Vitamin D Receptor rs731236 Polymorphism Modulates Cancer Cachexia Susceptibility and Overall Survival: A Real-World Study on Context- Dependent Vitamin D Signalling

Abstract Purpose Cancer-associated cachexia (CAC) is a complex metabolic syndrome characterised by progressive skeletal muscle loss, systemic inflammation, reduced treatment tolerance, and poor survival. Individual susceptibility to CAC varies considerably, suggesting a contribution of host genetic factors. Vitamin D plays an important role in muscle metabolism and inflammatory control through activation of the vitamin D receptor (VDR). VDR signalling influences myogenesis, mitochondrial function, insulin-like growth factor pathways, and pro-inflammatory cytokine expression, all of which are implicated in the pathophysiology of cachexia. Hence, VDR variants, including the rs731236 (A > G) polymorphism, which modifies receptor activity and downstream biological responses, may potentially affect CAC pathogenesis. This study aimed to investigate the association between the polymorphism and susceptibility to CAC as well as patients’ overall survival (OS). Methods To explore the implications of the rs731236 variant, a hospital-based study was conducted with 140 adult cancer patients. CAC was assessed using Fearon criteria and the CASC-IN screening tool. Genotyping of the VDR rs731236 polymorphism was performed through real-time PCR. Associations with CAC and OS were analysed using chi-square tests and Kaplan-Meier survival analysis, respectively. Results The rs731236 GG genotype was significantly associated with a lower CAC prevalence across diagnostic approaches ( p  < 0.05). GG genotype carriers also demonstrated significantly improved OS than carriers of AA/AG genotypes (Log-rank and Tarone-Ware tests, p  < 0.05). Conclusion The rs731236 polymorphism appears to influence susceptibility to CAC and cancer patient survival, adding to the existing evidence of a clinically relevant role for vitamin D signalling in supportive oncology care.