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]

Rojnić Putarek, Nataša (2015) 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]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

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. SUBJECTS 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. RESULTS: 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). CONCLUSION: 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.

Abstract in Croatian

UVOD: Zajedniĉko pojavljivanje dijabetesa melitusa tip 1 (DMT1) i autoimune bolesti štitnjaĉe (AITD) u iste osobe klasificira se kao varijanta autoimunog poliglandularnog sindroma tip 3 (APS3v). Do sada su poznata najmanje 3 podloţna gena za nastanak APS3v i to geni HLA razreda II, gen CTLA-4 i gen PTPN22, a svi su ukljuĉeni u prezentaciju antigena T stanicama. ISPITANICI I METODE: U studiju je ukljuĉeno 323 nesrodnih bolesnika, 165 s DMT1 (94 s DMT1 bez AITD, 71 s APS3v), u dobi od 1.5-16.7 godina, i 158 s AITD (127 s autoimunim tiroiditisom, AT i 31 s Gravesovom bolešću, GB) u dobi od 4.3-25.9 godina. Kontrolna skupina ĉini 94 zdravih, nesrodnih ispitanika u dobi od 4.7-21.5 godina. Titrovi antitijela na citoplazmu β-stanice (ICA), glutamiĉku kiselu fosfatazu (GAD) i tirozin fosfatazu (IA-2), genotip HLA-DRB1, DQB1, polimorfizmi A49G i C60T gena CTLA4 te mutacija R620W gena PTPN22 ispitani su u svim skupinama ispitanika. RESULTATI: Uĉestalost autoimunosti na β-stanice Langerhansovih otoĉića u bolesnika s AITD bila je 10.76% (17/158), statistiĉki znaĉajno viša nego u kontrolnoj skupini ispitanika (0%, 0/94; p=0.001). Viša je uĉestalost naĊena u bolesnika s AT (11.81%, 15/127) nego s GB (6.45%, 2/31). Povišeni titrovi sva tri antitijela na β-stanice Langerhansovih otoĉića naĊeni su u 3 bolesnika s AITD, a troje je imalo pozitivna dva od ta tri antitijela. Svih šestero bolesnika razvilo je DMT1 tijekom razdoblja istraţivanja od 2 i pol godine. Nije naĊena statistiĉki znaĉajna razlika u uĉestalosti haplotipa HLA visokog i srednjeg rizika za razvoj DMT1 u bolesnika s AITD i pozitivnom β-staniĉnom autoimunosti u odnosu na kontrolnu skupinu ispitanika. Haplotipovi HLA niskog rizika za razvoj DMT1 statistiĉki su znaĉajno rjeĊe prisutni u bolesnika s AITD (31,3%) u odnosu na kontrolne ispitanike (69,9%; p=0,003). Riziĉni G/G genotip polimorfizma A49G gena CTLA4 statistiĉki je znaĉajno ĉešći u bolesnika s AITD i β-staniĉnom autoimunosti u odnosu na one bez (p=0.024). ZAKLJUČAK: Rezultati ove studije upućuju da su bolesnici s AITD, posebno s AT skloni razvoju β-staniĉne autoimunosti i DMT1, osobito oni u kojih su naĊeni povišeni titrovi više antitijela na β-stanice Langerhansovih otoĉića.

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