In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
Abstract:
Platelet aggregation on ruptured or eroded atherosclerotic plaques can initiate arterial thromboses. GWAS have identified common loci associated with platelet aggregation, but cumulatively they account for only a small portion of the variability in platelet aggregation. We used whole genome sequencing (WGS) in 286 healthy subjects from families with early onset coronary artery disease (GeneSTAR Study) to identify additional genes harboring rare/novel functional variants that determine platelet aggregation at baseline and post-aspirin therapy (ASA, 81mg/day for 14 days). Deep ( 〉 30X) WGS was performed on the Illumina Hiseq platform with an average of ~3.7M variants per individual and analyses presented here were limited to coding functional (i.e., missense, stop-gained and stop-lost) variants that were either rare (MAF 〈 5%) or novel (not observed in public catalogs of variation). Using a 2-Step process, we: (1) tested for perfect co-segregation between these variants in each gene and a variety of dichotomized platelet aggregation phenotypes in n=34 subjects from 5 African American (AA) families and n=38 subjects from 7 European American (EA) families; (2) any gene with evidence across multiple families was then replicated in a set of independent samples (n=95 AA, n=119 EA) using Skat-O. To dichotomize phenotypes, ‘hyper-aggregators’ were defined as subjects in the upper 10th percentile while ‘normals’ were those between the 25th-75th percentile for each trait. We identified three novel genes harboring coding functional variants not previously reported to be associated with platelet aggregation in both races: (1) HMG20B, associated with baseline aggregation to ADP; (2) PGA5, associated with baseline aggregation to collagen; and (3) PLAC4, associated with post-ASA aggregation to collagen. HMG20B is involved in megakaryocyte development and platelet production and interacts with KIF4, a microtubule based motor protein, while the role of PGA5 and PLAC4 is less clear. Follow-up studies may identify new platelet biological pathways that can be targeted for clinical purposes.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.132.suppl_3.12566
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1466401-X
