Meisinger Christa, Prokisch Holger, Gieger Christian, Soranzo Nicole, Mehta Divya, Rosskopf Dieter, Lichtner Peter, Klopp Norman, Stephens Jonathan, Watkins Nicholas A, Deloukas Panos, Greinacher Andreas, Koenig Wolfgang, Nauck Matthias, Rimmbach Christian, Völzke Henry, Peters Annette, Illig Thomas, Ouwehand Willem H, Meitinger Thomas, Wichmann H-Erich, Döring Angela
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Am J Hum Genet. 2009 Jan;84(1):66-71. doi: 10.1016/j.ajhg.2008.11.015. Epub 2008 Dec 24.
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.
平均血小板体积（MPV）在心肌梗死和脑梗死中升高，是事件后发病率和死亡率的独立且强有力的预测指标。我们开展了一项全基因组关联研究（GWAS），即奥格斯堡地区合作健康研究（KORA）F3 500K研究，发现MPV与三个常见单核苷酸多态性（SNP）密切相关：位于12号染色体q24.31上WDR66基因内含子3内的rs7961894、位于3号染色体p13 - p21上ARHGEF3上游的rs12485738，以及位于17号染色体q11.2上TAOK1上游的rs2138852。我们在来自英国的另一项GWAS以及来自德国的两个基于人群的样本中重复验证了这三个SNP。在一项纳入10,048名受试者的联合分析中，rs7961894的p值为7.24×10⁻⁴⁸，rs12485738的p值为3.81×10⁻²⁷，rs2138852的p值为7.19×10⁻²⁸。这三个数量性状位点共同解释了MPV变异的4% - 5%。对382个极端样本中的WDR66进行深入序列分析，发现了20个新变异以及一个单倍型，该单倍型包含三个编码SNP和一个位于转录起始位点的与MPV相关的SNP（p = 6.8×10⁻⁵）。此外，表达分析表明WDR66转录本与MPV直接相关。这些发现不仅可能增进我们对血小板活化和功能的理解，还可能为多个新的研究途径提供重点。
