A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function

Abstract

Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genomewide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 ؎ 0.001 log fL; P < 1.08 ؋ 10 ؊24 ) and PLT (per-G effect ؊4.55 ؎ 0.80 10 9 /L; P < 7.19 ؋ 10 ؊8 ) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n ‫؍‬ 35; P ‫؍‬ .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n ‫؍‬ 84; P ‫؍‬ .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis. (Blood. 2009; 113:3831-3837) IntroductionPlatelets are anucleate blood cell fragments that play a key role in maintaining primary hemostasis and in wound healing. Mean platelet volume (MPV) and platelet count (PLT) are tightly regulated and inversely correlated in the healthy population. Increased MPV represents a strong, independent predictor of postevent outcome in coronary disease and myocardial infarction, 1,2 and changes of either parameter outside the normal ranges are routinely used to ascertain and manage a large number of clinical conditions. Studies in rodents, primates, and twins have confirmed that blood cell quantitative traits, such as MPV and PLT, have high heritability levels. [3][4][5] Genome-wide association studies that used dense genotyping in thousands of subjects have greatly improved the resolution of such complex polygenic traits in humans. 6,7 We therefore reasoned that it should be possible to identify novel quantitative trait loci (QTLs) for MPV and PLT by a similar approach. The identification of such loci will provide new insights in the complex cellular processes of megakaryopoiesis and platelet formation. In addition, it may contribute to our understanding of premalignant conditions such as polycythemia vera and particularly essential thrombocytosis (ET), in which somatically acquired mutations in the JAK2 gene explain only a fraction of cases. 8 Megakaryocytes (MKs), the platelet precursor cells, originate from pluripotent hematopoietic stem cells (HSCs) in a stepwise process of fate determination and proliferation controlled by the cytokine thrombopoietin 9 and several extracellular matrix proteins (ECMPs). [10][11][12] After migration of the MK progenitors from the HSC niche to the bone marrow, platelets are formed via the tightly regulated pro...

Complex Biological Profile of Hematologic Markers across Pediatric, Adult, and Geriatric Ages: Establishment of Robust Pediatric and Adult Reference Intervals on the Basis of the Canadian Health Measures Survey

“…However, MPV displayed an inverse correlation with platelet count, showing an increase with age that was most pronounced in early childhood, consistent with previous studies (1,24 ). Moreover, genomewide association studies have found that regulation of platelet count and volume in healthy individuals may occur as a result of highly heritable traits between individuals due to single nucleotide polymorphisms (28 ) in several genes that regulate megakaryopoiesis and proplatelet formation (29 ). Indeed, this genetic variability could explain the dynamic fluctuations in platelets across age groups in Canada, which is a diverse multiethnic population.…”

Common genetic factors for hematological traits in Humans

“…34 Associations at the WDR66 locus As with other hematological traits, GWAS have successfully identified the genetic loci associated with PLT-related traits. 24,27,28,32,34,38,43 The initial GWAS for MPV was conducted in European populations and identified WDR66, ARHGEF3 and TAOK1 as candidate genes responsible for the regulation of PLT. 24 Of these, a variant located in the genetic region of WDR66 showed the most significant association, explaining approximately 2.0% of the inter-individual variance in MPV.…”

Vessel wall BAMBI contributes to hemostasis and thrombus stability

“…[1][2][3][4][5] As part of this effort, we previously identified a panel of platelet membrane proteins that were expressed more highly in MKs and resting endothelial cells (ECs) than in other blood cell lineages, but with hitherto unknown roles in platelet function or thrombus formation. 6 Of the 279 genes identified, 4 (including bone morphogenetic protein and activin membrane-bound inhibitor [BAMBI]) were selected for functional analysis in zebrafish.…”