Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston.
Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston.
JAMA Netw Open. 2022 Mar 1;5(3):e222687. doi: 10.1001/jamanetworkopen.2022.2687.
Familial hypercholesterolemia variants impair clearance of cholesterol from the circulation and increase risk of coronary artery disease (CAD). The extent to which adherence to a healthy lifestyle is associated with a lower risk of CAD in carriers and noncarriers of variants warrants further study.
To assess the association of the interaction between familial hypercholesterolemia variants and adherence to a healthy lifestyle with risk of CAD.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used 2 independent data sets with gene sequencing and lifestyle data from the UK Biobank: a case-control study of 4896 cases and 5279 controls and a cohort study of 39 920 participants. Participants were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. The case-control study included participants with CAD and controls at enrollment. The cohort study used a convenience sample of individuals with available gene sequencing data. Statistical analysis was performed from April 2, 2019, to January 20, 2022.
Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist and adherence to a healthy lifestyle based on a 4-point scoring system (1 point for each of the following: healthy diet, regular exercise, not smoking, and absence of obesity).
Coronary artery disease, defined as myocardial infarction in the case-control study, and myocardial infarction, ischemic heart disease, or coronary revascularization procedure in the cohort study.
The case-control study included 10 175 participants (6828 men [67.1%]; mean [SD] age, 58.6 [7.2] years), and the cohort study included 39 920 participants (18 802 men [47.1%]; mean [SD] age at the end of follow-up, 66.4 [8.0] years). A variant was identified in 35 of 4896 cases (0.7%) and 12 of 5279 controls (0.2%), corresponding to an odds ratio of 3.0 (95% CI, 1.6-5.9), and a variant was identified in 108 individuals (0.3%) in the cohort study, in which the hazard ratio for CAD was 3.8 (95% CI, 2.5-5.8). However, this risk appeared to vary according to lifestyle categories in both carriers and noncarriers of familial hypercholesterolemia variants, without a significant interaction between carrier status and lifestyle (odds ratio, 1.2 [95% CI, 0.6-2.5]; P = .62). Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41]). The estimated risk of CAD by the age of 75 years varied according to lifestyle, ranging from 10.2% among noncarriers with a favorable lifestyle to 24.0% among noncarriers with an unfavorable lifestyle and ranging from 34.5% among carriers with a favorable lifestyle to 66.2% among carriers with an unfavorable lifestyle.
This study suggests that, among carriers and noncarriers of a familial hypercholesterolemia variant, significant gradients in risk of CAD are noted according to adherence to a healthy lifestyle pattern. Similar to the general population, individuals who carry familial hypercholesterolemia variants are likely to benefit from lifestyle interventions to reduce their risk of CAD.
重要性：家族性高胆固醇血症的变异会影响胆固醇从循环系统中的清除，并增加患冠状动脉疾病（CAD）的风险。携带和不携带变异体的个体，坚持健康生活方式与 CAD 风险降低之间的关联程度，值得进一步研究。
目的：评估家族性高胆固醇血症变异与坚持健康生活方式之间的相互作用与 CAD 风险之间的关联。
设计、地点和参与者：本横断面研究使用了来自英国生物库的 2 个独立数据集，进行了基因测序和生活方式数据的研究：一个是包含 4896 例病例和 5279 例对照的病例对照研究，另一个是包含 39920 例参与者的队列研究。参与者是在 2006 年 3 月 21 日至 2010 年 10 月 1 日期间从英国的 22 个地点招募的。病例对照研究包括在入组时患有 CAD 和对照的参与者。队列研究使用了具有可用基因测序数据的便利样本。统计分析于 2019 年 4 月 2 日至 2022 年 1 月 20 日进行。
暴露：致病性或可能致病性的 DNA 变异由临床实验室遗传学家分类，并根据 4 分制评分系统（健康饮食、规律运动、不吸烟和不存在肥胖症，每项各 1 分）来评估生活方式。
主要结果和措施：CAD，在病例对照研究中定义为心肌梗死，在队列研究中定义为心肌梗死、缺血性心脏病或冠状动脉血运重建术。
结果：病例对照研究纳入了 10175 名参与者（6828 名男性[67.1%]；平均[标准差]年龄为 58.6[7.2]岁），队列研究纳入了 39920 名参与者（18802 名男性[47.1%]；在随访结束时的平均[标准差]年龄为 66.4[8.0]岁）。在 4896 例病例中发现了 35 种变异（0.7%），在 5279 例对照中发现了 12 种变异（0.2%），对应的比值比为 3.0（95%可信区间，1.6-5.9），在队列研究中发现了 108 种变异（0.3%），CAD 的风险比为 3.8（95%可信区间，2.5-5.8）。然而，这种风险似乎根据携带者和非携带者的生活方式类别而有所不同，携带者和非携带者的家族性高胆固醇血症变异体之间没有显著的相互作用，比值比为 1.2（95%可信区间，0.6-2.5）；P=0.62）。在携带者中，与不良生活方式相比，良好的生活方式可使 CAD 的风险降低 86%（风险比，0.14[95%可信区间，0.04-0.41]）。根据生活方式，到 75 岁时 CAD 的估计风险也有所不同，在具有良好生活方式的非携带者中为 10.2%，在具有不良生活方式的非携带者中为 24.0%，在具有良好生活方式的携带者中为 34.5%，在具有不良生活方式的携带者中为 66.2%。
结论和相关性：本研究表明，在携带和不携带家族性高胆固醇血症变异体的个体中，根据坚持健康生活方式的模式，CAD 的风险呈显著梯度变化。与一般人群一样，携带家族性高胆固醇血症变异体的个体可能受益于生活方式干预，以降低其 CAD 的风险。
