Hypobaric hypoxia modulated structural characteristics of circulating cell-free DNA in high-altitude pulmonary edema

Abstract

The utility of cell free (cf) DNA has extended as a surrogate or clinical biomarker for various diseases. However, a more profound and expanded understanding of the diverse cfDNA population and its correlation with physiological phenotypes and environmental factors is imperative for utilizing its full potential. The high altitude (HA; altitude >2500 m above sea level) environment characterized by hypobaric hypoxia offers an observational case-control design to study the differential cfDNA profile in high-altitude pulmonary edema (HAPE) patients (n=112) and healthy HA sojourners (n=111). The present study investigated cfDNA characteristics such as concentration, fragment length size, degree of integrity, and subfractions reflecting mitochondrial-cfDNA copies in the two groups. The total cfDNA level was significantly higher in HAPE patients, and the level increased with increasing HAPE severity ( P=0.0036). A lower degree of cfDNA integrity of 0.346 in HAPE patients ( P=0.001) indicated the prevalence of shorter cfDNA fragments in circulation in patients compared to the healthy HA sojourners. A significant correlation of cfDNA characteristics with the peripheral oxygen saturation levels in the patient group demonstrated the translational relevance of cfDNA molecules. The correlation was further supported by multivariate logistic regression and receiver operating characteristic curve. Our study is the first to highlight the association of higher cfDNA concentration, a lower degree of cfDNA integrity, and increased mitochondrial-derived cfDNA population with HAPE disease severity. Further deep profiling of cfDNA fragments, which preserves cell-type specific genetic and epigenetic features, can provide dynamic physiological responses to hypoxia.