Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston.
JAMA Cardiol. 2022 Jul 1;7(7):715-722. doi: 10.1001/jamacardio.2022.1061.
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis.
To assess the contributions of rare and common genetic variation to risk of HCM in the general population.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.
Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.
Risk of HCM.
The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).
Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.
肥厚型心肌病（HCM）是年轻人心脏性猝死的主要原因。尽管罕见的遗传变异是 HCM 风险的既定因素，但最近常见的遗传变异也与疾病的发病机制有关。
评估罕见和常见遗传变异对普通人群中 HCM 风险的影响。
设计、地点和参与者：本研究对 UK Biobank（2006-2010 年数据）和 Mass General Brigham Biobank（2010-2019 年）进行了队列研究，评估了罕见遗传变异和常见变异（多基因）评分对 HCM 风险的相对和共同贡献。然后，在相关临床危险因素的背景下评估了罕见和常见变异预测因子。数据分析于 2021 年 5 月至 2022 年 2 月进行。
致病性罕见变异、常见变异（多基因）评分和临床危险因素。
HCM 风险。
主要研究人群包括来自 UK Biobank 的 184511 名个体。平均（SD）年龄为 56（8）岁，83690（45%）名参与者为男性，204（0.1%）名参与者患有 HCM。在 HCM 临床基因检测面板中包含的 51 个基因中，14 个核心基因（由美国医学遗传学和基因组学学院[ACMG]指定）中的致病性或可能致病性变异与 HCM 的患病风险增加 55 倍（95%CI，35-83）相关，而其余 37 个非 ACMG 基因中的变异则与 HCM 无显著相关性（OR，1.8；95%CI，0.6-4.0）。ClinVar 致病性或可能致病性 MYBPC3（OR，72；95%CI，39-124）和 MYH7（OR，61；95%CI，26-121）突变与 HCM 密切相关，ALPK3 中的功能丧失变异（OR，13；95%CI，4.4-28）也是如此。多基因评分与 HCM 密切相关（评分每增加一个标准差，OR 为 1.6；95%CI，1.4-1.8），在 Mass General Brigham Biobank 中也得到了一致的结果。遗传因素增强了对 HCM 的临床风险预测：罕见变异携带者状态和多基因评分与临床危险因素（肥胖、高血压、房颤和冠心病）的联合使用，提高了受试者工作特征曲线下面积，从 0.71（95%CI，0.65-0.77）到 0.82（95%CI，0.77-0.87）。
罕见和常见的遗传变异都在普通人群中对 HCM 易感性有很大的贡献，并提高了 HCM 风险预测，超过了临床因素所能达到的预测。
