Key result
The CaSR variant rs1042636 2968G homozygote was significantly more frequent in patients with idiopathic pulmonary arterial hypertension than healthy individuals (23.6% vs 17.5%; OR 1.864, P=0.001).
Why the study?
Pulmonary arterial hypertension is an incurable disease with mechanistically important extracellular CaSR, but the genetic link between the CaSR gene, function, and disease severity remained to be established.
Do CaSR gene variants increase susceptibility to and severity of idiopathic pulmonary arterial hypertension?
Case-Control
Do CaSR gene variants increase susceptibility to and severity of idiopathic pulmonary arterial hypertension?
Specific CaSR gene variants are associated with increased susceptibility to and severity of idiopathic pulmonary arterial hypertension, highlighting a potential prognostic and therapeutic target.
Answers are grounded in this paper and cite their sources.
CaSR rs1042636 association with IPAH susceptibility is hypothesis-generating; leaves open its prognostic or therapeutic value pending validation.
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 the CaSR gene and function to the disease severity. Methods: Sanger sequencing, Sugen/hypoxia pulmonary arterial hypertension rat model, CaSR mutated 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 in CaSR 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%; P =0.001, OR=1.864), and the minor alleles of rs6776158, rs1048213, and rs9883099, located in CaSR 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. Conclusions: Our functional genomic analysis thus indicates that the CaSR 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.
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Liu et al. (2022) conducted a case-control in Idiopathic pulmonary arterial hypertension (IPAH). CaSR variant rs1042636(A>G) 2968G homozygotes vs. Healthy individuals was evaluated on Idiopathic pulmonary arterial hypertension (IPAH) formation (OR 1.864, p=0.001). The CaSR variant rs1042636 2968G homozygote was significantly more frequent in patients with idiopathic pulmonary arterial hypertension than healthy individuals (23.6% vs 17.5%; OR 1.864, P=0.001).
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