Mitochondrial DNA sequencing reveals association of variants and haplogroup M33a2′3 with High altitude pulmonary edema susceptibility in Indian male lowlanders

Abstract

High Altitude Pulmonary Edema (HAPE) is a threatening disorder caused due to acute exposure to high altitude above 3000 m. Apart from multiple factors involved, the genetic factors also play an important function in the pathogenesis of HAPE. This study aims to evaluate the role of mtDNA polymorphism and their association with haplogroup in understanding the etiology of HAPE. In this study, all the HAPE susceptible and acclimatized control subjects could be classified into nine haplogroups pertaining mostly to Macrohaplogroup M and U. The frequency of haplogroup M was significantly higher in HAPE susceptibles whereas the haplogroup M33a2′3 was found only in HAPE susceptibles. The variant G4491A and A4944G of MT-ND2, A14002G of MT-ND5, and C8562T of MT-ATP8, were definition site of haplogroup M33a2′3. The frequency of A10398G of MT-ND3, A8701G of MT-ATP6 and C14766T of MT-CYB genes were significantly higher in HAPE susceptibles. mtDNA copy number also plays a significant synergistic role in HAPE susceptibility. Our findings suggests that variants in MT-ND2 and MT-ND5 were predicted to confer decreased protein stability in HAPE susceptibles and in particular, highly conserved variants G4491A, A4944G and A14002G associated with haplogroup M33a2′3 may be the primary cause of susceptibility to HAPE in Indian male lowlanders.

Analysis of human mitochondrial genome co-occurrence networks of Asian population at varying altitudes

“…Since, the biological effects of high altitude were observed at > 3000 m existence of these co-occurrence pairs seemed a possible combination of variants that affects mitochondrial bioenergetics. Variant 4491 of ND2 gene was found to be associated with high altitude pulmonary edema (HAPE) susceptible in low altitude population 46 whereas in our analysis, this variant was found to co-occur with 3394 and its exclusive presence in the higher altitude regions suggested its adaptive dependence. The variable sites forming the global connected nodes 9540 and 10873 were the ‘RSRS50’ ancestral variants 47 while 10400 and 16327 were markers of M sub-haplogroups 48 .…”

“…As the efficiency of the electron transport chain governs key aspects of aerobic energy metabolism 51 , several investigators have suggested that functional modifications of redox proteins, such as cytochrome b, may be involved in physiological adaptation to different thermal environments 26,27,52 . It is interesting to note that variants located in CYB gene (such as C14766T) are known to be significantly higher in the high-altitude pulmonary edema a disorder arising due to acute exposure to high altitude above 3000 m and it has been hypothesized to play a role in high altitude sickness 46 . The formation of local co-occurrence pairs and similarity clustering divided the altitude groups into the higher and the lower altitude regions.…”

Analysis of human mitochondrial genome co-occurrence networks of Asian population at varying altitudes

“…Since, the biological effects of high altitude were observed at >3000 m existence of these co-occurrence pairs seemed a possible combination of variants that affects mitochondrial bioenergetics. Variant 4491 of ND2 gene was found to be associated with high altitude pulmonary edema (HAPE) susceptible in low altitude population [46] whereas in our analysis, this variant was found to co-occur with 3394 and its exclusive presence in the higher altitude regions suggested its adaptive dependence. The variable sites forming the global connected nodes 9540 and 10873 were the 'RSRS50' ancestral variants [47] while 10400 and 16327 were markers of M sub-haplogroups [46].…”

“…Variant 4491 of ND2 gene was found to be associated with high altitude pulmonary edema (HAPE) susceptible in low altitude population [46] whereas in our analysis, this variant was found to co-occur with 3394 and its exclusive presence in the higher altitude regions suggested its adaptive dependence. The variable sites forming the global connected nodes 9540 and 10873 were the 'RSRS50' ancestral variants [47] while 10400 and 16327 were markers of M sub-haplogroups [46]. The markers 9540 and 10873 were found to be present throughout the human population, 10400 was known to be specific to Asian population and 16327 was known to be the marker of C sub-haplogroup of M haplogroup which was specific to Siberian and American regions.…”

“…As the efficiency of the electron transport chain governs key aspects of aerobic energy metabolism [51], several investigators have suggested that functional modifications of redox proteins, such as cytochrome b, may be involved in physiological adaptation to different thermal environments [26,27,52]. It is interesting to note that variants located in CYB gene (such as C14766T) are known to be significantly higher in the high-altitude pulmonary edema a disorder arising due to acute exposure to high altitude above 3000 m and it has been hypothesized to play a role in high altitude sickness [46]. The formation of local co-occurrence pairs and similarity clustering divided the altitude groups into the higher and the lower altitude regions.…”