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Background and Objective: Autoimmune Thyroid Diseases (AITDs), that include Graves' disease (GD) and Hashimoto thyroiditis (HT) are the most prevalent organ specific autoimmune ailments with a 7.1% of the total Indian population being affected. Our initial data showed an exaggerated inflammation in the circulating leukocytes and a decline in endogenous vitamin D levels and the vitamin D receptor expression in GD patients. The aim of the study is to find out the association of vitamin D receptor (VDR) gene polymorphisms with susceptibility to GD, and elucidate cellular stress pathways in the circulating leukocytes underlying the pathogenesis of GD. Methodology: 50 GD patients and 40 control subjects were recruited so far in the present study from Ramakrishna Mission Seva Pratishthan hospital OPD, Kolkata, West Bengal following necessary protocols. Various hematological and genetic parameters were studied from blood. Biochemical parameters and thyroid auto-abs were assessed with auto analyzer. Differential mRNA and protein expressions were determined by Real time PCR, and Western Blot respectively. Results: As expected, an extensive female preponderance found in the AITD patients (1:3.16 ratio). 4.7-fold increase in TSH-R antibody found in GD patients (4.363 ± 0.97 IU/L). Anti-TPO ab and anti-Tg ab were increased by 70.40-fold and 16.41-fold respectively in GD patients compared to controls. Low level of serum vitamin D (16.719 ± 1.248 ng/ml) and down regulation of mRNA expression of VDR (1.8-fold) found in GD patients, indicating a possible link with immune dysregulation in GD. PCR-RFLP studies revealed that 75% of GD patients have Apa1 (rs7975232) VDR polymorphism while 33% have Bsm1 (rs1544410) polymorphism. 83.3% of GD patients are found to be HLA-DQB2 positive. Consequently, major TH1 cytokines, TNF-a and IL-2 levels in serum were markedly enhanced by 29.60 and 1.314 folds respectively over controls (246.016 ± 57.522; 45.343 ± 3.352). We also found a significant ER stress in the PBMCs. mRNA expressions of IRE1-a, PERK and ATF6 were upregulated like 2.6, 1.5, 2.0-fold respectively compared to controls (P < 0.05), indicating activation of all three branches of UPR during ER stress. Conclusion: At this point of study, our data strongly suggest a marked shift in immune response with vitamin D deficiency GD patients, also vitamin D receptor gene expression was found to be down regulated. HLA-DQB2 expression was found to be strongly associated with GD. Also, the activation of ER stress pathways was observed in the GD patients. [ABSTRACT FROM AUTHOR]