Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema.
Hypoxia-inducible factor stimulates the expression of apelin, a potent vasodilator, in response to reduced blood arterial oxygen saturation. However, aberrations in the apelin system impair pulmonary vascular function, potentially resulting in the development of high-altitude (HA)-related disorders. This study aimed to elucidate the genetic and epigenetic regulation of apelin, apelin receptor (APLNR), and endothelial nitric oxide synthase (NOS3) in HA adaptation and HA pulmonary edema (HAPE). A genome-wide association study and sequencing identified variants of apelin, APLNR, and NOS3 that were validated in a larger sample size of HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and healthy highland natives (HLs). Apelin-13 and nitrite levels and apelin and NOS3 expression were down-regulated in HAPE-p (P < 0.001). Among the several studied polymorphisms, apelin rs3761581, rs2235312, and rs3115757; APLNR rs11544374 and rs2282623; and NOS3 4b/4a, rs1799983, and rs7830 were associated with HAPE (P < 0.03). The risk allele rs3761581G was associated with a 58.6% reduction in gene expression (P = 0.017), and the risk alleles rs3761581G and rs2235312T were associated with low levels of apelin-13 and nitrite (P < 0.05). The latter two levels decreased further when both of these risk alleles were present in the patients (P < 0.05). Methylation of the apelin CpG island was significantly higher in HAPE-p at 11.92% than in HAPE-f and HLs at ≤ 7.1% (P < 0.05). Moreover, the methylation effect was 9% stronger in the 5' UTR and was associated with decreased apelin expression and apelin-13 levels. The rs3761581 and rs2235312 polymorphisms and methylation of the CpG island influence the expression of apelin in HAPE.
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; Department of Biotechnology, University of Pune, Pune 411007, India;
Aastha
A
Mishra
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; Academy of Scientific and Innovative Research, New Delhi 110025, India; and.
Samantha
S
Kohli
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India;
Sanchi
S
Dua
Department of Medicine, Sonam Norboo Memorial Hospital, Leh, Ladakh, Jammu, and Kashmir 194101, India.
Tashi
T
Thinlas
Department of Medicine, Sonam Norboo Memorial Hospital, Leh, Ladakh, Jammu, and Kashmir 194101, India.
Ghulam
G
Mohammad
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; qpasha@igib.res.in.
M A Qadar
MA
Pasha
D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000531:Altitude; D000073861:Apelin; D000075244:Apelin Receptors; D016022:Case-Control Studies; D018899:CpG Islands; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D007194:India; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009573:Nitrites / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D011110:Polymorphism, Genetic; D011652:Pulmonary Circulation; D011654:Pulmonary Edema / Q000208:ethnology / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction; D055815:Young Adult
D020121:5' Untranslated Regions; C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D009573:Nitrites; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen
DNA methylation; correlation; haplotype; healthy Ladakhi highland natives; high-altitude pulmonary edema