Vitamin D Receptor Gene Variants Tied to Diabetic Foot Ulcer Risk in Kerala Study

Diabetic foot ulcers are among the most feared complications of type 2 diabetes, a wound that refuses to heal, threatens limb and life, and imposes staggering costs on patients and health systems alike. Now, a team of researchers in the southern Indian state of Kerala has added a striking new dimension to the search for who is most vulnerable: inherited variation in the vitamin D receptor gene. In a study published in the journal Biochemical Genetics, Remya Reveendran of the National Institute of Technology Calicut and colleagues report that two common variants of the vitamin D receptor, or VDR, gene are significantly associated with the risk of developing a diabetic foot ulcer, while vitamin D deficiency itself is markedly more common among ulcer patients than among people with diabetes who have avoided the complication.

The stakes of the question are enormous. Diabetic foot ulcers affect a substantial fraction of the world’s more than half a billion people living with diabetes, and their consequences rival those of many cancers. Previous research cited by the authors has shown that five-year mortality and direct costs of care for people with diabetic foot complications are comparable to those faced by cancer patients. Kerala, a state with one of India’s highest diabetes burdens and a well-documented ten-year cohort documenting the incidence of type 2 diabetes and prediabetes, offers a particularly important setting for this kind of investigation. Yet until now, genetic risk factors for foot ulcers in this population had been barely explored.

The research team focused on the vitamin D system for good reason. Vitamin D is far more than a bone-building nutrient; its active form, calcitriol, binds to the vitamin D receptor to regulate hundreds of genes involved in immune defence, inflammation, insulin secretion and tissue repair. Wound healing is an intricate biological process that depends on precisely coordinated cell migration, matrix remodelling and antimicrobial activity, all of which are influenced by vitamin D signalling. Small variations in the VDR gene, known as single nucleotide polymorphisms, can subtly alter how strongly the receptor is expressed or how efficiently it responds to its hormonal ligand, potentially shifting the balance between effective healing and chronic, non-healing wounds.

Reveendran and colleagues examined four of the most widely studied VDR polymorphisms, each named after the restriction enzyme originally used to detect it: rs7975232 (ApaI), rs731236 (TaqI), rs1544410 (BsmI) and rs2228570 (FokI). These variants sit at different points in the gene. The BsmI, ApaI and TaqI sites lie in or near the three-prime untranslated region, where they may influence messenger RNA stability, while FokI sits in the start codon region and is famous for creating two physically different versions of the receptor protein: a longer 427-amino-acid form and a shorter 424-amino-acid form that differs in its ability to activate target genes.

The study compared three groups: patients with diabetic foot ulcers, patients with type 2 diabetes but no foot ulcers, and non-diabetic controls, all recruited in Kerala. The researchers measured serum levels of 25-hydroxyvitamin D, the standard clinical marker of vitamin D status, and genotyped participants for the four polymorphisms. The mean 25-hydroxyvitamin D levels were low across the board, at 17.7 plus or minus 14.2 nanograms per millilitre in the foot ulcer group, 19.5 plus or minus 12.4 in the diabetes group and 20.6 plus or minus 13.9 in the controls. Those averages did not differ significantly between the groups, but when the researchers looked at deficiency as a categorical state rather than a continuous measurement, a clear signal emerged: the prevalence of vitamin D deficiency was significantly higher in the foot ulcer group than in either the diabetes or control groups, a difference the authors report with a chi-squared statistic of 6.03 and a p-value of 0.04.

The genetic findings were even more intriguing. Two of the four variants showed significant associations with foot ulcer risk. For rs731236, the TaqI polymorphism, carrying the AG genotype was associated with a reduced risk of diabetic foot ulcer compared with both the diabetes-only patients and the non-diabetic controls, with an odds ratio of 0.51 and a p-value below 0.05. In other words, people carrying that genotype were roughly half as likely to develop an ulcer. A strikingly similar protective pattern appeared for rs1544410, the BsmI polymorphism, where the TC genotype was associated with reduced risk, with an odds ratio of 0.51 and a p-value of 0.0219. The other two variants, FokI (rs2228570) and ApaI (rs7975232), showed no significant associations with ulcer susceptibility in this population.

