Dataset Information

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.

SUBMITTER: Sharma S

PROVIDER: S-EPMC6662842 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Sharma Swati S Singh Sayar S Gupta Rajinder K RK Ganju Lilly L Singh Shashi Bala SB Kumar Bhuvnesh B Singh Yamini Y

Scientific reports 20190729 1

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 pertai ...[more]

PMID: 31358833

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Project description:High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects (n = 6) compared with HAPE-resistant controls (n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scond and Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacin and Scond did not change significantly in hypoxia (P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena.NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.

Project description:New findingsWhat is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de-acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non-ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction.AbstractProlonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n = 11) left altitude and after de-acclimatization in Kathmandu for ∼7 days re-ascended with the lowlanders over 8-10 days to 5050 m. The second Sherpa group (non-ascent Sherpa, n = 12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P = 0.02) and PVR (P = 0.02). After ∼14 days at 5050 m, PASP decreased with supplemental oxygen (mean decrease: 3.9 mmHg, 95% CI 2.1-5.7 mmHg, P < 0.001); however, PVR was unchanged (P = 0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following ∼14 days at 5050 m altitude, there was no change in PVR to hypoxia or O2 supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia.

Dataset Information

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

Publications

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

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