Center for Genomic Medicine (A.V.K., R.L.C., M.E.T., S.K.), Massachusetts General Hospital, Boston.
Division of Cardiology (A.V.K., P.N., S.K.), Massachusetts General Hospital, Boston.
Circulation. 2019 Mar 26;139(13):1593-1602. doi: 10.1161/CIRCULATIONAHA.118.035658.
The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.
We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.
The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3%) carried a high polygenic score, associated with a 3.7-fold (95% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).
Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.
URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.
与家族性高胆固醇血症相关的单基因突变以及与早发心肌梗死相关的高多基因评分（多种常见变异的累积影响）通路的相对流行率和临床重要性仍不确定。全基因组测序可同时确定每个个体的单基因突变和多基因评分。
我们对在美国住院的 4 个种族亚组中年龄≤55 岁的 2081 例早发心肌梗死（急性心肌梗死）患者进行了深度覆盖全基因组测序，采用 2:1 的女性对男性入组设计。我们将这些基因组与 3761 名基于人群的对照进行了比较。我们首先鉴定了与家族性高胆固醇血症相关的罕见单基因突变个体。其次，我们计算了最近开发的 660 万个常见 DNA 变异的多基因评分，以量化常见变异带来的累积易感性。我们将高多基因评分定义为对照组分布的前 5%，因为此前已经证明该截定点与家族性高胆固醇血症突变具有相似的风险。
2081 例早发心肌梗死患者的平均年龄为 48 岁，其中 66%为女性。这些患者中有 36 例（1.7%）存在家族性高胆固醇血症突变，与心肌梗死的风险增加 3.8 倍（95%CI，2.1-6.8；P<0.001）相关。早发心肌梗死患者中有 359 例（17.3%）携带高多基因评分，与风险增加 3.7 倍（95%CI，3.1-4.6；P<0.001）相关。家族性高胆固醇血症突变患者的未治疗低密度脂蛋白胆固醇平均估计值为 206mg/dL，高多基因评分患者为 132mg/dL，其余人群为 122mg/dL。虽然在所有种族群体中都与风险增加相关，但高多基因评分在白人参与者中相关性最强（P 异质性=0.008）。
家族性高胆固醇血症突变和高多基因评分均与早发心肌梗死的风险增加 3 倍以上相关。然而，高多基因评分在早发心肌梗死患者中患病率高 10 倍。
网址：https://www.clinicaltrials.gov 。独特标识符：NCT00597922。
