Analysis of the Exonic Single Nucleotide Polymorphism rs182428269 of the NRF2 Gene in Patients with Diabetic Foot Ulcer

Abstract

The pivotal role of Nuclear factor erythroid-2-related factor 2 (NRF2) in redox homeostasis and wound healing has been well documented. However, the genetic mechanisms that regulate NRF2 in type 2 diabetes and diabetic foot ulcers remain unexplored. The present study investigated the association of single nucleotide polymorphism rs182428269 (-127C/T) in subjects with type 2 diabetes and diabetic foot ulcers. This cross-sectional study comprised 400 participants that included group I: normal glucose tolerant subjects (NGT, n=150), group II: type 2 diabetes mellitus subjects (T2DM, n=150) and group III: infected diabetic foot ulcer subjects (DFU, n=100). The non-synonymous SNP rs182428269 was selected based on in silico analysis and genotyped by PCR-restriction fragment length polymorphism (RFLP) followed by bidirectional Sanger sequencing. In addition, the gene expression of NRF2 in patients with polymorphism was analyzed by qPCR to evaluate the functional impact of the SNP. NRF2 expression was significantly decreased among the T2DM and DFU subjects when compared to the NGT subjects. Of particular interest, the homozygous mutant (TT) genotype of rs182428269 polymorphism was significantly associated with an increased risk for the development of T2DM (OR=1.95 (1.02-3.72), p=0.04) and DFU (OR=5.66 (2.98-10.76), p=0.0001). Furthermore, a progressive decline in NRF2 expression was observed among the T2DM and DFU subjects with "TT" genotype compared to the "CC" and "CT" genotypes. NRF2 polymorphism rs182428269 is associated with the pathogenesis of T2DM and DFU.