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

Abstract

Acute mountain sickness (AMS) occurs in up to 50% of individuals ascending to high altitudes greater than 2600 meters. An AMS Han Chinese and a normal Han group were compared for 17 simple nucleotide polymorphisms (SNPs) within 9 genes that have been associated with AMS. The SNPs were analyzed with respect to linkage disequilibrium (LD) between intra-and intergenic SNP alleles and alterations in transcriptional factor binding sites (TFBS). Included in the study was the angiotensin-converting enzyme (ACE) (rs4340), the angiotensinogen (AGT) (rs699) and the angotensin II type 1 receptor (AGTR1) (rs5186) SNPs from the renin-angiotension system (RAS) as well as the GNB3 (rs2071057) SNP from G-protein signaling and a LDL apolipoprotein B (APOB) (rs693) SNP. The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) SNP and two egl nine homolog 1 (EGLN1) SNPS (rs480902 and rs516651) from the hypoxia-inducible factor (HIF) oxygen signaling pathway were included. SNPs analyzed in the vascular endothelial growth factor (VEGF) signaling pathway are the v-akt murine thymoma viral oncogene homolog 3 (AKT3) (rs4590656 and rs2291409), the endothelial cell nitric oxide synthase 3 (eNOS3) (rs1007311 and rs1799983) and the (VEGFA) (rs79469752, rs13207351, rs28357093, rs1570360 and rs3025039). These SNP alleles alter the TFBS for TF binding. Pair-wise LD was computed between SNPs. An increase in LD occurred in 32 pair-wise comparisons while a decrease was found in 22 pair-wise comparisons between the AMS and controls. Increases and decreases in LD pairs were found within and between signaling pathways and systems indicating the interaction of SNP alleles or potential TFBS from different areas of the genome. The most drastic change in TFBS occurs with ACE (I/D) SNP (rs4340) where the ACE-I allele generates 84 potential TFBS while the ACE-D allele generates only four binding sites. The alteration in TFBS generated by the 17 SNPs is discussed with respect to AMS.

Identifying Alterations in Transcriptional Factor Binding Sites

“…The number of conserved TFBS between the two SNP alleles and unique TFBS per allele which have been previously determined [9][10][11][12][13][14][15][16][17][18][19][20] are included in the Table. The names of conserved and unique TFBS can be found in the previous studies [9][10][11][12][13][14][15][16][17][18][19][20] as referenced below the gene symbol in the Table.…”

“…Nine genes (see Results) whose rSNPs have been shown to be significantly associated with disease or sickness [9][10][11][12][13][14][15][16][17][18][19][20] are listed in the Table as well as the rSNP alleles and frequencies. The number of conserved TFBS between the two SNP alleles and unique TFBS per allele which have been previously determined [9][10][11][12][13][14][15][16][17][18][19][20] are included in the Table. The names of conserved and unique TFBS can be found in the previous studies [9][10][11][12][13][14][15][16][17][18][19][20] as referenced below the gene symbol in the Table.…”

“…The JASPAR CORE database [23,24] and ConSite [25] were used to identify the TFBS in previous studies [9][10][11][12][13][14][15][16][17][18][19][20]. JASPAR is a collection of transcription factor DNA-binding preferences used for scanning genomic sequences where ConSite is a web-based tool for finding cisregulatory elements in genomic sequences.…”

“…RegulomeDB also makes computational predictions to identify putative regulatory potential and functional variants. In present report, these analyses were conducted on nine previously studied genes whose rSNPs have significantly associated with disease or sickness [9][10][11][12][13][14][15][16][17][18][19][20].…”

“…A SNP occurring in a motif may increase or decrease the corresponding Transcription Factor's (TF) ability to bind DNA resulting in allelespecific gene expression [8]. Several studies have been made to identify changes in punitive TFBS created by regulatory (r) SNPs significantly associated with human disease or sickness [9][10][11][12][13][14][15][16][17][18][19][20]. However, among these studies to date, there hasn't been any conclusive evidence as to which TF alteration might be responsible for a given disease or sickness.…”