Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China (B.L., X.F., Z.C., X.L.,Y.X., L.Z., Q.H.).
Department of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Y.-P.W., Z.-C.J.).
Hypertension. 2022 Jul;79(7):1348-1360. doi: 10.1161/HYPERTENSIONAHA.121.18399. Epub 2022 Apr 28.
Pulmonary arterial hypertension is an incurable disease, in which the extracellular CaSR (calcium sensing receptor) is mechanistically important. This study was aimed to genetically link the gene and function to the disease severity.
Sanger sequencing, Sugen/hypoxia pulmonary arterial hypertension rat model, mutated rat, transcriptional reporter assay and measurement of CaSR activity were used.
Sanger sequencing identified a significant association between the variant rs1042636(A>G), located in exon 7, and idiopathic pulmonary arterial hypertension (IPAH) formation in patients. The frequency of 2968G homozygotes was higher in patients with IPAH compared with healthy individuals (23.6% versus 17.5%; =0.001, OR=1.864), and the minor alleles of rs6776158, rs1048213, and rs9883099, located in promoter, raised the IPAH odds ratio to 2.173. Patients with IPAH carrying heterozygotes or homozygotes genotype of rs1042636 showed markedly higher pulmonary artery pressure and reduced survival compared with individuals carrying the wild-type allele. The minor alleles of rs6776158, rs1048213, and rs9883099 increased CaSR expression in reporter assay. In Sugen/hypoxia pulmonary arterial hypertension rats, the point mutation replicating rs1042636 found in IPAH exacerbated pulmonary arterial hypertension severity by promoting the overexpression and the enhanced activity of CaSR.
Our functional genomic analysis thus indicates that the minor alleles of rs1042636, rs6776158, rs1048213, and rs9883099 contribute to the development and severity of IPAH. These findings may benefit clinical prognosis and treatment for IPAH.
肺动脉高压是一种无法治愈的疾病，其中细胞外钙敏感受体（calcium sensing receptor）在机制上很重要。本研究旨在将基因与功能遗传关联到疾病严重程度上。
使用 Sanger 测序、苏根/低氧肺动脉高压大鼠模型、突变大鼠、转录报告基因检测和钙敏感受体活性测定。
Sanger 测序确定了位于外显子 7 中的 rs1042636(A>G) 变异与特发性肺动脉高压（idiopathic pulmonary arterial hypertension，IPAH）患者的形成之间存在显著关联。与健康个体相比，IPAH 患者中 2968G 纯合子的频率更高（23.6%对 17.5%；=0.001，OR=1.864），位于启动子的 rs6776158、rs1048213 和 rs9883099 的次要等位基因使 IPAH 的优势比升高至 2.173。携带 rs1042636 杂合子或纯合子基因型的 IPAH 患者的肺动脉压明显升高，存活率降低，与携带野生型等位基因的个体相比。rs6776158、rs1048213 和 rs9883099 的次要等位基因在报告基因检测中增加了钙敏感受体的表达。在苏根/低氧肺动脉高压大鼠中，在 IPAH 中发现的复制 rs1042636 的点突变通过促进钙敏感受体的过表达和增强活性，加重了肺动脉高压的严重程度。
我们的功能基因组分析表明，rs1042636、rs6776158、rs1048213 和 rs9883099 的次要等位基因有助于 IPAH 的发生和严重程度。这些发现可能有益于 IPAH 的临床预后和治疗。
