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.

WITHDRAWN: Target region sequencing and gene polymorphism of Chinese Uyghur individuals with autoimmune thyroid diseases (AITDs)

“…Nevertheless, no uniform locus showed evidence for association with both GD and HT Uyghur patients, this may be due to genetic heterogeneity [39]. Consistent with previous studies, the polymorphisms of CD28 gene were considered as good candidates for GD patients [40], and the polymorphisms of STAT3 gene were good for HT [41]. Previously, the polymorphisms of IL2RA (CD25) gene was investigated in GD [42,43] and whether it is related to the aetiological variant of HT need more identification.…”

Evaluation of Quality of Life in the Brazilian Graves' Disease Population: Focus on Mild and Moderate Graves' Orbitopathy Patients

“…Moderate forms occur in 5–10% of GD patients and severe forms in 1% of patients (1). Although autoimmune mechanisms are clearly involved, given the role of thyrotropin receptor antibodies and several cytokines, its precise pathogenesis remains poorly understood (1, 4, 5) The onset and progression of GO seem to be influenced by several factors such as smoking, thyroid dysfunction, a strong genetic influence (6, 7), and choice of treatment modality (2). Active GO disease involves some degree of motility dysfunction, diplopia, and sight-threatening conditions such as dysthyroid optic neuropathy and serious corneal exposure, resulting in corneal ulceration, or scarring (2, 4).…”

Association between rs3087243 and rs231775 polymorphism within the cytotoxic T-lymphocyte antigen 4 gene and Graves' disease: a case/control study combined with meta-analyses

“…The principal characteristics and genotype distributions of the identified studies are shown in Table 3 . For SNP rs3087243 polymorphism, ten studies came from East Asian [ 12 – 21 ] and three studies from European population [ 22 – 24 ]. For the rs231775 polymorphism, there were 14 studies originated from East Asian [ 13 , 17 – 21 , 25 – 32 ], while the rest 8 studies were from European population [ 6 , 23 – 24 , 33 – 37 ].…”