29 Jun Calcium Sensing Receptor Variants Increase Pulmonary Hypertension Susceptibility
Hypertension, <a href=»https://www.ahajournals.org/toc/hyp/79/7″>Volume 79, Issue 7</a>, Page 1348-1360, July 1, 2022.
Background: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 theCaSRgene and function to the disease severity.Methods:Sanger sequencing, Sugen/hypoxia pulmonary arterial hypertension rat model,CaSRmutated rat, transcriptional reporter assay and measurement of CaSR activity were used.Results:Sanger sequencing identified a significant association between the variant rs1042636(A>G), located inCaSRexon 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%;P=0.001, OR=1.864), and the minor alleles of rs6776158, rs1048213, and rs9883099, located inCaSRpromoter, 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.Conclusions:Our functional genomic analysis thus indicates that theCaSRminor 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.