Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema

摘要: Hypoxia-inducible factor stimulates the expression of apelin, a potent vasodilator, in response to reduced blood arterial oxygen saturation. However, aberrations apelin system impair pulmonary vascular function, potentially resulting development high-altitude (HA)-related disorders. This study aimed elucidate genetic and epigenetic regulation receptor (APLNR), endothelial nitric oxide synthase (NOS3) HA adaptation edema (HAPE). A genome-wide association sequencing identified variants APLNR, NOS3 that were validated larger sample size HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), healthy highland natives (HLs). Apelin-13 nitrite levels down-regulated HAPE-p (P < 0.001). Among several studied polymorphisms, rs3761581, rs2235312, rs3115757; APLNR rs11544374 rs2282623; 4b/4a, rs1799983, rs7830 associated with HAPE 0.03). The risk allele rs3761581G was 58.6% reduction gene = 0.017), alleles rs2235312T low apelin-13 0.05). latter two decreased further when both these present patients Methylation CpG island significantly higher at 11.92% than HAPE-f HLs ≤ 7.1% Moreover, methylation effect 9% stronger 5' UTR levels. rs3761581 rs2235312 polymorphisms influence HAPE.