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

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. In this study, we assessed the association of four common vitamin D receptor (VDR) gene polymorphisms-rs7975232 (ApaI), rs731236 (TaqI), rs1544410 (BsmI), and rs2228570 (FokI)-with DFU in Kerala population. Mean serum 25-hydroxyvitamin D 25(OH)D) levels were 17.7 ± 14.2 ng/mL in the DFU group, 19.5 ± 12.4 ng/mL in the DM group, and 20.6 ± 13.9 ng/mL in the control group. Although the mean 25(OH)D levels did not differ significantly among the groups, the prevalence of vitamin D deficiency was significantly higher in the DFU group than in the DM and control groups (χ² = 6.03, P = 0.04), indicating a greater burden of vitamin D deficiency among patients with diabetic foot ulcers. Among the SNPs studied, rs731236 and rs1544410 showed significant associations with DFU. The AG genotype of rs731236 was associated with a reduced risk of DFU compared to both DM patients and non-diabetic Controls (p < 0.05, OR = 0.51). Similarly, the TC genotype of rs1544410 showed a protective association (p = 0.0219, OR = 0.51). No significant associations were found for rs2228570 and rs7975232. Functional docking analysis of rs2228570 indicated favourable calcitriol binding to both VDR isoforms, with slightly higher affinity for the shorter 424 aa variant (- 7.8 vs. - 7.7 kcal/mol). these findings suggest that vitamin D deficiency and genetic variation in the VDR gene, particularly rs731236 and rs1544410, may contribute to susceptibility to diabetic foot ulcer in the Kerala population, warranting further validation in larger, multicentre studies and functional investigations.