RESUMEN
Purpose: The human vascular endothelial growth factor (VEGF)-A gene transcribes a signaling protein involved in the regulation of angiogenesis, vasculogenesis and endothelial cell growth. Two insertion/deletion (I/D) simple nucleotide polymorphisms (SNPs, rs34357231 & rs35569394) in the promoter region of the gene have been significantly associated with several human diseases. These SNPs were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to the diseases. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the VEGFA gene from 2.7 kb upstream of the transcriptional start site to 1.6 kb past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region of the VEGFA gene alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. The VEGFA-deletion (D) allele of these SNPs has been found to be a risk factor for diabetic retinopathy, diabetic microvascular complications in patients with type 1 diabetes mellitus, breast cancer in north Indian patients, and bladder cancer. The changes in TFs associated with the TFBS are examined with respect to these human diseases. Conclusion: The VEGFA-insertion (I) allele provides punitive TFBS for the AR, EGR1 & 2, KLF5 and SP1 TFs whose BS do not occur with the VEGFA-D allele. These TFs have been linked to prostate cancer, cancer suppression and oncogenic processes and if not regulating the VEGFA gene may pose a risk for disease.
RESUMEN
Purpose: The DIO2 gene transcribes the deiodinase type 2 enzyme that changes the thyroid prohormone, thyroxine (T4), to the biologically active triiodothyronine (T3) hormone. T3 plays a vital part in the regulation of energy balance and glucose metabolism. DIO2 single-nucleotide polymorphisms (SNPs) were computationally examined with respect to changes in punitive transcriptional factor binding sites (TFBS) and these changes were discussed in relation to human disease. Methods: The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all the TFBS in the DIO2 gene from 2.4 kb upstream of the transcriptional start site to 508 bp past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results: Regulatory SNPs (rSNPs) in the promoter region novel SNP (-2035bp), 5’UTR (rs12885300), intron one (rs225010, 225011 and rs225012), exon two [rs225014 (Thr92Ala)] and 3’ UTR (rs6574549, rs225015 and rs225017) of the DIO2 gene are in linkage disequilibrium. These rSNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS. Conclusion: The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF DIO2 regulation. These regulatory changes were discussed with respect to changes in human health resulting in disease or sickness.