ImportanceFamilial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.ObjectiveTo assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.Design, Setting, and ParticipantsA total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.ExposuresLDL-C, cumulative past LDL-C, FH variant status.Main Outcomes and MeasuresCox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.ResultsOf the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.Conclusions and RelevanceIn this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

中文翻译：

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家族性高胆固醇血症变异和胆固醇升高个体的心血管风险

重要性家族性高胆固醇血症 (FH) 是一种遗传性疾病，通常会导致严重高低密度脂蛋白胆固醇 (LDL-C) 和过早冠心病 (CHD) 的高风险。然而，FH 变异对 LDL-C 中度升高的个体中 CHD 风险的影响尚未得到很好的量化。 目的 评估中度（130-189 mg/dL）和重度（≥190 mg/dL）个体中 FH 变异相关的 CHD 风险。 dL) LDL-C 升高，并量化美国成年人中因 FH 变异导致的过多 CHD 死亡。设计、环境和参与者来自 6 项美国队列研究（社区动脉粥样硬化风险研究、冠状动脉风险发展）的总共 21 426 名先前未患有 CHD 的个体包括青年人研究、心血管健康研究、弗雷明汉心脏研究后代队列、杰克逊心脏研究和动脉粥样硬化多种族研究），其中 63 人患有 FH 变异。数据收集时间为 1971 年至 2018 年，中位随访时间 (IQR) 为 18 (13-28) 年。数据分析时间为 2023 年 3 月至 5 月。暴露 LDL-C、过去累积的 LDL-C、FH 变异状态。主要结果和测量 Cox 比例风险模型估计 FH 变异与突发 CHD 之间的关联。心血管疾病政策模型预测美国成年人中与 FH 变异相关的过多 CHD 死亡。结果在 21 426 名先前没有 CHD 的个体（平均 [SD] 年龄 52.1 [15.5] 岁；12 041 [56.2%] 女性）中，FH 变异为在 22 名 LDL-C 中度升高的个体 (0.3%) 和 33 名 LDL-C 严重升高的个体 (2.5%) 中发现。在LDL-C中度和严重升高的个体中，与有和没有FH变异的患者相比，发生CHD的调整后风险比分别为2.9（95% CI，1.4-6.0）和2.6（95% CI，1.4-4.9）。当进一步调整基线 LDL-C 水平时，FH 变异与 CHD 之间的关联略有减弱，而在调整过去累积的 LDL-C 暴露后，这种关联不再具有统计学意义。在没有 CHD 病史且 LDL-C 为 130 mg/dL 或更高的 20 岁及以上美国成年人中，超过 417 000 人携带 FH 变异，预计 LDL-C 中度升高的人群中将有超过 12 000 人因 CHD 死亡。与没有 FH 变异的个体相比，LDL-C 严重升高的患者的 C 和 15 000。结论和相关性在这项汇总队列研究中，FH 变异的存在与 2 倍高的 CHD 风险相关，即使 LDL-C仅适度升高。CHD 风险增加的主要原因似乎是，与没有 FH 变异的个体相比，FH 变异个体的累积 LDL-C 暴露量更高。需要进一步的研究来评估在传统表型 FH 筛查中添加基因检测的价值。