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HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM

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Abstract

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 × 10–6) and decrease of TA (p < 4.57 × 10–4) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10–5) 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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Funding

The authors received financial support from DST-WoSA Grant (CR) (Department of Science and Technology), New Delhi (Ref. No.: SR/WOS-A/LS-657/2016), and Tissue Typing Services, Madurai Kamaraj University (KB).

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Authors and Affiliations

  1. Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India

    Rathika Chinniah, Vandit Sevak, Sasiharan Pandi, Padma Malini Ravi & Balakrishnan Karuppiah

  2. Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA

    Murali Vijayan

  3. The Madurai Institute of Diabetes and Endocrine Practice Research, Madurai, Tamil Nadu, 625 001, India

    Arun Kannan

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  1. Rathika Chinniah
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  2. Vandit Sevak
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Chinniah, R., Sevak, V., Pandi, S. et al. HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM. Immunogenetics 73, 291–305 (2021). https://doi.org/10.1007/s00251-021-01212-x

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