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自发性冠状动脉夹层易感性基因座的鉴定。

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection.

机构信息

Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota.

Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

出版信息

JAMA Cardiol. 2020 Aug 1;5(8):929-938. doi: 10.1001/jamacardio.2020.0872.

Abstract

IMPORTANCE

Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.

OBJECTIVE

To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility.

DESIGN, SETTING, AND PARTICIPANTS: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019.

MAIN OUTCOMES AND MEASURES

Genetic loci and positional candidate genes associated with SCAD.

RESULTS

This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1).

CONCLUSIONS AND RELEVANCE

This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.

摘要

重要性

自发性冠状动脉夹层(SCAD)是一种特发性疾病,主要影响年轻至中年女性,已成为急性冠状动脉综合征、心肌梗死和心脏性猝死的重要原因。

目的

确定与 SCAD 易感性相关的常见单核苷酸变异(SNV)。

设计、地点和参与者:本中心全基因组关联研究分析了大约 500 万个经基因分型和推断的 SNV 以及随后在 2011 年 8 月 30 日至 2018 年 8 月 2 日期间纳入 Mayo 诊所 SCAD 登记处的个体中进行的 SNV 靶向复制分析结果。数据分析于 2017 年 6 月 21 日至 2019 年 12 月 30 日进行。

主要结果和措施

与 SCAD 相关的遗传基因座和位置候选基因。

结果

这项研究包括 484 名患有 SCAD 的白人女性(平均年龄[标准差],46.6[9.2]岁)和 1477 名白人女性对照(平均年龄[标准差],64.0[14.5]岁),以及 183 名患有 SCAD 的白人女性(平均年龄[标准差],47.1[9.9]岁)和 340 名白人女性对照(平均年龄[标准差],51.0[15.3]岁)。与 SCAD 风险相关的关联在 3 个基因座达到全基因组显著水平(1q21.3[OR,1.78;95%CI,1.51-2.09;P=2.63×10-12],6p24.1[OR,1.77;95%CI,1.51-2.09;P=7.09×10-12],和 12q13.3[OR,1.67;95%CI,1.42-1.97;P=3.62×10-10]),7 个基因座具有关联的证据(1q24.2[OR,2.10;95%CI,1.58-2.79;P=2.88×10-7],3q22.3[OR,1.47;95%CI,1.26-1.71;P=6.65×10-7],4q34.3[OR,1.84;95%CI,1.44-2.35;P=9.80×10-7],8q24.3[OR,2.57;95%CI,1.76-3.75;P=9.65×10-7],15q21.1[OR,1.75;95%CI,1.40-2.18;P=7.23×10-7],16q24.1[OR,1.91;95%CI,1.49-2.44;P=2.56×10-7],和 21q22.11[OR,2.11;95%CI,1.59-2.82;P=3.12×10-7]),在调整了前 5 个主要成分后。在复制队列中验证了 10 个风险等位基因中的 5 个。在发现队列和复制队列的荟萃分析中,发现 5 个 SNV 的关联具有统计学意义,且效应大小较大(1q21.3[OR,1.77;95%CI,1.54-2.03;P=3.26×10-16],6p24.1[OR,1.71;95%CI,1.49-1.97;P=4.59×10-14],12q13.3[OR,1.69;95%CI,1.47-1.94;P=1.42×10-13],15q21.1[OR,1.79;95%CI,1.48-2.17;P=2.12×10-9],和 21q22.11[OR,2.18;95%CI,1.70-2.81;P=1.09×10-9])。每个索引 SNV 位于或靠近动脉组织中高度表达的基因内,并且之前与 SCAD(PHACTR1)和/或其他血管疾病(LRP1、LINC00310 和 FBN1)相关。

结论和相关性

本研究揭示了与 SCAD 相关的 5 个复制风险基因座和位置候选基因,其中大多数与冠状动脉外动脉疾病相关。此外,3 个 SNV 的替代等位基因先前与动脉粥样硬化性冠状动脉疾病相关,进一步表明冠状动脉粥样硬化与动脉夹层的等位基因易感性。

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