VEGFA SNPs and transcriptional factor binding sites associated with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau

Abstract

Mountain sickness (MS) occurs among humans visiting or inhabiting high altitude environments. We conducted genetic analyses of seven single nucleotide polymorphisms (SNPs) in the promoter region of VEGFA gene for lowland (Han) and highland (Tibetan) Chinese. The seven SNPs were evaluated in Han and Tibetan patients with acute (A) and chronic (C) MS. We compared 64 patients with AMS with 64 Han unaffected with MS, as well as 48 CMS patients with 32 unaffected Tibetans. The SNPs studied are rs699947, rs34357231, rs79469752, rs13207351, rs28357093, rs1570360, and rs2010963 which are found in the promoter ranging from -2,578 to -634 bp from the transcriptional start site (TSS), respectively. Direct sequencing was used to identify individual genotypes for these SNPs. Arterial oxygen saturation of hemoglobin (SaO2) was found to be significantly associated with the rs699947, rs34357231, rs13207351, and rs1570360 SNPs in Han patients with AMS, while the rs2010963 SNP was found to approach significance in the AMS study group, but found to be significantly associated in the normal Tibetan study group. The Han and Tibetan control groups were found to diverge significantly for the rs28357093 and rs2010963 SNPs, as measured by genetic distances of 0.073 and 0.054, respectively. All the SNPs are found in transcriptional factor binding sites (TFBS), and their possible role in gene regulation was evaluated with regard to MS. MS was found to be significantly associated with these SNPs compared with their Han and Tibetan control groups, indicating that these nucleotide substitutions result in TFBS changes which apparently have a physiological effect on the development of high altitude sickness.

<i>ADRBD1</i> (GRK2), <i>TBXA2R</i> and <i>VEGFA</i> rSNPs in KLF4 and SP1 TFBS Exhibit Linkage Disequilibrium

“…LD between SNPs in the regulatory region of a gene can indicate strong associations of certain haplotypes with sickness or disease [28]. Consequently, an evaluation was made within the ADRBK1 [9], TBXA2R [10] [11] and VEGFA [12] genes for the rSNPs in LD [26] and their effect on potential KLF/SP TFBS (Table).…”

“…This concept is examined for ADRBK1, TBXA2R and VEGFA rSNPs found in potential SP1 and KLF4 TFBS within these genes. These rSNPs within each gene have been reported to be in linkage disequilibrium (LD) [26]- [28] and this disequilibrium in conjunction with their SP1 and KLF4 TFBS were examined in this study. In this report LD is considered to be the non-random association of rSNP alleles within the gene.…”

SNPs, Linkage Disequilibrium and Transcriptional Factor Binding Sites Associated with Acute Mountain Sickness among Han Chinese at the Qinghai-Tibetan Plateau

“…The illness will resolve itself if no additional altitude is attempted; however, in some cases the descent to a lower altitude is necessary in order to reverse the condition. The precise pathogenesis of AMS is not well understood, but hypoxia is considered to be the major factor [4][5][6][7], which raises the question of why some individuals are susceptible to the sickness while others are not, under the same high altitude environment.In an effort to provide in cite into this question, we have previously published on known genetic associations of simple nucleotide polymorphisms (SNPs) with high altitude sickness [8][9][10][11]. In the present study, we examine the interaction of seventeen SNPs in nine genes [8][9][10][11] with regard to AMS and the effect these SNPs have on potential changes in transcriptional factor binding sites (TFBS).…”

“…LD between SNPs in the regulatory region of a gene can be used as a method of identifying associations of certain haplotypes that lead to sickness or disease in a population [9,11].This can be achieved when levels of LD between SNPs within haplotypes are seen to change substantially in a disease or sickness group when compared to the normal baseline population. In such cases, the relationship between LD, SNPs and TFBS can be used to identify potential binding changes for TFs responsible for gene regulation.…”

“…In such cases, the relationship between LD, SNPs and TFBS can be used to identify potential binding changes for TFs responsible for gene regulation. Such TFBS changes could result in disease or sickness [11,[24][25][26][27][28][29]. In this report, LD is considered to be the non-random association of SNP alleles within and between genes.…”