Department of Epidemiology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
Nat Commun. 2017 Jun 14;8:15805. doi: 10.1038/ncomms15805.
Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<r<-0.55) and blood pressure (-0.35<r<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
心率变异性（HRV）降低反映出心脏迷走神经控制减弱，与更高的心脏发病率和死亡率风险相关。在对欧洲血统的 53174 个人进行的三个 HRV 特征的两阶段全基因组关联研究的荟萃分析中，我们在八个基因座中检测到了 17 个全基因组显著 SNP。HRV SNP 标记了非同义 SNP（在 NDUFA11 和 KIAA1755 中）、表达数量性状基因座（eQTLs）（影响 GNG11、RGS6 和 NEO1）或位于窦房结中优先表达的基因（GNG11、RGS6 和 HCN4）中。遗传风险评分占 HRV 方差的 0.9%至 2.6%。HRV 与心率（-0.74<r<-0.55）和血压（-0.35<r<-0.20）之间存在显著的遗传相关性。这些发现为迷走神经心律调节的遗传性变异提供了具有临床意义的生物学见解，其中遗传变异（GNG11、RGS6）在 G 蛋白异三聚体作用于 GIRK 通道诱导起搏细胞膜超极化方面发挥着关键作用。
