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Open Access 01-01-2017 | Original Article

CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves’ disease and modulates clinical phenotype of disease

Authors: Edyta Pawlak-Adamska, Irena Frydecka, Marek Bolanowski, Anna Tomkiewicz, Anna Jonkisz, Lidia Karabon, Anna Partyka, Oskar Nowak, Marek Szalinski, Jacek Daroszewski

Published in: Endocrine | Issue 1/2017

Abstract

Graves’ disease, an autoimmune disease with heterogeneous symptoms including Graves’ orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.

Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves’ disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves’ disease patients. CTLA-4c.49A>G, CTLA-4g.319C>T, and CT60 were genotyped by PCR–RFLP; Jo31 and CD28c.17+3C>T by minisequencing; CTLA-4g.*642AT(8_33) and ICOSc.1554+4GT(8_15)—PCR and fluorescence-based technique. CD28c.17+3T>C(rs3116496)T/CTLA-4g.319C>T(rs5742909)C/CTLA-4c.49A>G(rs231775)G/CTLA-4g.*642AT(8_33)(AT_16–21)/CT60(rs3087243)G/Jo31(rs11571302)G/ICOSc.1554+4GT(8_15)(m) and TCA(AT_<16)GT(m) haplotypes increased risk of Graves’ disease, especially in males, as well as overall Graves’ orbitopathy development with severe outcome. TCG(AT_16–21)GG(l) haplotype increased risk of Graves’ disease and reduced the chance of successful medical treatment. Although this haplotype was mainly observed in patients without signs of Graves’ orbitopathy, if Graves’ orbitopathy developed it favored a Graves’ orbitopathy outcome. Haplotype TCA(AT_>21)GT(m) increased Graves’ disease risk in women and, in all patients, was linked to Graves’ disease without Graves’ orbitopathy. TCG(AT_<16)GG(m) haplotype was predominantly observed in patients without Graves’ orbitopathy, whereas TCA(AT_16–21)GG(m) was absent in those patients. TCA(AT_16–21)GG(m) occurred in patients with a mild Graves’ orbitopathy outcome. The marker CTLA-4g.*642AT(8_33) was the only independent Graves’ disease risk factor, whereas CT60 was an independent factor for disease progression. Sporadic Graves’ disease was related to presence of CTLA-4c.49A>G[A] and the rare CTLA-4g.319C>T[T] allele variant. Familial background of the disease was exclusively associated with CTLA-4g.*642AT(8_33)[AT_>21]/[AT_>21] genotype. CD28/CTLA-4/ICOS loci may confer inherited susceptibility to Graves’ disease or may be involved in susceptibility to Graves’ disease and play a pathogenetic role.

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Title: CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves’ disease and modulates clinical phenotype of disease
Authors: Edyta Pawlak-Adamska
Irena Frydecka
Marek Bolanowski
Anna Tomkiewicz
Anna Jonkisz
Lidia Karabon
Anna Partyka
Oskar Nowak
Marek Szalinski
Jacek Daroszewski
Publication date: 01-01-2017
Publisher: Springer US
Published in: Endocrine / Issue 1/2017
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-016-1096-1

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