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, 9 (1), 10975

Mitochondrial DNA Sequencing Reveals Association of Variants and Haplogroup M33a2'3 With High Altitude Pulmonary Edema Susceptibility in Indian Male Lowlanders


Mitochondrial DNA Sequencing Reveals Association of Variants and Haplogroup M33a2'3 With High Altitude Pulmonary Edema Susceptibility in Indian Male Lowlanders

Swati Sharma et al. Sci Rep.


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.

Conflict of interest statement

The authors declare no competing interests.


Figure 1
Figure 1
Distribution of variants and haplogroups in HAPE susceptibles and acclimatized control. (a) Total numbers of variants were higher in HAPE susceptibles compared to Acclimatized control (b)Total number of coding and noncoding variants were higher in HAPE susceptibles (c) Shows percentage of haplogroup in HAPE susceptibles and Acclimatized control. Frequency of haplogroup M is higher in HAPE susceptibles.
Figure 2
Figure 2
Gene distributions in mitochondrial genome. (a-i) Sample with variant presence in HAPE susceptibles and Acclimatized Control groups, Red bar represents percentage of HAPE susceptible samples where the Blue bar represents percentage of Acclimatized Control samples having variants at a given genomic coordinate, (a-ii) Difference fraction of variant percentage between HAPE susceptibles and Acclimatized Control sample. Positive value represent higher in HAPE susceptibles where negative value represents higher in Acclimatized Control (b) Showing total number of variants in each group wrt to mitochondrial genome.
Figure 3
Figure 3
Overlapped secondary structure of Complex I subunit. (a) Showing overlapped secondary structure of MT-ND5 gene of HAPE susceptible and Acclimatized Control. The dark blue portion suggests a change in amino acid from Threonine to Alanine at position 556. (b) Overlapping of secondary structure of MT-ND2 gene in HAPE susceptible and acclimatized control showing a change from Ileu159Val. Changes in amino acids and negative free energy change (∆∆G) shows destability of protein in HAPE susceptibles.

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