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Identification of Global DNA Methylation Signatures in Patients of High Altitude Induced Venous Thrombo-Embolism (HA-VTE)

Background: Pathophysiology of venous thrombo-embolism (VTE) depends upon several acquired, inherited and environmental risk factors, including high altitude (HA) exposure. The present study aims to gain insights into pathophysiological mechanism(s) of high altitude induced VTE (HA-VTE) by studying global methylation signatures. Methodology: Blood samples were collected from Indian Army volunteers divided into four study groups; sea level control (SLC), sea level VTE patients (SL-VTE), high altitude control (HAC) and high altitude VTE patients (HA-VTE). Methylation patterns were studied using whole genome bisulfate sequencing. Differentially methylated genes and pathways were identified by comparing percentage methylation. Results: Highest DM was observed in SL-VTE (1162 gene) compared to SLC where in hyper methylation was predominant (62.9%) compared to hypo methylation (37.05%). A reverse trend was observed in HA-VTE, where hypo methylation (61.69%) was predominant over hyper methylation (38.30%) in a total of 296 DM genes. Differential hypomethylation of genes involved in cell adhesion/platelet activity (CADM1, PTPRK, PDGFA) and immune response (CXCL12, IL4, IRF4, NLRP1) was observed in HA-VTE whereas genes encoding transcription factors (GSC, RPSKA1), trans membrane receptor (NOTCH2) and growth factor (TGFB2) were hypermethylated in comparison to SL-VTE. Methylation pattern of HA-VTE compared to HAC showed hypomethylation in genes involved in oxidative phosphorylation (CPOX), immune response and stress response (NDRG1), while those involved in signaling mechanisms (KALRN), neurotransmitter release (TMPRSS2) and transcription factor (ELF1) were hyper-methylated. Conclusions: Our study for the first time reveals genome wide methylation pattern in HA-VTE group where in differential hypo methylation in cell adhesion and inflammation genes was observed.