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

• Published in: Endocrine Vol. 55; no. 1; pp. 186 - 199
• Main Authors: Pawlak-Adamska, Edyta, Frydecka, Irena, Bolanowski, Marek, Tomkiewicz, Anna, Jonkisz, Anna, Karabon, Lidia, Partyka, Anna, Nowak, Oskar, Szalinski, Marek, Daroszewski, Jacek
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2017; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; CD28 antigen; CD28 Antigens - genetics; CTLA-4 Antigen - genetics; CTLA-4 protein; Diabetes; Endocrinology; Female; Gene Frequency; Genetic diversity; Genetic Predisposition to Disease; Genotype; Graves Disease - genetics; Graves Ophthalmopathy - genetics; Haplotypes; Humanities and Social Sciences; Humans; Inducible T-Cell Co-Stimulator Protein - genetics; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; multidisciplinary; Original; Original Article; Phenotype; Polymerase chain reaction; Polymorphism, Single Nucleotide; Science; Sex differences; Young Adult; Graves’ disease; Gene polymorphism; Haplotype; Graves’ orbitopathy; CD28/CTLA-4/ICOS
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-016-1096-1

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 CD28 c.17+3T>C(rs3116496), CTLA-4 g.319C>T(rs5742909), CTLA-4 c.49A>G(rs231775), CTLA-4 g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOS c.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-4 c.49A>G, CTLA- 4g.319C>T, and CT60 were genotyped by PCR–RFLP; Jo31 and CD28 c.17+3C>T by minisequencing; CTLA-4 g.*642AT(8_33) and ICOS c.1554+4GT(8_15)—PCR and fluorescence-based technique. CD28 c.17+3T>C(rs3116496)T/ CTLA-4 g.319C>T(rs5742909)C/ CTLA-4 c.49A>G(rs231775)G/ CTLA-4 g.*642AT(8_33)(AT 16–21 )/CT60(rs3087243)G/Jo31(rs11571302)G/ ICOS c.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-4 g.*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-4 c.49A>G[A] and the rare CTLA-4 g.319C>T[T] allele variant. Familial background of the disease was exclusively associated with CTLA-4 g.*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.