Elucidating the Role of Vitamin D Receptor (VDR) Polymorphisms in Genetic Susceptibility to Systemic Lupus Erythematosus: A Case-Control Study From Western India

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder influenced by genetic and environmental factors. Vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms are suggested to modulate immune dysregulation in SLE. This study aimed to investigate the association of VDR polymorphisms (BsmI, ApaI, TaqI and FokI), serum 25-hydroxyvitamin D [25-OH vitamin D] levels and clinical phenotypes in Indian SLE patients. A hospital-based case–control study was conducted on clinically diagnosed SLE patients (n = 297) fulfilling American College of Rheumatology (ACR) criteria and healthy controls (n = 100). Serum 25-OH vitamin D levels, autoantibody profile and complement components were evaluated by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and nephelometry. Genotyping for VDR polymorphisms BsmI (rs1544410) B/b, ApaI (rs7975232) A/a, TaqI (rs731236) T/t and FokI (rs2228570) F/f was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were statistically analysed using chi-square tests, logistic regression and correlation analysis. The median age at evaluation in SLE patients was 29 years, with a female predominance (91.9%). Median serum 25-OH vitamin D levels were 30.4 ng/mL, with lower levels observed in patients with arthritis (p = 0.012), neurological involvement (p = 0.015) and active disease (p = 0.025). Serum 25-OH vitamin D inversely correlated with disease activity (r = −0.127, p = 0.032), anti-cardiolipin antibody (ACLA) immunoglobulin G (IgG) (p < 0.001) and anti-phospholipid antibody (APLA) IgG (p = 0.030). Among VDR polymorphisms, BsmI b allele conferred reduced disease risk (odds ratio [OR] = 1.85, p < 0.001). TaqI genotypes (Tt: OR = 2.29 and tt: OR = 6.48, p < 0.05) and t allele (OR = 2.15, p < 0.001) and FokI genotypes (Ff: OR = 4.13 and ff: OR = 3.14, p <0.05) were strongly associated with increased susceptibility to SLE. ApaI variants were significantly associated with alopecia, haematological manifestations, disease activity and low complement component 3 (C3) levels, whereas BsmI and FokI polymorphisms were associated with neurological manifestations (p < 0.05). Vitamin D receptor gene (VDR gene) polymorphisms may contribute to phenotypic variability and immune dysregulation in Indian SLE patients, suggesting that gene–environment interactions between vitamin D status and VDR variants may influence SLE susceptibility and clinical heterogeneity.