Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.
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DOI:
10.1038/ng.3874
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发表时间:
2017-07
期刊:
影响因子:
30.8
通讯作者:
Saleheen D
Saleheen D
中科院分区:
生物学1区
文献类型:
--
作者:
Howson JMM;Zhao W;Barnes DR;Ho WK;Young R;Paul DS;Waite LL;Freitag DF;Fauman EB;Salfati EL;Sun BB;Eicher JD;Johnson AD;Sheu WHH;Nielsen SF;Lin WY;Surendran P;Malarstig A;Wilk JB;Tybjærg-Hansen A;Rasmussen KL;Kamstrup PR;Deloukas P;Erdmann J;Kathiresan S;Samani NJ;Schunkert H;Watkins H;CARDIoGRAMplusC4D;Do R;Rader DJ;Johnson JA;Hazen SL;Quyyumi AA;Spertus JA;Pepine CJ;Franceschini N;Justice A;Reiner AP;Buyske S;Hindorff LA;Carty CL;North KE;Kooperberg C;Boerwinkle E;Young K;Graff M;Peters U;Absher D;Hsiung CA;Lee WJ;Taylor KD;Chen YH;Lee IT;Guo X;Chung RH;Hung YJ;Rotter JI;Juang JJ;Quertermous T;Wang TD;Rasheed A;Frossard P;Alam DS;Majumder AAS;Di Angelantonio E;Chowdhury R;EPIC-CVD;Chen YI;Nordestgaard BG;Assimes TL;Danesh J;Butterworth AS;Saleheen D

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冠状动脉疾病(CAD)是全球发病率和死亡率的主要原因。尽管迄今为止已有58个基因组区域与CAD相关,但大多数遗传性尚无法解释,表明其他易感基因座有待鉴定。一个有效的发现策略可能是大规模评估全基因组关联研究(GWAS)提出的有希望的关联。因此,我们使用来自早期GWAS结果的靶向基因阵列对56,309名参与者进行了基因分型,并对先前基因分型的194,427名参与者进行了荟萃分析,共得到88,192例CAD病例和162,544例对照。我们确定了25个新的SNP-CAD关联(P <5x 10 -8,固定效应荟萃分析)来自15个基因组区域,包括细胞粘附、白细胞迁移和动脉粥样硬化相关基因内或附近的SNP(PECAM 1,rs 1867624)、凝血和炎症(PROCR,rs 867186 [p.Ser219Gly])和血管平滑肌细胞分化(LMOD 1,rs 2820315)。这些区域与细胞类型特异性基因表达和血浆蛋白水平的相关性揭示了潜在的新疾病机制。
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD to date, most of the heritability is unexplained, indicating additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and meta-analysed results with 194,427 participants previously genotyped to give a total of 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD-associations (P < 5x10-8, in fixed effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leucocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 [p.Ser219Gly]) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell type-specific gene expression and plasma protein levels shed light on potential novel disease mechanisms.
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