Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
PLoS Genet. 2024 Sep 9;20(9):e1011151. doi: 10.1371/journal.pgen.1011151. eCollection 2024 Sep.
Genetic studies of blood pressure (BP) traits to date have been performed on conventional measures by brachial cuff sphygmomanometer for systolic BP (SBP) and diastolic BP, integrating several physiologic occurrences. Genetic associations with central SBP (cSBP) have not been well-studied. Genetic discovery studies of BP have been most often performed in European-ancestry samples. Here, we investigated genetic associations with cSBP in a Chinese population and functionally validated the impact of a novel associated coiled-coil domain containing 93 (CCDC93) gene on BP regulation. An exome-wide association study (EWAS) was performed using a mixed linear model of non-invasive cSBP and peripheral BP traits in a Han Chinese population (N = 5,954) from Beijing, China genotyped with a customized Illumina ExomeChip array. We identified four SNP-trait associations with three SNPs, including two novel associations (rs2165468-SBP and rs33975708-cSBP). rs33975708 is a coding variant in the CCDC93 gene, c.535C>T, p.Arg179Cys (MAF = 0.15%), and was associated with increased cSBP (β = 29.3 mmHg, P = 1.23x10-7). CRISPR/Cas9 genome editing was used to model the effect of Ccdc93 loss in mice. Homozygous Ccdc93 deletion was lethal prior to day 10.5 of embryonic development. Ccdc93+/- heterozygous mice were viable and morphologically normal, with 1.3-fold lower aortic Ccdc93 protein expression (P = 0.0041) and elevated SBP as compared to littermate Ccdc93+/+ controls (110±8 mmHg vs 125±10 mmHg, P = 0.016). Wire myography of Ccdc93+/- aortae showed impaired acetylcholine-induced relaxation and enhanced phenylephrine-induced contraction. RNA-Seq transcriptome analysis of Ccdc93+/- mouse thoracic aortae identified significantly enriched pathways altered in fatty acid metabolism and mitochondrial metabolism. Plasma free fatty acid levels were elevated in Ccdc93+/- mice (96±7mM vs 124±13mM, P = 0.0031) and aortic mitochondrial dysfunction was observed through aberrant Parkin and Nix protein expression. Together, our genetic and functional studies support a novel role of CCDC93 in the regulation of BP through its effects on vascular mitochondrial function and endothelial function.
迄今为止，血压（BP）特征的遗传研究一直是通过肱动脉袖带血压计对收缩压（SBP）和舒张压进行常规测量来进行的，综合了多种生理现象。与中心 SBP（cSBP）的遗传相关性尚未得到很好的研究。BP 的遗传发现研究最常在欧洲血统样本中进行。在这里，我们在中国人群中研究了与 cSBP 的遗传相关性，并通过对新发现的卷曲螺旋域包含 93 个（CCDC93）基因对 BP 调节的影响进行功能验证。在中国北京的汉族人群（N = 5954）中，使用非侵入性 cSBP 和外周血压特征的混合线性模型进行了外显子组全关联研究（EWAS），该人群使用定制的 Illumina ExomeChip 阵列进行了基因分型。我们鉴定了与三个 SNP 的四个 SNP-特征关联，其中两个是新关联（rs2165468-SBP 和 rs33975708-cSBP）。rs33975708 是 CCDC93 基因的编码变异，c.535C>T，p.Arg179Cys（MAF = 0.15%），与 cSBP 增加相关（β = 29.3mmHg，P = 1.23x10-7）。CRISPR/Cas9 基因组编辑用于模拟小鼠中 Ccdc93 缺失的影响。纯合性 Ccdc93 缺失在胚胎发育第 10.5 天之前导致致命。Ccdc93+/-杂合子小鼠具有生存能力且形态正常，主动脉 Ccdc93 蛋白表达降低 1.3 倍（P = 0.0041），与同窝对照 Ccdc93+/+相比 SBP 升高（110±8mmHg 与 125±10mmHg，P = 0.016）。Ccdc93+/-主动脉的钢丝肌电图显示乙酰胆碱诱导的松弛受损，苯肾上腺素诱导的收缩增强。Ccdc93+/-小鼠胸主动脉的 RNA-Seq 转录组分析表明，脂肪酸代谢和线粒体代谢中发生了明显富集的途径改变。Ccdc93+/-小鼠的血浆游离脂肪酸水平升高（96±7mM 与 124±13mM，P = 0.0031），并且通过 Parkin 和 Nix 蛋白表达的异常观察到主动脉线粒体功能障碍。综上所述，我们的遗传和功能研究支持 CCDC93 通过其对血管线粒体功能和内皮功能的影响，在调节 BP 方面发挥新的作用。
