Unique mutations in mitochondrial DNA and associated pathways involved in high altitude pulmonary edema susceptibility in Indian lowlanders

Abstract

High altitude pulmonary edema (HAPE) is a life threatening non-cardiogenic pulmonary edema that occurs in an otherwise healthy individuals travelling to altitude above 2500 m. Earlier studies have reported association of mutations in nuclear (nDNA) and mitochondrial DNA (mtDNA) with HAPE susceptibility. However, the molecular mechanisms involved in the pathobiology of HAPE have not been fully understood. The present study investigates the genetic predisposition to HAPE by analyzing the mtDNA mutations in HAPE susceptibles (n = 23) and acclimatized controls (n = 23) using next generation sequencing. Structural analysis of mutations was done using SWISS Model server and stability was determined using ΔΔG values. Meta-analysis of GSE52209 dataset was done to identify differentially expressed genes (DEGs) in HAPE susceptibles and acclimatized controls. Fourteen non-synonymous, conserved and pathogenic mutations were predicted using SIFT and PolyPhen scoring in protein coding genes, whereas six mutations in mt-tRNA genes showed association with HAPE (p ≤ 0.05). The structural analysis of these mutations revealed conformational changes in critical regions in Complexes I–V which are involved in subunit assembly and proton pumping activity. The protein–protein interaction network analysis of DEGs showed that HIF1α, EGLN2, EGLN3, PDK1, TFAM, PPARGC1α and NRF1 genes form highly interconnected cluster. Further, pathway enrichment analysis using DAVID revealed that “HIF-1 signaling”, “oxidative phosphorylation” and “Metabolic pathways” had strong association with HAPE. Based on the findings it appears that the identified mtDNA mutations may be a potential risk factor in development of HAPE with the associated pathways providing mechanistic insight into the understanding of pathobiology of HAPE and sites for development of therapeutic targets.

Communicated by Ramaswamy H. Sarma

Keywords:

• HAPE
• high altitude
• hypoxia
• mitochondrial DNA
• next generation sequencing

Acknowledgements

The authors are grateful to the commanding officers and the Indian army troops from different units for volunteering to participate in the study. The authors also express gratitude to the Army Medical Corps authorities including Director General of Armed Force Medical Services, Staff Duties Directorate (DGAFMS, SD) branch for logistic support and officer in-charge of High Altitude Medical Research Centre (HAMRC), Leh for collecting HAPE samples.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work is part of the research project “TASK-190 and DIP-265” supported by the Defence Research and Development Organization (DRDO), India.