Abstract 1068

Background:

We have previously shown that platelet aggregation, an essential component of pathogenesis of acute coronary syndromes, has higher heritability in African Americans than Caucasians. However, a genome-wide association study of native platelet function in African Americans has not been reported.

Methods:

Platelet-rich plasma (PRP) was isolated from blood samples obtained from the discovery (GeneSTAR, N=835) and replication (Platelet Genes and Physiology Study, N=119) cohorts. Optical aggregation was used to measure maximal aggregation in PRP after samples were stimulated with arachidonic acid, collagen, ADP, or epinephrine. Genotyping was conducted with Illumina 1M arrays. For each cohort, age- and sex-adjusted linear mixed models were used to test for association between each SNP and each phenotype under an additive model.

Results:

Of the 117 SNPs that were significant (P< 5 × 10−8) in the discovery sample, 50 SNPs in 4 regions were also significant in the replication sample (Table). Among the replicated SNPs, a previously reported SNP in European Americans, rs12041331, in the PEAR1 gene was associated with ADP- and epinephrine-mediated aggregation. 47 SNPs in the 17q21.31 region, in one LD block, were associated with collagen-mediated aggregation.

Conclusions:

In this first GWAS of native agonist-mediated platelet aggregation in African Americans, we have discovered, and replicated in an independent sample, 4 regions that are associated with platelet aggregation. Several genes in the identified regions are expressed in platelets and further study of these genes may provide novel insights in platelet biology.

Most significant SNPs associated with native platelet aggregation in the discovery and replication cohorts

SNP (MA)Chr:PositionGeneFunctionMAF-GSMAF-PGAPPhenoES, P (GS)ES, P (PGAP)
rs12041331(A) 1:155136338 PEAR1 Intron 38% 32% ADP −9.2, 5.8 × 10−9 −6.5, 0.03 
      Epi −17.9, 8.3 × 10−17 −14.7, 0.001 
rs11202221(G) 10:8592294 BMPR1A intron 8% 9% ADP −12.7, 4.8 × 10−8 −16.4, 2.4 × 10−5 
rs1800547(G) 17:41407682 MAPT intron 6% 7% Col 0.09, 7.8 × 10−10 2.5, 0.03 
rs7216411(C) 17:43443943   5% 6% Col 0.99, 5.4 × 10−17 2.7, 0.03 
SNP (MA)Chr:PositionGeneFunctionMAF-GSMAF-PGAPPhenoES, P (GS)ES, P (PGAP)
rs12041331(A) 1:155136338 PEAR1 Intron 38% 32% ADP −9.2, 5.8 × 10−9 −6.5, 0.03 
      Epi −17.9, 8.3 × 10−17 −14.7, 0.001 
rs11202221(G) 10:8592294 BMPR1A intron 8% 9% ADP −12.7, 4.8 × 10−8 −16.4, 2.4 × 10−5 
rs1800547(G) 17:41407682 MAPT intron 6% 7% Col 0.09, 7.8 × 10−10 2.5, 0.03 
rs7216411(C) 17:43443943   5% 6% Col 0.99, 5.4 × 10−17 2.7, 0.03 

Abbreviations: MA = minor allele; MAF = minor allele frequency; GS = GeneSTAR; PGAP = Platelet Genes and Physiology Study; ES = effect size; P = p-value.

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
acute coronary syndromes, african american, agonists, arachidonic acid, collagen, epinephrine, genome-wide association study, genotype determination, introns, phenobarbital

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2012 by The American Society of Hematology
2012
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