Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population

BackgroundType 2 diabetes (T2D) is known as an inflammatory disease. NRF2 (Nuclear Factor Erythroid 2 Like2) encodes a transcription factor that binds to antioxidant response elements (AREs) and regulates the expression of genes involved in many antioxidant responses.ObjectiveThis study aimed to gain insight into individual anti-inflammatory activity to prevent T2D development in humans.MethodsWe performed a genome-wide association study (GWAS) to identify genetic variants influencing NRF2 expression in LCLs (lymphoblastoid cell lines) generated from 74 different individuals. Association analyses between T2D or its related traits and genetic risk score (GRS) calculated by combining genetic variants detected from GWAS for cellular NRF2 expression were performed using data from 8715 subjects. The T2D prediction model using GRS was evaluated by measuring the area under the curve (AUC) of the receiver operating characteristics (ROC) curve.ResultsOur GWAS identified six genetic variants (SNP) showing suggestive evidence of associations with cellular NRF2 expression (P<10(-6)). Logistic regression analysis demonstrated that GRS was associated with an increased risk of T2D (P value=0.003, OR=1.13). In addition, linear regression analyses showed positive associations between GRS and fasting glucose (P value=0.028, =0.62), 2-h glucose (P value=0.0004, =1.13) and HbA1C (P value=0.033, =0.03). In the T2D prediction model using GRS, the AUC of the ROC curve was 0.69.ConclusionThis study highlights genetic variants associated with cellular NRF2 expression and suggests that the GRS of NRF2 expression-associated variants is likely to be a useful indicator of T2D development in the human population.