. Subjects had a mean age of 45 years; 62% were white and 38% black. Platelet aggregation to collagen, epinephrine, and ADP was measured in platelet rich plasma, at baseline and after 2 weeks of aspirin (ASA, 81 mg/d), and genotype-phenotype associations were examined separately by ethnicity using multivariable generalized linear models adjusted for covariates. The C allele of SNP rs2768759 [A/C], located in the promoter region of the gene, was common in whites and uncommon in blacks (allele frequency 70.2% versus 17.7%). The C allele was generally associated in both ethnic groups with increased aggregation of native platelets to each agonist. After ASA, the associations were stronger and more consistent and remained significant when post-ASA aggregation was adjusted for baseline aggregation, consistent with a relationship between the C allele and reduced platelet responsiveness to ASA. The PEAR1 SNP explained up to 6.9% of the locus specific genetic variance in blacks and up to 2.5% of the genetic variance in whites after ASA.

Conclusions: PEAR1 appears to play an important role in agonist-induced platelet aggregation and in the response to ASA in both whites and blacks.

Figure 1

PEAR1 SNPs successfully genotyped in whites (A) and African Americans (B) with associated LD blocks. The values provided are d′ estimates from the HapMap database. The SNP of interest, rs2768759, is noted by an arrow.

Figure 2

Prevalence of genotypes for rs2768759 by ethnicity

Figure 3

Map of PEAR1 gene and location of rs2768759 at potential GR-binding site 10 kb upstream from the transcriptional start site. The genetic coordinate of rs2768759 is 155119087. rs2768759 is located between PEAR1 and the next gene upstream, NTRK1.