An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN

Abstract

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI 858-1700). Because PAR-1 density was stable with time (r 2 76%, P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the 2 1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression , because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn14 A/T intronic variation may therefore be clinically relevant. (Blood.

A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways

“…[2][3][4][5][6][7][8] Interestingly the level of responsiveness within an individual is remarkably consistent over time, regardless of agonist, or function outcome measure. [2][3][4][8][9][10] This, coupled with evidence from studies in siblings, 11 twins, 12 and in families with a history of premature coronary artery disease (CAD), 13 suggests a high level of heritability of platelet response. It is therefore of interest to define the genetic loci that regulate this continuous quantitative trait (QT).…”

“…[2][3][4]10,25,26 The robustness of the observed genetic associations has been limited for many studies by small cohort sizes and, with a few exceptions, by inadequate selection of single nucleotide polymorphisms (tagSNPs) to ascertain underlying sequence variation. 27 So, while the reported associations for C807T (rs1126643) in ITGA2, which encodes the ␣2 integrin, 20 the GP6 haplotype, 25 and the Kozac sequence in GP1BA, 23,28 have been replicated, others have been less reproducible.…”

P2Y 12 H2 Haplotype Is Associated With Peripheral Arterial Disease

“…Genotyping of ␣ IIb ␤ 3 PL A1/A2 and ␣ 2 ␤ 1 807C/T gene polymorphisms were performed as previously described. 10,11 …”

Protease-activated receptors in hemostasis

“…For example, a polymorphism in an intron of the PAR1 gene (f2r) results in a lower density of PAR1 on the platelet surface and decreased aggregation in response to PAR1 agonists. 103 However, in a clinical study with 660 patients who underwent percutaneous coronary intervention, there was no evidence of increased major adverse cardiovascular events or bleeding risk correlated with the polymorphism. 107 The recently described difference in reactivity between PAR4 sequence variants provides the most compelling evidence that single nucleotide polymorphisms can influence a physiological response downstream of PARs.…”

“…[101][102][103][104][105][106] The challenge is establishing a direct link from the identified polymorphisms to receptor expression or function, and ultimately to a physiological output. For example, a polymorphism in an intron of the PAR1 gene (f2r) results in a lower density of PAR1 on the platelet surface and decreased aggregation in response to PAR1 agonists.…”