Shared and distinct genetics of pure type 1 diabetes and type 1 diabetes with celiac disease, homology in their auto-antigens and immune dysregulation states: a study from North India

Acta Diabetol. 2024 Jun;61(6):791-805. doi: 10.1007/s00592-024-02258-5. Epub 2024 Mar 14.

Abstract

Aim: This study was undertaken to explicate the shared and distinctive genetic susceptibility and immune dysfunction in patients with T1D alone and T1D with CD (T1D + CD).

Methods: A total of 100 T1D, 50 T1D + CD and 150 healthy controls were recruited. HLA-DRB1/DQB1 alleles were determined by PCR-sequence-specific primer method, SNP genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP-array and genotyping for INS-23 Hph1 A/T was done by RFLP. Autoantibodies and cytokine estimation was done by ELISA. Immune-regulation was analysed by flow-cytometry. Clustering of autoantigen epitopes was done by epitope cluster analytical tool.

Results: Both T1D alone and T1D + CD had a shared association of DRB1*03:01, DRB1*04, DRB3*01:07/15 and DQB1*02. DRB3*01:07/15 confers the highest risk for T1D with relative risk of 11.32 (5.74-22.31). Non-HLA gene polymorphisms PTPN22 and INS could discriminate between T1D and T1D + CD. T1D + CD have significantly higher titers of autoantibodies, expression of costimulatory molecules on CD4 and CD8 cells, and cytokine IL-17A and TGF-β1 levels compared to T1D patients. Epitopes from immunodominant regions of autoantigens of T1D and CD clustered together with 40% homology.

Conclusion: Same HLA genes provide susceptibility for both T1D and CD. Non-HLA genes CTLA4, PTPN22 and INS provide further susceptibility while different polymorphisms in PTPN22 and INS can discriminate between T1D and T1D + CD. Epitope homology between autoantigens of two diseases further encourages the two diseases to occur together. The T1D + CD being more common in females along with co-existence of thyroid autoimmunity, and have more immune dysregulated state than T1D alone.

Keywords: Celiac disease; Epitopes; Genetic polymorphism; Immune dysfunction; Type 1 diabetes.

MeSH terms

  • Adolescent
  • Adult
  • Autoantibodies / blood
  • Autoantibodies / immunology
  • Autoantigens* / genetics
  • Autoantigens* / immunology
  • CTLA-4 Antigen / genetics
  • Case-Control Studies
  • Celiac Disease* / genetics
  • Celiac Disease* / immunology
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1* / genetics
  • Diabetes Mellitus, Type 1* / immunology
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • HLA-DQ beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Humans
  • India / epidemiology
  • Male
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22* / genetics
  • Young Adult

Substances

  • PTPN22 protein, human
  • HLA-DQB1 antigen