Abstract 17828: Genome-wide Association Study Identifies Two Loci Associated with Platelet Distribution Width in Healthy Adults
Platelet distribution width (PDW) is a measure of heterogeneity in circulating platelet volume and reflects platelet turnover or activation. We have previously found that higher PDW is associated with increased risk of all-cause and cardiovascular (CV) mortality. PDW has an estimated heritability of 40%. Identifying genes associated with PDW may provide clues regarding platelet-related causes of CV disease. Here we report the first genome-wide association study (GWAS) of PDW. PDW was measured using a Coulter Counter in healthy individuals (European Americans = 607, African Americans = 534) with a family history of premature coronary artery disease. Genotyping was conducted with Illumina 1M arrays. For each race, age and sex adjusted additive linear mixed models were used to test for association between each SNP and PDW. Results from both races were pooled using inverse-variance-weighted meta-analysis. Two loci were significantly (P < 5 x 10-8) associated with PDW. The lead SNP in the 20q13.32 region, rs34524896, was in the TUBB1 gene. This locus has been previously associated with platelet count, and the TUBB1 transcript is found in large quantities in megakaryocytes and platelets. Beta-tubulin, the product of the TUBB1 gene, is important in normal platelet function and is essential for maintaining the discoid shape of platelets. A rare functional mutation, Q43P, in this gene is associated with abnormal platelet morphology, abnormal agonist-mediated platelet aggregation, and decreased risk of acute coronary syndromes. The other significant SNP, rs7359230 located in the 15q26.1 region, is intergenic (Table); the mechanism through which this region may affect PDW is unknown. In this first GWAS of PDW, we have identified two loci, one of which is located in the TUBB1 gene. Our findings further highlight the importance of TUBB1 in platelet biology and suggest a possible connection between PDW and CV mortality through beta-tubulin mediated effects on platelet function.
- © 2012 by American Heart Association, Inc.