Genetic polymorphisms and diabetic foot ulcer susceptibility: a systematic review and meta-analysis of Indian...

Diabetic foot ulcers (DFUs) represent a severe microvascular complication of diabetes mellitus (DM), leading to high morbidity, frequent hospitalizations, and lower-limb amputations. India, with a rapidly growing diabetic population, faces an escalating DFU burden exacerbated by limited healthcare access and genetic diversity. While clinical risk factors such as neuropathy, ischemia, and infection are well documented, variability in ulcer occurrence among individuals with similar profiles suggests a significant genetic component. This systematic review and meta-analysis aimed to synthesize evidence from Indian studies examining the association between genetic polymorphisms and DFU susceptibility. Following PRISMA 2020 guidelines, databases including Pub Med, Science Direct, and Google Scholar were searched up to July 2025. Nineteen genetic comparisons from case-control studies were analyzed with forest plot using RevMan 5.4.1, with subgroup analyses conducted for key biological pathways: inflammation, angiogenesis, immune response, and extracellular matrix (ECM) remodeling. Pooled results revealed a nearly threefold increased risk of DFU among carriers of risk alleles (OR 2.76; 95% CI 1.93-3.94; p < 0.00001). Angiogenesis-related polymorphisms, particularly HIF-1α and VEGF, showed the strongest associations (OR 4.97 and 5.60, respectively), underscoring the central role of vascular dysfunction. HSP70 (C243T_2; OR 19.45) and Nrf2 variants demonstrated exceptionally high effect sizes, linking impaired oxidative stress response and proteostasis to ulcer chronicity. Immune pathway variants, including TLR4, contributed moderately, while ECM-related polymorphisms showed smaller but significant effects. These findings establish DFU as a multifactorial genetic disorder shaped by interactions among angiogenic, inflammatory, immune, and structural pathways. Future multicentric genomic studies are warranted to validate high-effect variants and support the development of personalized prevention and treatment strategies for DFU in Indian populations.