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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-05, Vol.112 (19), p.6134-6139
• Main Authors: Mishra, Aastha, Kohli, Samantha, Dua, Sanchi, Thinlas, Tashi, Mohammad, Ghulam, Pasha, M. A. Qadar
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Adolescent; Adult; Alleles; Altitude; Apelin; Apelin Receptors; Biological Sciences; Case-Control Studies; CpG Islands; Cross-Sectional Studies; DNA Methylation; Edema; Epigenetics; Female; Gene expression; Gene Expression Regulation; Genes; Genetic Variation; Genome-Wide Association Study; Genotype; Homeostasis; Humans; Hypoxia; India; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - genetics; Male; Methylation; Middle Aged; Nitric oxide; Nitric Oxide Synthase Type III - genetics; Nitrites - chemistry; Oxygen - chemistry; Polymorphism; Polymorphism, Genetic; Pulmonary Circulation; Pulmonary Edema - ethnology; Pulmonary Edema - genetics; Receptors, G-Protein-Coupled - genetics; Signal Transduction; Young Adult
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1422759112

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 rs3761581 G was associated with a 58.6% reduction in gene expression ( P = 0.017), and the risk alleles rs3761581 G and rs2235312 T 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. Significance Exposure to a high-altitude (HA) hypobaric hypoxia environment produces physiological changes. Among these, the changes in the apelin signaling system are significant because this system regulates vascular and oxygen homeostasis. This study demonstrates that the HA environment stimulates the apelin system to distinguish genetic variants and the methylation profile of CpG islands that may impair or improve pulmonary vascular function, thereby resulting in HA pulmonary edema (HAPE) in patients or adaptation in healthy controls. Of the several variants of this system, apelin rs3761581 G and rs2235312 T , individually and in combination, and a greater methylation of a CpG island in the 5′ UTR, associated with low levels of apelin