title: CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves' disease and modulates clinical phenotype of disease.
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)(AT16-21)/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(AT16-21)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(AT16-21)GG(m) was absent in those patients. TCA(AT16-21)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.
authors.affiliation: Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, Wroclaw, 53-114, Poland. epawlak@iitd.pan.wroc.pl.
authors.forename: Edyta
authors.initials: E
authors.lastname: Pawlak-Adamska
authors.affiliation: Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, Wroclaw, 53-114, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Frydecka
authors.affiliation: Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, Wroclaw, 50-367, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bolanowski
authors.affiliation: Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, Wroclaw, 53-114, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tomkiewicz
authors.affiliation: Department of Forensic Medicine, Wroclaw Medical University, M. Curie-Sklodowska 52, Wroclaw, 50-369, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonkisz
authors.affiliation: Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, Wroclaw, 53-114, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Karabon
authors.affiliation: Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, Wroclaw, 53-114, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Department of Human Evolutionary Biology, Institute of Anthropology, Adam Mickiewicz University, Umultowska 89, Poznan, 61-614, Poland.
authors.forename: Oskar
authors.initials: O
authors.lastname: Nowak
authors.affiliation: Department of Ophthalmology, Wroclaw Medical University, Borowska 213, Wroclaw, 50-556, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Szalinski
authors.affiliation: Department of Endocrinology, Diabetes and Isotope Therapy, Wroclaw Medical University, L. Pasteur 4, Wroclaw, 50-367, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Daroszewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D049970:Graves Ophthalmopathy / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein
keywords: CD28/CTLA-4/ICOS; Gene polymorphism; Graves’ disease; Graves’ orbitopathy; Haplotype