Shah Sonia, Nelson Christopher P, Gaunt Tom R, van der Harst Pim, Barnes Timothy, Braund Peter S, Lawlor Debbie A, Casas Juan-Pablo, Padmanabhan Sandosh, Drenos Fotios, Kivimaki Mika, Talmud Philippa J, Humphries Steve E, Whittaker John, Morris Richard W, Whincup Peter H, Dominiczak Anna, Munroe Patricia B, Johnson Toby, Goodall Alison H, Cambien Francois, Diemert Patrick, Hengstenberg Christian, Ouwehand Willem H, Felix Janine F, Glazer Nicole L, Tomaszewski Maciej, Burton Paul R, Tobin Martin D, van Veldhuisen Dirk J, de Boer Rudolf A, Navis Gerjan, van Gilst Wiek H, Mayosi Bongani M, Thompson John R, Kumari Meena, MacFarlane Peter W, Day Ian N M, Hingorani Aroon D, Samani Nilesh J
Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.
Circ Cardiovasc Genet. 2011 Dec;4(6):626-35. doi: 10.1161/CIRCGENETICS.111.960203. Epub 2011 Sep 30.
Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH.
We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in ≈2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22 × 10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74 × 10(-8)), 15q25.2 (NMB, rs2292462, P=3.23 × 10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26 × 10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes.
These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait.
心电图左心室肥厚（ECG-LVH）在临床上被广泛评估，并在某些情况下提供预后信息。有证据表明ECG-LVH具有显著的遗传性。我们对4种常用的ECG-LVH测量指标进行了大规模的以基因为中心的关联分析。
我们计算了来自3个基于人群队列的10256名个体的索科洛夫-里昂指数、康奈尔乘积、12导联QRS电压总和以及12导联QRS电压乘积，并使用定制的基因芯片（Illumina HumanCVD BeadChip 50K芯片）对他们的DNA进行分型，该芯片在约2100个与心血管相关的基因中包含49094个遗传变异。我们在另外11777名个体中对有前景的关联进行了随访。我们鉴定并重复了4个与ECG-LVH指标相关的基因座：3p22.2（SCN5A，rs6797133，P = 1.22×10⁻⁷）与康奈尔乘积相关，12q13.3（PTGES3，rs2290893，P = 3.74×10⁻⁸）、15q25.2（NMB，rs2292462，P = 3.23×10⁻⁹）和15q26.3（IGF1R，rs4966014，P = 1.26×10⁻⁷）与12导联QRS电压总和相关。在12q13.3、15q25.2和15q26.3基因座携带6个增加性状等位基因的个体与携带0至1个等位基因的个体相比，12导联QRS电压总和处于最高十分位数的比值比为1.60（95%可信区间：1.20至2.29）。12q13.3和15q25.2基因座的主要单核苷酸多态性在单核细胞中显示出显著的表达数量性状位点效应。
这些发现为ECG-LVH的遗传决定因素提供了新的见解。这些发现有助于增进我们对决定这一具有预后重要性性状的机制的理解。
