Genetic Polymorphism of the Nrf2 Promoter Region (rs35652124) Is Associated with the Risk of Diabetic Foot Ulcers
Teena Rajan, Dhamodharan Umapathy, Daoud Ali, Rajesh Kesavan, Kunka Mohanram Ramkumar
Abstract
The genetic polymorphism in the nuclear factor erythroid 2-related factor 2 (Nrf2) gene has been reported as one of the prognosis markers for various diseases, including cancer. Nrf2 is a key transcription factor involved in wound healing by regulating angiogenesis. We investigated the genetic association of NRF2 single-nucleotide polymorphism rs35652124 with T2DM and DFU and assessed its functional impact. A total of 400 subjects were recruited for the study and categorized into three groups: infected DFU patients (DFU, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>100</mml:mn></mml:math>), T2DM patients without complications (T2DM, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>150</mml:mn></mml:math>), and healthy adults with normal glucose tolerance (NGT, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>150</mml:mn></mml:math>). The subjects were genotyped by PCR-RFLP, and the polymorphism was identified by bidirectional Sanger sequencing. The expression of NRF2 , IL-10 , TNF-α , and IL-6 was studied by qPCR to evaluate the functional impact of rs35652124. The “TT” genotype of rs35652124 was associated with a significant risk for T2DM [<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mtext>OR</mml:mtext><mml:mo>=</mml:mo><mml:mn>2.2</mml:mn></mml:math> (1.2-4.2), <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.01</mml:mn></mml:math>] and DFU [<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mtext>OR</mml:mtext><mml:mo>=</mml:mo><mml:mn>7.9</mml:mn></mml:math> (4-14.9), <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.0001</mml:mn></mml:math>]. A significant decrease in transcriptional levels of NRF2 and IL-10 and a remarkable increase in TNF-α and IL-6 were observed in subjects with TT genotype. In conclusion, rs35652124 (TT) is a harmful genetic variant that predisposes to insulin resistance and impaired angiogenesis. Hence, it may serve as a diagnostic genetic marker for T2DM and DFU in combination with different inflammatory markers.