SNPs, linkage disequilibrium, and chronic mountain sickness in Tibetan Chinese

Buroker, Norman E.; Ning, Xue-Han; Zhou, Zhao-Nian; Li, Kui; Cen, Weijun; Wu, Xiu-Feng; Zhu, Wei-Zhong; Scott, C. Ronald; Chen, Shi-Han

doi:10.2147/hp.s117967

Cited by 13 publications

(12 citation statements)

References 75 publications

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“…Studies of VEGFA SNPs in the pathogenesis of CMS have indicated that genetic variations of VEGFA have pathophysiological effects on CMS development [20, 26]. Here we found that the frequencies of the major alleles of rs699947, rs1570360, rs2010963, and rs3025039 in the Sherpa highlanders (0.824, 0.892, 0.667, and 0.833, respectively) were equivalent to those in heathy Tibetans dwelling on the Tibetan Plateau (0.828, 0.907, 0.567, and 0.897, respectively) (Table 4).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic variations of VEGFA are apparently related to pathophysiological effects affecting CMS susceptibility, likely through targeting transcription factor binding sites (TFBS) of VEGFA [20, 21, 26]. Hypoxia-induced gene expression was described as a transcriptional mechanism mediated by hypoxia-responsive elements (HREs) present in the promoter region in the 5′ flanking region of VEGFA [28, 29].…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations ofVEGFAin Sherpa highlanders

Droma¹,

Kinjo²,

Nozawa³

et al. 2020

Preprint

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24Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 25 partly by one of the adaptation mechanisms promoting increases of microcirculatory 26 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 27 Hypoxia stimulates vascular endothelial growth factor (VEGF), which is an important 28 signaling protein involved in hypoxia-stimulated vasculogenesis and angiogenesis. Our 29 present study included 51 Sherpas dwelling in Namche Bazaar village (3440 m) and 76 30 non-Sherpa lowlanders residing in Kathmandu (1300 m) in Nepal. In these participants, 31 we measured plasma VEGF-A concentrations and genotyped five single-nucleotide 32 polymorphisms (SNPs) of VEGFA: rs699947, rs8333061, rs1570360, and rs2010963 in 33 the 5ʹ-untranslated region (5ʹ-UTR); and rs3025039 in the 3ʹ-UTR. The average 34 circulating VEGF-A level in Sherpas did not respond to hypoxia at the high altitude in 35 3440 m, remaining equivalent to the level in non-Sherpa lowlanders at low altitude. Allele 36 discriminations for the analyzed SNPs revealed significant genetic divergences of 37 rs699947, rs8333061, and rs2010963 in Sherpa highlanders compared with non-Sherpa 38 lowlanders, East Asians, South Asians, and the global population; however, consistency 39 with the indigenous Tibetan highlanders from the Tibet Plateau. On the other hand, the 40 SNP rs3025039 in the 3ʹ-UTR presented constant preserved genetic variation among 41 global populations. Our findings indicated that the physiological sea-level VEGF-A 42 concentration in Sherpa highlanders at high altitude was probably linked with the 43 significant variations of VEGFA in Sherpas that regulate the gene expression in a manner 44 of tolerance to hypoxia through production of the optimal biological level of VEGF-A at 45 high altitudes. Precise angiogenesis at high altitude contributes to the adaptive levels of 46 capillary density and microcirculation, providing efficient and effective diffusion of 3 47 oxygen to tissues and representing human adaptation to high-altitude hypoxia 48 environment. 49 Author summary 50 Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, 51 partly by one of the adaptation mechanisms promoting increases of microcirculatory 52 blood flow and capillary density at high altitude for restoring oxygen supply to tissues. 53 Vascular endothelial growth factor (VEGF) is mainly stimulated by hypoxia, and is an 54 important signaling protein involved in hypoxia-stimulated vasculogenesis and 55 angiogenesis. Interestingly, we found that the circulating VEGF-A level in Sherpa 56 highlanders did not respond to hypoxia at high altitude. Furthermore, allele discrimination 57 of the single nucleotide polymorphisms (SNPs) of VEGFA revealed significant 58 divergences of rs699947, rs8333061, and rs2010963 within the VEGFA regulation region 59 in Sherpa highlanders compared to the non-Sherpa lowlanders, East Asians, South Asians, 60 and the global population; however, consistency w...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypoxia-tolerant vascular endothelial growth factor-A (VEGF-A) and the genetic variations ofVEGFAin Sherpa highlanders

Droma¹,

Kinjo²,

Nozawa³

et al. 2020

Preprint

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“…Based on subgroup analysis, minor allele in East Asian was related to an increased risk of CRC. This SNP is located in 3'UTR of vascular endothelial growth factor gene which may affect hsa‐miR‐591 target sites . This gene affects angiogenesis, tumor growth, and metastasis .…”

Section: Discussionmentioning

confidence: 99%

“…This SNP is located in 3'UTR of vascular endothelial growth factor gene which may affect hsa-miR-591 target sites. 186 This gene affects angiogenesis, tumor growth, and metastasis. 187 It is also related to CRC outcomes and treatment.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐binding site polymorphisms and risk of colorectal cancer: A systematic review and meta‐analysis

et al. 2019

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Genetic variations in miRNAs binding site might participate in cancer risk. This study aimed to systematically review the association between miRNA‐binding site polymorphisms and colorectal cancer (CRC). Electronic literature search was carried out on PubMed, Web of Science (WOS), Scopus, and Embase. All types of observational studies till 30 November 2018 were included. Overall 85 studies (21 SNPs) from two systematic searches were included analysis. The results showed that in the Middle East population, the minor allele of rs731236 was associated with decreased risk of CRC (heterozygote model: 0.76 [0.61‐0.95]). The minor allele of rs3025039 was related to increased risk of CRC in East Asian population (allelic model: 1.25 [1.01‐1.54]). Results for rs3212986 were significant in overall and subgroup analysis (P < .05). For rs1801157 in subgroup analysis the association was significant in Asian populations (including allelic model: 2.28 [1.11‐4.69]). For rs712, subgroup analysis revealed a significant (allelic model: 1.41 [1.23‐1.61]) and borderline (allelic model: 0.92 [0.84‐1.00]) association in Chinese and Czech populations, respectively. The minor allele of rs17281995 increased risk of CRC in different genetic models (P < .05). Finally, rs5275, rs4648298, and rs61764370 did not show significant associations. In conclusion, minor allele of rs3025039, rs3212986, and rs712 polymorphisms increases the risk of CRC in the East Asian population, and heterozygote model of rs731236 polymorphism shows protective effect in the Middle East population. In Europeans, the minor allele of rs17281995 may increase the risk of CRC, while rs712 may have a protective effect. Further analysis based on population stratifications should be considered in future studies.

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“…VEGFA is a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. It induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels.VEGFA is also a key regulator of hypoxia.There are several VEGFA SNPs associated with high altitude sickness that create alterations in punitive TFBS for the gene [26][27][28][147][148][149].…”

Section: Vascular Endothelial Growth Factor (Vegf)-amentioning

confidence: 99%