1.
Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.
Chen, MH, Yanek, LR, Backman, JD, Eicher, JD, Huffman, JE, Ben-Shlomo, Y, Beswick, AD, Yerges-Armstrong, LM, Shuldiner, AR, O'Connell, JR, et al
Platelets. 2019;(2):164-173
-
-
Free full text
-
Abstract
Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.
2.
Genetic Variants of PEAR1 are Associated with Platelet Function and Antiplatelet Drug Efficacy: A Systematic Review and Meta-Analysis.
Xiang, Q, Zhou, S, Lewis, JP, Shuldiner, AR, Ren, G, Cui, Y
Current pharmaceutical design. 2017;(44):6815-6827
Abstract
BACKGROUND Platelet endothelial aggregation receptor 1 (PEAR1) may affect platelet-platelet contact and aggregation. The aim of this study was to assess the association between PEAR1 polymorphisms and risks of platelet aggregation. METHODS We searched the PubMed, EmBase, and Cochrane Library electronic databases for articles published through November 30th. 2016. Meta-analysis was performed to examine the relationship between PEAR1 and platelet aggregation and sensitivity analysis by removing individual study from meta-analysis. We collected and analyzed the results of 5 trials involving 5466 patients. RESULTS Our results demonstrated that the G allele of rs12041331 was associated with a greater platelet aggregation by multiple agonists, both in the presence and absence of antiplatelet drugs, in several separate cohorts of different ethnicities along with an apparent allelic dose-response effect. However, the results of studies on rs2768759 locus were inconsistent and further studies are required. In the presence or absence of antiplatelet drugs treatment, the lowest platelet aggregation was observed in rs2768759 wild-type (AA) patients, followed by heterozygous (AC) and homozygous mutant (CC). CONCLUSION PEAR1 rs12041331 is associated with platelet function and antiplatelet drug pharmacodynamics. Future studies on relationship between single nucleotide polymorphisms of PEAR1 and incidence of cardiovascular diseases are required.
3.
Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials.
Gao, LG, Cao, J, Mao, QX, Lu, XC, Zhou, XL, Fan, L
Atherosclerosis. 2013;(2):328-34
Abstract
OBJECTIVE Increased platelet activity predicts adverse cardiovascular events. The objective was to assess the effects of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA)-supplementation on platelet aggregation. METHODS AND RESULTS We conducted a meta-analysis of randomized controlled trials identified using PubMed, Embase and the Cochrane Library. Fifteen studies were included. In comparison to placebo using the random-effect model, n-3 PUFA-supplementation significantly reduced adenosine diphosphate-induced platelet aggregation (standard mean difference [SMD] = -1.23 with 95% confidence interval [CI] -2.24 to -0.23, p = 0.02) and platelet aggregation units, determined using the VerifyNow(®) rapid platelet-function assay system (SMD = -6.78 with 95% CI -12.58 to -0.98, p = 0.02). There was a trend toward decreased collagen-induced (SMD = -0.70 with 95% CI -0.72 to 0.33, p = 0.18) and arachidonic acid-induced platelet aggregation (SMD = -0.43 with 95% CI -2.26 to 1.40, p = 0.64) compared with controls; however, statistical significance was not reached. CONCLUSIONS Our meta-analysis demonstrates that n-3 PUFA-supplementation is associated with a significant reduction in platelet aggregation when the participants were at poor health status, but not in healthy persons. High-risk patients with cardiovascular disease and even diabetics may potentially benefit from n-3 PUFAs therapy. However, n-3 PUFAs may not be effective in primary prevention. Larger trials need to be carried out to confirm the present findings.