Association between Age at Diagnosis of Graves' Disease and Variants in Genes Involved in Immune Response

Jurecka‐Lubieniecka, Beata; Płoski, Rafał; Kula, Dorota; Król, Aleksandra; Bednarczuk, Tomasz; Kołosza, Zofia; Tukiendorf, Andrzej; Szpak‐Ulczok, Sylwia; Stanjek-Cichoracka, Anita; Polańska, Joanna; Jarząb, Barbara

doi:10.1371/journal.pone.0059349

Cited by 38 publications

(44 citation statements)

References 44 publications

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“…Other Polish studies [29, 30, 31] focused mostly on CTLA-4 c.49A>G (rs231775) and revealed a significant association of this marker with disease; however, we did not. On the other hand, the association of the marker CT60 (rs3087243) observed in our group was not as significant as in another study of Polish patients with GD [29].…”

Section: Discussioncontrasting

confidence: 88%

“…This finding may provide some evidence in support of our hypothesis; specifically that the superiority of the association defined as one susceptible locus expressed as the haplotype over the individual polymorphism association. As compared to other studies, which describe only univariate analyses [28, 29, 30, 31], our research takes a deeper and more detailed approach. The most GD-essential genetic marker in our study, CTLA-4 g.*642AT(8_33), was also relevant in other populations [2, 18, 25].…”

Section: Discussionmentioning

confidence: 99%

“…In regard to immune-related genes, comprehensive fine mapping of the CD28 / CTLA-4 / ICOS region showed an association signal within a 6.1-Kb 3′ region of CTLA-4 [18]. To date, most research has focused on univariate association studies of single polymorphisms—especially the highly polymorphic CTLA-4 [8, 9, 16, 18, 21, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36], with several functional polymorphisms having been observed within this gene [8–26]. Similar findings concerning GO and CTLA-4 polymorphisms have been reported [37].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Some papers have confirmed an association between HLADRB1*03 and GO [48]–[49]. However, other authors have not found differences in the distribution of the HLADRB1*03 allele in GD patients with or without GO [10], [27], [50]–[51]. There is no sufficient evidence to support a correlation between the C(1858)T polymorphism in the PTPN22 gene and GO [29], [42].…”

Section: Discussionmentioning

confidence: 99%

Association between Polymorphisms in the TSHR Gene and Graves' Orbitopathy

et al. 2014

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BackgroundGraves' orbitopathy (GO) as well as Graves' disease (GD) hyperthyroidism originate from an autoimmune reaction against the common auto-antigen, thyroid-stimulating hormone receptor (TSHR). GO phenotype is associated with environmental risk factors, mainly nicotinism, as well as genetic risk factors which initiate an immunologic reaction. In some patients GO is observed before diagnosis of GD hyperthyroidism, while it can also be observed far after diagnosis. The intensity of GO symptoms varies greatly in these patients. Thus, the pathogenesis of GD and GO may correlate with different genetic backgrounds, which has been confirmed by studies of correlations between GO and polymorphisms in cytokines involved in orbit inflammation. The aim of our analysis was to assess genetic predisposition to GO in young patients (age of diagnosis ≤30 years of age), for whom environmental effects had less time to influence outcomes than in adults.Methods768 GD patients were included in the study. 359 of them had clinically evident orbitopathy (NOSPECS ≥2). Patients were stratified by age at diagnosis. Association analyses were performed for genes with a known influence on development of GD - TSHR, HLA-DRB1, cytotoxic T-lymphocyte antigen 4 (CTLA4) and lymphoid protein tyrosine phosphatase (PTPN22).ResultsThe rs179247 TSHR polymorphism was associated with GO in young patients only. In young GO-free patients, allele A was statistically more frequent and homozygous carriers had a considerable lower risk of disease incidence than patients with AG or GG genotypes. Those differences were not found in either elderly patients or the group analyzed as a whole.ConclusionsAllele A of the rs179247 polymorphism in the TSHR gene is associated with lower risk of GO in young GD patients.

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“…Так, в ряде иссле дований показана ассоциация различных полимор физмов гена TNF α и БГ в различных популяциях [13,14,15,16,17]. В недавнем исследовании был вы явлен TNFb3 TNF 308 G гаплотип, имеющий самую сильную ассоциацию с БГ, по данным современного метаанализа [18].…”

Section: Discussionunclassified

Imbalance of the “ligandreceptor” tumor necrosis factor αsystem and TNFRI expression in thyroid tissue in patients with Graves' disease

Саприна¹,

Прохоренко²,

Martynova³

et al. 2013

Clinical and Experimental Thyroidology

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56 Оригинальные работыЦелью исследования явилось изучение состояния системы "лиганд-рецептор" фактора некроза опухолей α (TNF α) в зависимости от функционально морфологических исходов болезни Грейвса (БГ). Было показано, что активация систе мы TNF α наблюдается на фоне "мягкого" и "доброкачественного" клинического течения БГ и сочетается с появлени ем морфологических маркеров аутоиммунного тиреоидита (онкоцитарная трансформация тиреоидного эпителия).

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Association between Age at Diagnosis of Graves' Disease and Variants in Genes Involved in Immune Response

Cited by 38 publications

References 44 publications

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

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

Association between Polymorphisms in the TSHR Gene and Graves' Orbitopathy

Imbalance of the “ligandreceptor” tumor necrosis factor αsystem and TNFRI expression in thyroid tissue in patients with Graves' disease

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