Introduction In high-burden nations like India, tuberculosis (TB) continues to be a significant global public health concern. HIV infection, diabetes mellitus, and low socioeconomic status are examples of comorbid illnesses that increase susceptibility to tuberculosis (TB), and the introduction of multidrug-resistant tuberculosis (MDR-TB) has made disease control even more challenging. The time-consuming nature of conventional drug susceptibility testing (DST) emphasizes the critical need for quick biomarkers to forecast treatment outcomes and resistance. Because of their possible impact on host immunity and MDR-TB risk, genetic variations particularly vitamin D receptor (VDR) polymorphisms have drawn attention. Methods Studies published between 2000 and 2024 were the subject of an extensive examination of the literature. Relevance led to the selection of 213 articles. Keywords including vitamin D, VDR polymorphisms, MDR-TB, pulmonary tuberculosis, and immune response were used to search databases such as PubMed, Web of Science, and Google Scholar. To guarantee comprehensive coverage, both original research articles and reviews were included. Results Low serum vitamin D levels were consistently linked to an elevated risk of MDR-TB and pulmonary tuberculosis (PTB), according to the investigation. Certain VDR polymorphisms have often been associated with altered immunological responses and an increased risk of disease, especially mutant forms like FokI and TaqI. Treatment response and disease progression have also been discovered to be influenced by immunological modulation and dietary variables. Discussion These results imply that vitamin D levels and VDR polymorphisms could be useful biomarkers for the diagnosis and prognosis of MDR-TB. Knowing the genetic susceptibility of the host may help develop individualized treatment plans and enhance the management of MDR-TB. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261295571 , identifier CRD420261295571.
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