Genome-wide meta-analyses identifies 7 loci associated with platelet aggregation in response to agonists

National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 07/2010; 42(7):608-13. DOI: 10.1038/ng.604
Source: PubMed


Platelet function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in this process. We tested association of 2.5 million SNPs with platelet aggregation responses to three agonists (ADP, epinephrine and collagen) in two cohorts of European ancestry (N<or=2,753 in the Framingham Heart Study, N<or=1,238 in the Genetic Study of Atherosclerosis Risk). We identified associations of seven loci with platelet aggregation near or within GP6 (P=4.6x10(-13)), PEAR1 (P=3.4x10(-12)), ADRA2A (P=3.3x10(-11)), PIK3CG (P=3.1x10(-9)), JMJD1C (P=1.6x10(-8)), MRVI1 (P=2.0x10(-8)) and SHH (P=4.5x10(-8)). Six of these loci replicated at P<0.05 in an additional African-American cohort (N<or=840 in the Genetic Study of Atherosclerosis Risk). These results provide insights into platelet aggregation pathways and may suggest new antiplatelet therapeutic targets.

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    • "Nonetheless, an understanding of the responsible genes and underlying mechanisms remains limited to date. In this regard, genome wide association studies (GWAS) have identified loci associated with platelet number, platelet volume and ex vivo platelet aggregation [4,5], but the effect sizes have been quite small. Furthermore, most of the identified loci are not in protein-coding genomic regions. "
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    ABSTRACT: BackgroundHuman blood platelets are essential to maintaining normal hemostasis, and platelet dysfunction often causes bleeding or thrombosis. Estimates of genome-wide platelet RNA expression using microarrays have provided insights to the platelet transcriptome but were limited by the number of known transcripts. The goal of this effort was to deep-sequence RNA from leukocyte-depleted platelets to capture the complex profile of all expressed transcripts.ResultsFrom each of four healthy individuals we generated long RNA (≥40 nucleotides) profiles from total and ribosomal-RNA depleted RNA preparations, as well as short RNA (<40 nucleotides) profiles. Analysis of ~1 billion reads revealed that coding and non-coding platelet transcripts span a very wide dynamic range (≥16 PCR cycles beyond β-actin), a result we validated through qRT-PCR on many dozens of platelet messenger RNAs. Surprisingly, ribosomal-RNA depletion significantly and adversely affected estimates of the relative abundance of transcripts. Of the known protein-coding loci, ~9,500 are present in human platelets. We observed a strong correlation between mRNAs identified by RNA-seq and microarray for well-expressed mRNAs, but RNASeq identified many more transcripts of lower abundance and permitted discovery of novel transcripts.ConclusionsOur analyses revealed diverse classes of non-coding RNAs, including: pervasive antisense transcripts to protein-coding loci; numerous, previously unreported and abundant microRNAs; retrotransposons; and thousands of novel un-annotated long and short intronic transcripts, an intriguing finding considering the anucleate nature of platelets. The data are available through a local mirror of the UCSC genome browser and can be accessed at:
    BMC Genomics 01/2013; 14(1):1. DOI:10.1186/1471-2164-14-1 · 3.99 Impact Factor
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    • "Concludingly, IRAG prevented arterial thrombosis (Antl et al., 2007). Recently, it was reported that IRAG is one of seven proteins which exhibited a polymorphism which was associated with enhanced platelet aggregability known to be a major factor for the incidence of cardiovascular diseases (Johnson et al., 2010). A recent study showed that IRAG might be involved in the activation and attachment of osteoclasts (Yaroslavskiy et al., 2010). "

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