小柯机器人

英国牛津大学Hugh Watkins研究组在研究中取得进展。他们揭示常见的遗传变异和可改变的危险因素是厚型心肌病（HCM）易感性和表达性的基础。相关论文发表在2021年1月26日出版的《自然-遗传学》杂志上。

他们报告了2,780例病例和47,486个对照的全基因组关联研究，该研究确定了HCM的12个全基因组显著易感基因座。单核苷酸多态性遗传力显示出很强的多基因影响，特别是对于肌节蛋白阴性的HCM（64％的病例； h2g = 0.34±0.02）。

遗传风险评分在一项验证性研究中显示出对HCM几率的重大影响，将最低五分位数的几率减半，将最高五分位数的几率加倍，并且还影响了肌节变异体携带者的表型严重性。孟德尔随机化确定舒张压（DBP）是肌节蛋白阴性HCM的关键可修正危险因素，DBP的标准偏差增加会使HCM危险增加四倍。常见变异和可改变的危险因素在HCM中具有重要作用，他们建议在临床上可行。

据了解，HCM是一种常见的严重遗传性心脏病。肌节基因中罕见的致病变异会引起HCM，但具有无法解释的表型异质性。而且，大多数患者不携带此类变体。

附：英文原文

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

Author: Andrew R. Harper, Anuj Goel, Christopher Grace, Kate L. Thomson, Steffen E. Petersen, Xiao Xu, Adam Waring, Elizabeth Ormondroyd, Christopher M. Kramer, Carolyn Y. Ho, Stefan Neubauer, Rafik Tadros, James S. Ware, Connie R. Bezzina, Martin Farrall, Hugh Watkins

Issue&Volume: 2021-01-25

Abstract: 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.

DOI: 10.1038/s41588-020-00764-0

Source: https://www.nature.com/articles/s41588-020-00764-0

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