ImportanceSpontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases.ObjectiveTo determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls.Design, Setting, and ParticipantsThis genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023.ExposuresPRS for SCAD comprised of 7 single-nucleotide variants.Main Outcomes and MeasuresDisease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS.ResultsA total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10−4; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10−4). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes.Conclusions and RelevanceExtreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

中文翻译：

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自发性冠状动脉夹层家族的多基因风险

重要性 自发性冠状动脉夹层 (SCAD) 是导致急性冠脉综合征的一个鲜为人知的原因，该综合征主要影响女性。迄今为止的证据表明，其遗传结构复杂，而少数病例有家族史。目的确定罕见和常见遗传变异对家族性病例 SCAD 风险的贡献，后者通过多基因风险评分 (PRS) 的比较）与那些患有散发性 SCAD 和健康对照的人。设计、设置和参与者这项遗传关联研究分析了患有 SCAD 的家庭、患有散发性 SCAD 的个体和健康对照。对所有参与者进行了基因分型。参与者是在 2017 年至 2021 年期间招募的。为所有参与者计算了 SCAD 的 PRS。还评估了与结缔组织疾病 (CTD) 相关的基因中是否存在罕见变异。SCAD 患者是通过社交媒体或单一医疗中心招募的。使用了先前发布的老年健康个体的对照数据库。数据分析时间为 2022 年 1 月至 2023 年 10 月。暴露的 SCAD PRS 由 7 个单核苷酸变异组成。主要结果和措施与 PRS 相关的疾病状态（家族性 SCAD、散发性 SCAD 或健康对照）。结果共有 13 个患有 SCAD 的家庭（27包括 173 名散发性 SCAD 个体和 12 名未受影响个体，以及 1127 名健康对照者。共有 188 例 SCAD 患者（94.0%）为女性，其中 27 例家族性 SCAD 患者中 25 例，173 例散发性 SCAD 患者中 163 例；来自 SCAD 家族的 12 名未受影响个体中，6 名 (50%) 为女性；1127 名健康对照者中，672 名（59.6%）为女性。与健康对照相比，成为受影响的家庭成员或患有散发性 SCAD 的几率与 SCAD PRS 显着相关（其中优势比 [OR] 代表 PRS 每增加 1-SD，几率就会增加）（受影响的家庭成员： OR，2.14；95% CI，1.78-2.50；调整后磷= 1.96 × 10−4; 散发性 SCAD：OR，1.63；95% CI，1.37-1.89；调整过的磷= 5.69 × 10−4）。对于未受影响的家庭成员，没有发现这种关联（OR，1.03；95% CI，0.46-1.61；调整后磷= .91) 与对照相比。此外，患有家族性 SCAD 的患者在对照 PRS 分布的前五分位数中所占比例过高（OR，3.70；95% CI，2.93-4.47；调整后磷= .001); 散发性 SCAD 患者也表现出类似的模式（OR，2.51；95% CI，1.98-3.04；调整后磷= .001)。家庭中受影响的个体在 CTD 相关基因中不存在任何罕见的有害变异。结论和相关性常见遗传风险的极端聚集似乎在 SCAD 家族聚集以及散发病例易感性中发挥着重要作用，尽管还需要进一步研究。