在人群中对QTc延长的单基因和多基因贡献
Victor Nauffal1,2, Valerie N Morrill2, Sean J Jurgens2,3,4
1Division of Cardiovascular Medicine (V.N.), Brigham and Women's Hospital, Boston, MA.
Circulation
|April 7, 2022
概括
罕见和常见的遗传变异都会显著影响QT间隔的持续时间. 对QT延长的综合遗传评估应包括多基因和单基因风险因素.
科学领域:
- 心血管遗传学
- 人类遗传学
- 药物基因组学
背景情况:
- QT 间隔的持续时间受影响于影响心脏复极化的罕见基因变异和常见多基因变异.
- 目前针对不明原因的QT延长的临床基因测试主要集中在罕见的单一基因变异.
- 大规模的生物存储库可以研究罕见和常见变异对人口QT间隔的综合影响.
研究的目的:
- 研究罕见和常见的基因变异对QT间隔持续时间的共同贡献.
- 评估多基因风险评分 (PRS) 和罕见变异与大群体的QTc之间的关联.
主要方法:
- 在英国生物库的84,630名参与者中进行了全基因组关联研究 (GWAS).
- 使用常见变体创建多基因风险评分 (PRS).
- 在TOPMed计划中识别和分析10个QT相关基因的罕见变异 (26,976名参与者).
主要成果:
- GWAS确定了54个独立的QTc位点 (21个新型,12个复制).
- 有1,110,494种常见变异的PRS与QTc有很强的关联 (ΔQTc/分数PRS=1. 4毫秒).
- 罕见变异携带者表现出更长的QTc (ΔQTc = 10. 9毫秒);23. 7%的QTc> 480毫秒的患者患有罕见变异或高PRS.
结论:
- 人群QTc持续时间受到罕见变异和多基因风险的显著影响.
- 多基因风险对QTc持续时间有很大影响.
- 综合多基因和单基因风险评估对于了解QTc延长至关重要.
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