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

作者：Jones Chris I; Bray Sarah; Garner Stephen F; Stephens Jonathan; de Bono Bernard; Angenent Will G J; Bentley David; Burns Philippa; Coffey Alison; Deloukas Panos; Earthrowl Mark; Farndale Richard W; Hoylaerts Marc F; Koch Kerstin; Rankin Angela; Rice Catherine M; Rogers Jane; Samani Nilesh J; Steward Michael; Walker Adam; Watkins Nicholas A; Akkerman Jan Willem; Dudbridge Frank; Goodall Alison H^*; Ouwehand Willem H

来源：Blood, 2009, 114(7): 1405-1416.

DOI：10.1182/blood-2009-02-202614

Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3' untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca(2+) levels after activation with ADP(P < .004). These data provide novel insights into key hubs within platelet signaling networks. (Blood.2009;114:1405-1416)

• 出版日期2009-8-13