ArticleProceedings of the National Academy of Sciences of the United States of America2015
Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 55 citations in OpenAlex.
- Altitude hypoxia and hypoxemia: pathogenesis and management.Signal transduction and targeted therapy · 2026Review
- HiLand Resource: A Comprehensive Database of Highland Human Populations.Genomics, proteomics & bioinformatics · 2025Article
- DNA methylation in adaptation to high-altitude environments and pathogenesis of related diseases.Human genomics · 2025Review
- AZU1 as a DNA Methylation-Driven Gene: Promoting Oxidative Stress in High-Altitude Pulmonary Edema.Antioxidants (Basel, Switzerland) · 2025Article
- Chasing genes at high-altitude.Experimental physiology · 2025Article
- Skeletal Muscle as Endocrine Organ.Advances in experimental medicine and biology · 2025Review
- Dysregulation of metabolites and high-altitude illnesses development under plateau conditions.Frontiers in physiology · 2025Review
- Hypobaric hypoxia modulated structural characteristics of circulating cell-free DNA in high-altitude pulmonary edema.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Hypobaric hypoxia drives selection of altitude-associated adaptative alleles in the Himalayan population.The Science of the total environment · 2024Article
- The Telomere-Telomerase System Is Detrimental to Health at High-Altitude.International journal of environmental research and public health · 2023Article
- Differential methylation in EGLN1 associates with blood oxygen saturation and plasma protein levels in high-altitude pulmonary edema.Clinical epigenetics · 2022Article
- TheInternational journal of environmental research and public health · 2022Article
- Apelin Association with Hepatic Fibrosis and Esophageal Varices in Patients with Chronic Hepatitis C Virus.The American journal of tropical medicine and hygiene · 2022Article
- Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics.Cells · 2022Review
- The genomic basis of high-elevation adaptation in wild house mice (Mus musculus domesticus) from South America.Genetics · 2022Article
- Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure.Frontiers in pharmacology · 2022Article
- The deleterious impact of a non-synonymous SNP on protein structure and function is apparent in hypertension.Journal of molecular modeling · 2021Article
- Article
- Hypertensive Patients Exhibit Enhanced Thrombospondin-1 Levels at High-Altitude.Life (Basel, Switzerland) · 2021Article
- Exposomes to Exosomes: Exosomes as Tools to Study Epigenetic Adaptive Mechanisms in High-Altitude Humans.International journal of environmental research and public health · 2021Review
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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