To probe the biology behind the FokI variant, the team turned to computational molecular docking, a technique that predicts how strongly two molecules bind to each other. They modelled the binding of calcitriol, the active hormonal form of vitamin D, to both protein isoforms generated by the FokI polymorphism. The docking analysis indicated favourable calcitriol binding to both receptor versions, with a slightly higher affinity for the shorter 424-amino-acid variant, at minus 7.8 kilocalories per mole versus minus 7.7 for the longer form. Although the difference is small, such subtle changes in ligand affinity can, in principle, translate into differences in receptor signalling output, and previous studies have linked FokI variation to oxidative stress and wound outcomes in diabetic foot patients in other populations, including work in Iran and Indonesia.

The protective associations of the TaqI and BsmI variants fit into a growing international literature. Meta-analyses have examined VDR polymorphisms in susceptibility to type 2 diabetes itself, and systematic reviews of genetic polymorphisms and diabetic foot risk have catalogued associations across multiple ethnic groups. A recent prospective observational study at a South Indian tertiary care facility also explored the interplay between vitamin D status and VDR genotype in foot ulcer patients. The Kerala findings add population-specific evidence from a region where diabetes prevalence is exceptionally high and where earlier clinical surveys have documented the heavy burden of foot complications in both hospital podiatry clinics and rural communities. Because genetic associations can vary substantially between populations owing to differences in allele frequencies and environmental exposures, regionally grounded studies like this one are essential for building a complete global picture.

What makes the study particularly compelling is the convergence of two independent signals: a higher burden of vitamin D deficiency among ulcer patients and a protective effect of specific VDR genotypes. Together, they suggest that the vitamin D axis may influence not just whether someone develops diabetes, but whether the disease culminates in its most disabling complication. The authors caution, however, that these findings require validation in larger, multicentre studies and that functional investigations will be needed to establish exactly how the TaqI and BsmI variants alter receptor biology and wound healing. The study was supported by the Department of Science and Technology’s Science and Engineering Research Board and the Department of Biotechnology of the Government of India, and involved collaboration between the National Institute of Technology Calicut, the Nutrition Research Centre in Thiruvananthapuram, the Kerala University of Health Sciences and the Rajiv Gandhi Centre for Biotechnology.

If the associations hold up, the implications could be significant. Vitamin D status is modifiable through supplementation and sensible sun exposure, and genetic screening could one day help identify patients with diabetes who carry a heightened risk of foot ulcers before the first wound appears, allowing intensified preventive care for those who need it most. With diabetes prevalence projected to double globally by 2050 and foot ulcers already consuming a disproportionate share of diabetes-related healthcare spending, even modest advances in risk prediction could translate into many thousands of limbs and lives saved. For now, the Kerala study stands as a reminder that the answer to one of diabetes’ oldest clinical puzzles may lie partly in the fine print of the genome, written in the language of a sunshine vitamin.

Subject of Research: Association of vitamin D receptor gene polymorphisms and vitamin D deficiency with diabetic foot ulcer risk in type 2 diabetes

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

Article References: Reveendran, R., Thankam, S. K., Anish, T. S., Jose, L., Jones, S., & Vasu, S. T. (2026). Genetic Association of VDR Polymorphism with Diabetic Foot Ulcers in Type 2 Diabetes: Evidence from Kerala, India. Biochemical Genetics. https://doi.org/10.1007/s10528-026-11450-x

Image Credits: AI Generated

DOI: 10.1007/s10528-026-11450-x

Keywords: diabetic foot ulcer, type 2 diabetes, vitamin D receptor, VDR polymorphism, vitamin D deficiency, Kerala, genetic association, single nucleotide polymorphism, TaqI, BsmI, wound healing, calcitriol