Genetic Association of VDR Variants with Diabetic Foot Ulcers in Type 2 Diabetes: Evidence from Kerala, India

Background: Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus (DM), contributing significantly to morbidity and healthcare burden. Kerala, a South Indian state, has a high prevalence of diabetes, yet limited data exist on the genetic risk factors for DFU in this population. Vitamin D, beyond its role in calcium homeostasis, is crucial for immune regulation and wound healing. Methods In this study, plasma vitamin D levels were evaluated in individuals with DFU (n=112), DM without ulcers (n=112), and non-diabetic controls (n=112). We also assessed the association of four common vitamin D receptor (VDR) gene polymorphisms—rs7975232 (ApaI), rs731236 (TaqI), rs1544410 (BsmI), and rs2228570 (FokI)—with DFU and DM. Results The arithmetic mean 25(OH)D levels were 17.7 ± 14.2 ng/mL (DFU), 19.5 ± 12.4 ng/mL (DM), and 20.6 ± 13.9 ng/mL (controls). Geometric means were lower across all groups, with 12.7 ng/mL (DFU), 15.4 ng/mL (DM), and 15.7 ng/mL (controls), indicating widespread vitamin D deficiency, especially in DFU cases. Among the SNPs studied, rs731236 and rs1544410 showed statistically significant associations with DFU. The AG genotype of rs731236 was significantly associated with a reduced risk of DFU compared to both DM patients and non-diabetic controls (p < 0.05, OR ≈ 0.5), indicating a strong protective effect. Similarly, the TC genotype of rs1544410 showed a protective association against DFU (p = 0.0219, OR = 0.51). In contrast, the AA genotype of rs731236 and TT genotype of rs1544410 were marginally associated with increased DFU risk. No significant associations were found for rs2228570 and rs7975232. However, the ff genotype of rs2228570, which is associated with a less active VDR protein, was predominantly observed among study participants. VDR polymorphisms, especially rs731236 and rs1544410, may significantly influence DFU susceptibility in the Kerala population and hold promise as genetic risk markers. Routine vitamin D screening could aid early risk assessment in diabetic individuals.