Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB1*03, DRB1*04 and DRB1*07 and decreased frequencies of DRB1*10, DRB1*14, and DRB1*15 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB1*03-homo (p < 0.002) and DRB1*04-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB1*04-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB1*03-pooled (p < 0.0006), DRB1*03-hetero (p < 0.0006) and DRB1*03-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB1*04-pooled (p < 0.040), DRB1*04-hetero (p < 0.060), and DRB1*04-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB1*04-pooled (p < 0.0022), and DRB1*04-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45 CD14, CD19, CD14 and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10) and decrease of TA (p < 4.57 × 10) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB1*03 + AA, *03 + AG, *03 + GG and *04 + GG and protective associations for DRB1*10 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.
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