Common genetic polymorphisms are excluded from functional hypoxia response elements

Abstract

A wide range of diseases course with an unbalance between the consumption of oxygen by tissues and its supply. This situation triggers a transcriptional response, mediated by the hypoxia inducible factors (HIFs), that aims to restore oxygen homeostasis. Little is known about the inter-individual variation in this response and its role in the progression of disease. Herein, we sought to identify common genetic variants affecting hypoxia response elements (HREs) and characterize their effect on transcription. To this end, we constructed a list of genome-wide HIF-binding regions from publicly available experimental datasets and studied the genetic variability in these regions by integration of human variability deposited in the dbSNP database. Our analysis revealed that, although we found 141 SNPs that disrupt potential HREs in HIF-bound regions, the proportion of functional HREs affected by variants is significantly lower than expected by chance. These data strongly suggest that functional HREs are under negative selection.