Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.

Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.
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常见的遗传变异和可改变的危险因素是肥厚型心肌病的易感性和表达性的基础。

DOI:
10.1038/s41588-020-00764-0
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发表时间:
2021-03
期刊:
影响因子:
30.8
通讯作者:
Watkins H
Watkins H
中科院分区:
生物学1区
文献类型:
--
作者:
Harper AR;Goel A;Grace C;Thomson KL;Petersen SE;Xu X;Waring A;Ormondroyd E;Kramer CM;Ho CY;Neubauer S;HCMR Investigators;Tadros R;Ware JS;Bezzina CR;Farrall M;Watkins H

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肥厚型心肌病 (HCM) 是一种常见、严重的遗传性心脏病。肌节基因中罕见的致病性变异会导致 HCM,但具有无法解释的表型异质性。此外,大多数患者不携带此类变异。我们报告了一项针对 2,780 例病例和 47,486 名对照的全基因组关联研究,确定了 12 个全基因组显着的 HCM 易感位点。单核苷酸多态性遗传力表明强烈的多基因影响,特别是对于肌节阴性的 HCM(64% 的病例;h2g = 0.34 ± 0.02)。在一项验证研究中,遗传风险评分显示出对肥厚性心肌病的几率有重大影响,最低五分之一的几率减半,最高五分之一的几率加倍,并且还影响肌节变异携带者的表型严重程度。孟德尔随机化将舒张压 (DBP) 确定为肌节阴性 HCM 的一个关键的可改变危险因素,DBP 每增加一个标准差,HCM 风险就会增加四倍。常见变异和可改变的危险因素在 HCM 中具有重要作用,我们认为这些在临床上是可行的。
Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.
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影响因子: --
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