Abstract
Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson’s chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95%CI: 1.020–2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95%CI: 1.250–5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor.
Highlights
High altitude polycythemia (HAPC) is characterized by excessive erythrocytosis and is encountered in 5 to 18% of the population residing at the Qinghai-Tibetan Plateau [1,2]
To initially screen the mitochondrial DNA (mtDNA) single nucleotide polymorphisms (SNP) sites which may be associated with HAPC, we selected 100 participants, composed of 50 patients and 50 matched controls of similar age, occupation, birthplace, and time spent on the plateau for full-length mtDNA sequencing
Previous epidemiological investigations of HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau have demonstrated that HAPC is significantly correlated with the age of the subjects, time spent on the plateau, and labor intensity [3,21,22]
Summary
High altitude polycythemia (HAPC) is characterized by excessive erythrocytosis (females, Hb $19 g/dL; males, Hb $21 g/dL) and is encountered in 5 to 18% of the population residing at the Qinghai-Tibetan Plateau [1,2]. There is no effective prevention or treatment for this disease because its pathogenesis is poorly understood. It is a severe public health problem in China and Andean countries because millions of plateau residents may be at risk. Simonson et al [5] found that, in Tibetans, hemoglobin concentration was closely related to the single nucleotide polymorphisms (SNP) of several genes. These results suggest that HAPC presents obvious racial and individual differences in susceptibility
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