A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways.
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 function (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.
Jones
Chris I
CI
Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom.
Bray
Sarah
S
Garner
Stephen F
SF
Stephens
Jonathan
J
de Bono
Bernard
B
Angenent
Will G J
WG
Bentley
David
D
Burns
Philippa
P
Coffey
Alison
A
Deloukas
Panos
P
Earthrowl
Mark
M
Farndale
Richard W
RW
Hoylaerts
Marc F
MF
Koch
Kerstin
K
Rankin
Angela
A
Rice
Catherine M
CM
Rogers
Jane
J
Samani
Nilesh J
NJ
Steward
Michael
M
Walker
Adam
A
Watkins
Nicholas A
NA
Akkerman
Jan-Willem
JW
Dudbridge
Frank
F
Goodall
Alison H
AH
Ouwehand
Willem H
WH
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D001792:Blood Platelets / Q000166:cytology / Q000502:physiology*; D015550:Cell Degranulation / Q000235:genetics*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005060:Europe; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D023281:Genomics; D005838:Genotype; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D044465:White People
D020413:3' Untranslated Regions; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019007:P-Selectin; C502809:PEAR1 protein, human; D011956:Receptors, Cell Surface; D000244:Adenosine Diphosphate; D003094:Collagen