An Investigation of the RS2274924 and RS3750425 Polymorphisms in the TRPM6 Gene in the Etiology of Idiopathic Pulmonary Arterial Hypertension

<title>Abstract</title> <p>Idiopathic pulmonary arterial hypertension (IPAH) is a subtype of pulmonary hypertension characterized by increased pulmonary vascular resistance of unknown etiology. The transient receptor potential melastatin 6 (TRPM6) gene encodes a magnesium (Mg²⁺)-sensitive ion channel expressed in lung and endothelial cells and has been associated with hypomagnesemia. This study investigated the association of TRPM6 rs2274924 and rs3750425 polymorphisms and promoter methylation levels with IPAH susceptibility compared with healthy controls. The study included 198 IPAH patients and 198 healthy individuals. Genomic DNA was isolated from blood samples, and rs2274924 and rs3750425 variants were analyzed using real-time PCR TaqMan genotyping. TRPM6 promoter methylation levels were determined by quantitative methylation-specific qRT-PCR following bisulfite modification of DNA. No significant differences were observed between patients and controls regarding rs2274924 genotype distributions or allele frequencies. In contrast, the CT heterozygous genotype of rs3750425 was significantly more frequent in patients than in controls (40% vs. 28%, p = 0.036), whereas allele frequencies showed borderline significance (p = 0.073). Promoter methylation analysis revealed no significant differences between groups. Haplotype analysis demonstrated a significant increase in the TT/CT haplotype in IPAH patients, consistent with the genotype findings. In conclusion, no association was identified between rs2274924 and IPAH. However, the rs3750425 CT genotype may contribute to IPAH susceptibility through magnesium-related mechanisms. Larger studies are needed to confirm these findings and clarify the role of TRPM6 variants in IPAH pathogenesis.</p>