Povezanost biljega polimofizma gena HLA razreda II, CTLA-4 i PTPN22 te specifičnih autoantitijela protiv beta stanica Langerhansovih otočića s nastankom dijabetesa melitusa tipa 1 u bolesnika s autoimunom bolešću štitnjače The association of HLA class II, CTLA-4 and PTPN22 genetic polymorphisms and autoantibodies to beta Langerhans islet cells in development of type I diabetes in patients with autoimmune thyroid disease

摘要

BACKGROUND: Co-occurrence of type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD) in the same patient is classified as variant of autoimmune polyglandular syndrome type 3 (APS3v). At least three susceptibility genes for this syndrome have been identified, HLA class II, CTLA-4 and PTPN22 gene, all involved in T-cells antigen presentation.udSUBJECTS AND METHODS: The study comprised of 323 unrelated patients, 165 with T1D (94 with T1D alone, 71 with APS3v), aged 1.5-16.7 years, and 158 with AITD (127 with autoimmune thyroiditis, AT and 31 with Graves disease, GD), aged 4.3-25.9 years. The control group consisted of 94 unrelated healthy subjects, aged 4.7-21.5 years. Islet cell cytoplasmic (ICA), glutamic acid decarboxylase (GADA) and thyrosin phosphatase islet (IA-2) autoantibodies as well as HLA-DRB1, DQB1 genotypes, A49G and C60T polymorphisms of CTLA4 gene and R620W mutation of PTPN22 gene were analysed in all groups.udRESULTS: The prevalence of β-cell autoimmunity in patients with AITD was 10.76% (17/158), significantly higher than in control subjects (0%, 0/94; p=0.001). Higher prevalence was found in patients with AT (11.81%, 15/127) than GD (6.45%, 2/31). All three β-cell autoantibodies were found in 3 patients, and three patients were positive to two autoantibodies. All six of them developed T1D during the investigation period of 2.5 years. No difference in frequency of high or moderate risk HLA haplotypes for development of T1D in patients with AITD and β-cell autoimmunity and control subjects was found. Low risk HLA haplotypes for development of T1D were found more frequently in control subjects than in patients with AITD and islet autoimmunity (69.9% vs 31.3%, p=0.003). Disease associated G/G genotype of CTLA4 gene A49G polymorphism was significantly more common in AITD patient with islet autoimmunity than in ones without (p=0.024).udCONCLUSION: Our results indicate that patients with AITD, and in particular AT, are prone to develop β-cell autoimmunity and T1D, especially those with positive multiple islet cell autoantibodies.