Genetic determinants of cellular homeostasis contributing to the risk of type 2 diabetes

Genetic variation in the genes involved in the maintenance of cellular homeostasis may influence susceptibility to type 2 diabetes (T2D). However, the nature of the interplay among these loci and their prognostic value remains unclear. In this study, we analyzed variants in the FOXO3A, FOXO3, FOXO1, HMOX1, and SIRT1 genes. The HMOX1 rs2071746*T/T genotype was associated with an increased risk of T2D (OR = 1.36, PFDR = 0.030), whereas the FOXO1 rs9549240 (OR = 0.52, PFDR = 0.002) and SIRT1 rs3758391 (OR = 0.80, PFDR = 0.015) genotypes exhibited a protective effect. We detected nonlinear interactions, including FOXO1 rs9549240*G + SIRT1 rs3758391*T + SIRT1 rs7895833*A and HMOX1 rs2071746*A + SIRT1 rs3758391*T + SIRT1 rs7895833*A, with significant synergistic effects (SF = 3.19 and 2.56, P < 0.03). Models incorporating these interactions achieved an AUC of 69.8%, which increased to 86.2% when combined with age, sex, and the body mass index. These findings suggest that interactions between the pathways regulating oxidative stress and metabolism may contribute to the genetic predisposition to T2D.