A Genome-wide Association Study Identifies Three Loci Associated with Mean Platelet Volume
A Genome-wide Association Study Identifies Three Loci Associated with Mean Platelet Volume
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DOI：
10.1016/j.ajhg.2008.11.015
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发表时间：
2009-01-09
影响因子：
9.8
通讯作者：
Doering, Angela
中科院分区：
文献类型：
--
作者：
Meisinger, Christa;Prokisch, Holger;Doering, Angela
平均血小板体积（MPV）在心肌梗死和脑梗死中增加，是事件后发病率和死亡率的独立和强有力的预测因子。我们进行了一项全基因组关联研究（GWAS），KORA（Kooperative Gesundheitsforschung in der Region Augsburg）F3 500 K研究，发现MPV与三种常见的单核苷酸多态性（SNP）密切相关：rs7961894位于染色体12q24.31上WDR 66的内含子3内，rs 12485738位于染色体3 p13-p21上ARHGEF 3的上游，rs 2138852位于染色体17q11.2上TAOK 1的上游。我们在来自英国的另一个GWAS和来自德国的两个基于人群的样本中复制了所有三个SNP。在包括10，048名受试者的联合分析中，SNP的rs7961894 p值为7.24 x 10（-48），rs 12485738为3.81 X 10（-27），rs 2138852为7.19 x 10（-28）。这3个数量性状基因座共解释MPV变异的4%~ 5%。对来自极端人群的382个样本中WDR 66的深入序列分析揭示了20个新的变异体和一个单倍型，该单倍型具有三个编码SNP和一个位于与MPV相关的转录起始位点的SNP（p = 6.8 x 10（-5））。此外，表达分析表明WDR 66转录本与MPV直接相关。这些发现不仅可以增强我们对血小板活化和功能的理解，而且还可以为几种新的研究途径提供焦点。
Mean platelet volume (MPV) is increased in myocardial and cerebral infarction and is an independent and strong predictor for postevent morbidity and mortality. We conducted a genome-wide association study (GWAS), the KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K study, and found MPV to be strongly associated with three common single-nucleotide polymorphisms (SNPs): rs7961894 located within intron 3 of WDR66 on chromosome 12q24.31, rs12485738 upstream of the ARHGEF3 on chromosome 3p13-p21, and rs2138852 located upstream of TAOK1 on chromosome 17q11.2. We replicated all three SNPs in another GWAS from the UK and in two population-based samples from Germany. In a combined analysis including 10,048 subjects, the SNPs had p values of 7.24 x 10(-48) for rs7961894, 3.81 X 10(-27) for rs12485738, and 7.19 x 10(-28) for rs2138852. These three quantitative trait loci together accounted for 4%-5% of the variance in MPV. In-depth sequence analysis of WDR66 in 382 samples from the extremes revealed 20 new variants and a haplotype with three coding SNPs and one SNP at the transcription start site associated with MPV (p = 6.8 x 10(-5)). In addition, expression analysis indicated a direct correlation of WDR66 transcripts and MPV. These findings may not only enhance our understanding of platelet activation and function, but may also provide a focus for several novel research avenues.