Shorter telomere length, higher telomerase activity in association with tankyrase gene polymorphism contribute to high-altitude pulmonary edema.

Abstract

High-altitude pulmonary edema (HAPE) is a noncardiogenic form of pulmonary edema, which is induced upon exposure to hypobaric hypoxia at high altitude (HA). Hypobaric hypoxia generates reactive oxygen species that may damage telomeres and disturb normal physiological processes. Telomere complex comprises of multiple proteins, of which, tankyrase (TNKS) is actively involved in DNA damage repairs. We hence investigated the association of TNKS and telomeres with HAPE to delineate their potential role at HA. The study was performed in three groups, High-altitude pulmonary edema patients (HAPE-p, n = 200), HAPE-resistant sojourners (HAPE-r, n = 200) and highland permanent healthy residents (HLs, n = 200). Variants of TNKS were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Plasma TNKS level was estimated using enzyme-linked immunosorbent assay, expression of TNKS and relative telomere length were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and telomerase activity was assessed by the telomere repeat amplification protocol assay. TNKS poly-ADP ribosylates the telomere-repeat factor (TRF), which is a negative regulator of telomere length. Consequently, TRF expression was also measured by RT-qPCR. The TNKS heterozygotes rs7015700GA were prevalent in HLs compared to the HAPE-p and HAPE-r. The plasma TNKS was significantly decreased in HAPE-p than HAPE-r (P =0.006). TNKS was upregulated 9.27 folds in HAPE-p (P = 1.01E-06) and downregulated in HLs by 3.3 folds (P = 0.02). The telomere length was shorter in HAPE-p compared to HAPE-r (P =0.03) and HLs (P= 4.25E-4). The telomerase activity was significantly higher in HAPE-p compared to both HAPE-r (P= 0.01) and HLs (P= 0.001). HAPE-p had the lowest TNKS levels (0.186 ± 0.031ng/μl) and the highest telomerase activity (0.0268 amoles/μl). The findings of the study indicate the association of TNKS and telomeres with HA adaptation/maladaptation.