Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10-5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10-8) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis (TGFB1, ITGB5, CDH13 and RHOA) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights.

译文

冠状动脉疾病 (CAD) 是世界上发病率和死亡率的主要原因。鉴定新的遗传决定因素可能为开发预测,预防和治疗CAD的创新策略提供新的机会。因此,我们使用UK Biobank提供的新数据对cardiogrampusc4d中P <× 10-5的独立遗传变异进行了荟萃分析。在所研究的161个基因变异中,有71个达到了基因组广泛意义 (p  <  5  ×   10-8),包括15个新基因座。这些新基因座包括参与血管生成的多个基因 (TGFB1,ITGB5,CDH13和RHOA) 和TGFB1基因座中的2个独立变体。我们还将SGEF确定为新型CAD基因座之一中的候选基因。根据小鼠研究,SGEF以前被建议作为治疗靶标。CAD的遗传风险评分可预测复发性CAD事件和心血管死亡率。我们还确定了CAD与其他心血管疾病 (包括心力衰竭和房颤) 之间的显着遗传相关性。总之,我们大大增加了令人信服地与CAD相关的基因座的数量,并提供了更多的生物学和临床见解。

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