Cross‐altitude analysis suggests a turning point at the elevation of 4,500 m for polycythemia prevalence in Tibetans

Zhang, Hui; He, Yaoxi; Cui, Chaoying; Ouzhuluobu,; Baimakangzhuo,; Duojizhuoma,; Dejiquzong, -; Bianba,; Gonggalanzi,; Pan, Yongyue; Qula,; Kangmin,; Cirenyangji,; Baimayangji,; Bai, Caijuan; Guo, Wei; Yangla,; Peng, Yi; Zhang, Xiaoming; Xiang, Kun; Yang, Zhaohui; Liu, Shiming; Tao, Xiang; Gengdeng,; Zheng, Wangshan; Guo, Yongbo; Wu, Tianyi; Qi, Xuebin; Su, Bing

doi:10.1002/ajh.24809

Cited by 14 publications

(8 citation statements)

References 13 publications

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“…In addition, our study showed that the increase in Hb with altitude in the Andes region was higher than that observed in a previous study of young men in Switzerland 18 . Our own and the previous study findings suggest that the magnitude of an increase in Hb by altitude may vary between regions, 36 and also among ethnic groups within a region, as suggested previously 37 . This is important to consider if adjustment of Hb by altitude is accepted.…”

Section: Discussionsupporting

confidence: 69%

“…Adjustment is recommended for PSC and for men and women of all ages 2,3 as well as for all populations living at high altitudes worldwide. However, different studies have demonstrated that the association between Hb and altitude depends on the population group (young children versus women of reproductive age), 19 ethnicity (Tibetan versus Han), 37 and region (Andean versus European), 36 suggesting that altitude‐based adjustments may need to be tailored according to the population group.…”

Section: Discussionmentioning

confidence: 99%

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Changes in hemoglobin levels with age and altitude in preschool‐aged children in Peru: the assessment of two individual‐based national databases

Gonzáles

Tapia

Vásquez‐Velásquez

2020

Annals of the New York Academy of Sciences

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According to the World Health Organization, the cutoff hemoglobin (Hb) value for defining anemia is 11 g/dL in preschool‐aged children, and Hb measurements should be corrected above an altitude of 1000 meters. This study sought to determine the altitude at which the Hb value increases compared with that at sea level, Hb changes with age and region in Peru, the prevalence of anemia according to three different models used to correct Hb for altitude, and the association of the Hb value with stunting. Two individual‐based Peruvian national databases were analyzed. Hb increased from an altitude of 375 meters. Hb concentration was lower at younger ages and higher at older ages. The increase in Hb with increasing altitude was lower in southern Peru. Implementing the different models for Hb measurement correction resulted in a higher and lower prevalence of anemia at altitudes >2500 and <2500 m, respectively, using the CDC adjustment. In children aged 6–23 months, the rate of stunting was lower in those with an Hb level of 10–12 g/dL (including mild anemia). In conclusion, the adjustment of Hb values for altitude should be considered before 1000 m and reference ranges should be adjusted to smaller groups of children instead of the same reference range for children aged 6–59 months.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Changes in hemoglobin levels with age and altitude in preschool‐aged children in Peru: the assessment of two individual‐based national databases

Gonzáles

Tapia

Vásquez‐Velásquez

2020

Annals of the New York Academy of Sciences

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“…For example, positive selection has been found on prolyl hydroxylase 2 (PHD2) coding gene EGLN1 , where adaptive amino acid changing mutations increased HIF-2α degradation to reduce the hemoglobin (Hb) concentration in Tibetans, protecting them from polycythemia, a condition considered as a blunted physiological response at high altitude 6 . Consistent with this observation, recent studies showed that the Tibetan specific HIF-2α adaptive mutation down regulates its own expression 7,8 . Therefore, hypoxia adaptation selected genes more likely play anti-hypoxia or anti-HIF1/2 dependent roles to make animals or humans behave normally under hypoxic environments.…”

Section: Introductionsupporting

confidence: 61%

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression

et al. 2019

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Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.

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“…CMS, characterized by excessive erythrocytosis leading to reduced life expectancy, is quite common in Andean native populations and in lowlanders living at high altitude but is rarely observed in Tibetans. This shows the prominent role of [Hb] in adaptation to high altitude and a better adaptation of Tibetans to altitude than Andeans (Zhang et al, 2017). Interestingly, although mean [Hb] appears highly different between these populations, the heritability of this trait is quite high with 0.86 in Tibetans and 0.87 in Bolivians (Beall et al, 1998).…”

Section: Discussionmentioning

confidence: 84%

The Genetic Architecture of Chronic Mountain Sickness in Peru

et al. 2019

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Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10 −9 ). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2 , CAST , and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude.

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Cross‐altitude analysis suggests a turning point at the elevation of 4,500 m for polycythemia prevalence in Tibetans

Cited by 14 publications

References 13 publications

Changes in hemoglobin levels with age and altitude in preschool‐aged children in Peru: the assessment of two individual‐based national databases

Changes in hemoglobin levels with age and altitude in preschool‐aged children in Peru: the assessment of two individual‐based national databases

YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression

The Genetic Architecture of Chronic Mountain Sickness in Peru

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