Identifying Changes in Punitive Transcriptional Factor Binding Sites Created by PPAR<i>α/δ/γ</i> SNPs Associated with Disease

Abstract

Single nucleotide polymorphisms (SNPs) located in the PPARα/δ/γ genes that have been previously found to be significantly associated with human disease or a condition were also found to alter the genes punitive transcriptional factor binding sites (TFBS). Two alleles (C/G) of the PPARα SNP (rs1800206) were found to generate 7 common and 8 unique punitive TFBS. One of the unique TFBS created by the minor G (0.02) allele is for the T-Box 4 (TBX4) transcription factor which is associated with heritable pulmonary arterial hypertension. Two alleles (A/G) of the PPARδ SNP (rs2016520) were found to generate 20 unique punitive TFBS while the two alleles (C/G) of the PPARδ SNP (rs9794) were found to generate 11 common and 11unique punitive TFBS. The alleles of the PPARγ SNPs (rs10865710, rs12629751, rs709158, rs1805192 and rs3856806) were found to generate 15, 12, 16, 2 and 21 common and 9, 4, 12, 4 and 7 unique punitive TFBS, respectively. These changes in TFBS are discussed with relation to alterations in gene expression that may result in disease or change in human condition.

SNPs, transcriptional factor binding sites and disease

“…The TBX4 transcription factor is associated with the disease heritable pulmonary arterial hypertension [97], which may in part be responsible for the variation in lipid serum levels and disease risks found to be significantly associated with the this SNP. The occurrence of the G allele in the Han Chinese population is 0.02 [94] which is a frequency that might be expected among heritable diseases. This SNP has also been associated with changes in triglyceridemia, total cholesterol, low-density lipoprotein-cholesterol (LDL-c),highdensity lipoprotein-cholesterol (HDL-c) and apolipoprotein A1 (APOA1) plasma concentrations in populations of African-Americans, Caucasians and Indians [95,96,98,99].…”

“…One of its SNPs (rs10865710) has been associated with obesity risk, systemic sclerosis and low-density lipoprotein-cholesterol in Han Chinese [85,89,92]. The rs10865710 SNP (C/G) common C-allele creates a unique punitive TFBS for the POU class 2 homeobox 2 (POU2F2) which does not occur with the minor G-allele [94]. This TF is found in immunoglobulin gene promoters and the absence of this BS with the minor G-allele in part may be responsible for the association of this SNP with systemic sclerosis.…”

“…One of its SNPs (rs2016520) has been associated with obesity risk and intracerebral hemorrhages while a second SNP (rs9794) has been found to be associated with hypertriglyceridemia and obesity in Han Chinese [85,90,93]. The rs2016520 SNP (A/G) common A-allele creates unique punitive TFBS for the neuronal differentiation 2 (NEUROD2) and oligodendrocyte transcription factor 3 (OLIG3) TFs which do not occur with the minor G-allele [94]. The NEUROD2 TF is a transcriptional regulator implicated in neuronal determination while the OLIG3 TF promotes formation and maturation of oligodendrocytes, especially within the brain.…”

“…The rs1800206 PPARα SNP (C/G) has been associated with variation in lipid serum levels in Caucasian and Indian populations [95,96], hypertriglyceridemia risk, dyslipidemia risk and low-density lipoprotein-cholesterol risk in Han Chinese [86,87,92]. The minor G allele generates a unique punitive T-Box 4 (TBX4) TFBS not found with the common G-allele [94]. The TBX4 transcription factor is associated with the disease heritable pulmonary arterial hypertension [97], which may in part be responsible for the variation in lipid serum levels and disease risks found to be significantly associated with the this SNP.…”

“…There have been several PPARα/δ/γ SNPs significantly associated with various human diseases or conditions [85][86][87][88][89][90][91][92][93]. Some of the PPARα/δ/γ SNPs were found to create alterations in punitive TFBS and these potential changes were examined with respect to disease [94]. The rs1800206 PPARα SNP (C/G) has been associated with variation in lipid serum levels in Caucasian and Indian populations [95,96], hypertriglyceridemia risk, dyslipidemia risk and low-density lipoprotein-cholesterol risk in Han Chinese [86,87,92].…”