A meta-analysis and genome-wide association study of platelet count and mean platelet volume in african americans.
A meta-analysis and genome-wide association study of platelet count and mean platelet volume in african americans.
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DOI：
10.1371/journal.pgen.1002491
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Reiner AP
中科院分区：
文献类型：
--
作者：
Qayyum R;Snively BM;Ziv E;Nalls MA;Liu Y;Tang W;Yanek LR;Lange L;Evans MK;Ganesh S;Austin MA;Lettre G;Becker DM;Zonderman AB;Singleton AB;Harris TB;Mohler ER;Logsdon BA;Kooperberg C;Folsom AR;Wilson JG;Becker LC;Reiner AP
最近在欧洲血统的人中报道了与血小板计数和平均血小板体积（MPV）相关的几种遗传变异。在这项对 7 项招募非裔美国人的全基因组关联研究 (GWAS) 的荟萃分析中，我们的目的是确定与血小板计数和 MPV 相关的新遗传变异。对于所有队列，在调整年龄、性别和人口分层后，使用加性模型进行 GWAS 分析。对于两种血小板表型，使用逆方差加权固定效应模型进行荟萃分析。在 GeneSTAR 队列的参与者中进行了全血血小板聚集测定。十个独立区域的遗传变异与血小板计数相关（N = 16,388），p<5×10−8，其中 5 个在之前的 GWAS 中与血小板计数无关。与血小板计数相关的新遗传变异位于以下区域（最显着的 SNP、最接近的基因和 p 值）：6p22（rs12526480、LRRC16A、p = 9.1×10−9）、7q11（rs13236689、CD36、p = 2.8×10−9）、10q21 （rs7896518，JMJD1C，p = 2.3×10−12），11q13（rs477895，BAD，p = 4.9×10−8）和20q13（rs151361，SLMO2，p = 9.4×10−9）。其中三个基因座（10q21、11q13 和 20q13）在欧洲裔美国人 (N = 14,909) 中复制，一个 (11q13) 在西班牙裔美国人 (N = 3,462) 中复制。对于 MPV (N = 4,531)，3 个区域的遗传变异在 p<5×10−8 时显着，其中两个区域也与血小板计数相关。之前报道的在本研究中也很重要的区域是血小板计数的 6p21、6q23、7q22、12q24 和 19p13 以及 MPV 的 7q22、17q11 和 19p13。 1 个区域中最显着的 SNP 也与全血 (12q24) 中 ADP 诱导的最大血小板聚集相关。因此，通过对纳入非裔美国人的 GWAS 进行荟萃分析，我们发现了 5 个与血小板计数相关的新区域，其中 3 个区域在其他种族群体中得到了复制。此外，我们还发现了一个与血小板聚集相关的区域，可能在动脉粥样硬化血栓形成中发挥潜在作用。个体之间血小板计数和平均血小板体积的大部分差异是可遗传的。我们对来自七个人群的 16,000 多名非裔美国人参与者进行了全基因组关联研究，以确定与血小板计数和平均血小板体积变化相关的遗传变异。我们观察到统计学上显着的证据（p值<5×10−8），10个基因组区域与血小板计数相关，3个与平均血小板体积相关。在显着相关的区域中，我们发现了 5 个以前在其他人群中未报告过的新区域。这 5 个区域中的 3 个也与欧洲裔美国人和西班牙裔美国人的血小板计数有关。所有这些区域都含有已知或可能在确定血小板计数和/或平均血小板体积中发挥作用的基因。我们进一步发现这些区域之一也与激动剂诱导的血小板聚集有关。进一步的研究将确定这些基因组区域在血小板生物学中发挥的确切作用。这项研究和其他研究产生的知识不仅可以帮助我们更好地了解血小板生物学，还可以引导我们发现新的抗血小板药物。
Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10−8 of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10−9), 7q11 (rs13236689, CD36, p = 2.8×10−9), 10q21 (rs7896518, JMJD1C, p = 2.3×10−12), 11q13 (rs477895, BAD, p = 4.9×10−8), and 20q13 (rs151361, SLMO2, p = 9.4×10−9). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10−8, two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis. The majority of the variation in platelet count and mean platelet volume between individuals is heritable. We performed genome-wide association studies in more than 16,000 African American participants from seven population-based cohorts to identify genetic variants that correlate with variation in platelet count and mean platelet volume. We observed statistically significant evidence (p-value<5×10−8) that 10 genomic regions were associated with platelet count and 3 were associated with mean platelet volume. Of the regions that were significantly associated, we found 5 novel regions that were not reported previously in other populations. Three of these 5 regions were also associated with platelet count in European Americans and Hispanic Americans. All these regions contain genes that are either known to have or potentially may have a role in determining platelet count and/or mean platelet volume. We further found that one of these regions was also associated with agonist-induced platelet aggregation. Further studies will determine the exact role played by these genomic regions in platelet biology. The knowledge generated by this and other studies will not only help us better understand platelet biology but can also lead us to the discovery of new anti-platelet drugs.
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影响因子：
4.5
作者：
Casto AM;Feldman MW
通讯作者：
Feldman MW
影响因子：
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通讯作者：
Silverstein, Roy L.
影响因子：
4.5
作者：
Chasman DI;Paré G;Mora S;Hopewell JC;Peloso G;Clarke R;Cupples LA;Hamsten A;Kathiresan S;Mälarstig A;Ordovas JM;Ripatti S;Parker AN;Miletich JP;Ridker PM
通讯作者：
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影响因子：
9.8
作者：
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通讯作者：
Boomsma, Dorret I.
DOI：
10.1375/136905299320565735
发表时间：
1999-12-01
期刊：
Twin research : the official journal of the International Society for Twin Studies
影响因子：
--
作者：
Evans, D M;Frazer, I H;Martin, N G
通讯作者：
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