Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor.
JAMA Cardiol. 2022 Oct 1;7(10):1045-1055. doi: 10.1001/jamacardio.2022.2970.
The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD.
To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features.
DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy.
Burden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD.
This study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10-4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10-4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10-3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10-3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD.
In this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.
自发性冠状动脉夹层（SCAD）的新兴遗传基础在某些患者中被定义为部分复杂和单基因的，涉及主要位于血管结缔组织疾病（CTD）相关基因中的变体。这些遗传影响在高危 SCAD 表型中尚未得到明确界定，确定个体的高危亚组可能有助于指导 SCAD 的临床遗传评估。
确定和量化具有高危临床特征的 SCAD 个体中罕见遗传变异的负担。
设计、设置和参与者：对具有高危 SCAD 的个体进行全外显子组测序（WES），随后进行病例对照关联分析和个体变异注释。通过对先前通过测序定义的血管 CTD 和/或 SCAD 以及通过全基因组关联研究（GWAS）和动脉表达定量性状位点的共定位优先的基因进行基于计算机的分析，对遗传变异进行致病性注释。通过将 SCAD 个体的聚集变体与健康匹配对照或基因组聚集数据库（gnomAD）进行比较，对 WES 数据进行无偏基因组关联分析。该研究在一家三级护理中心进行。在加拿大 SCAD 登记处遗传学研究中，选择了具有高危 SCAD 表型的个体，并定义为围产期 SCAD、复发性 SCAD 或有动脉病变家族史的个体中的 SCAD。
高危 SCAD 个体 DNA 测序定义的遗传变异负担。
这项研究共纳入了 336 名参与者（平均[标准差]年龄 53.0[9.5]岁；301 名女性参与者[90%]）。在 17.0%（94 名中的 16 名）具有高危 SCAD 的个体中发现了血管 CTD 基因的变异，与 gnomAD 相比，这些变异是富集的（比值比，2.6；95%置信区间，1.6-4.2；P=7.8×10-4），主要显著信号出现在 COL3A1（比值比，13.4；95%置信区间，4.9-36.2；P=2.8×10-4）和 Loeys-Dietz 综合征基因（比值比，7.9；95%置信区间，2.9-21.2；P=2.0×10-3）中。在高危 SCAD 患者中（94 名中的 6 名）观察到的 GWAS 优先基因中的变异也呈富集状态（比值比，3.6；95%置信区间，1.6-8.2；P=7.4×10-3）。在 COL3A1、TGFBR2 和 ADAMTSL4 基因中，有 4 名个体的变异被注释为可能致病或致病性。全基因组聚集变体检测鉴定了与围产期 SCAD 相关的新关联。
在这项遗传研究中，约 1/5 的高危 SCAD 表型个体携带 SCAD 目前相关基因中的罕见遗传变异。在出现 SCAD 的亚组个体中可能需要进行遗传筛查。
