Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population

Liu, Bingli; Yang, Shaoying; Liu, Wei; Xue, Lu; Chen, Xia; Pan, Chun-Ming; Gu, Zhaohui; Zhan, Ming; Zhang, Xiaomei; Liang, Jun; Gao, Guan-Qi; Wen, Du; Yuan, Guoyue; Ren, Ying; Zhao, Shuang‐Xia; Song, Huai-Dong

doi:10.1530/eje-13-0517

Cited by 11 publications

(14 citation statements)

References 32 publications

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“…They focused in a 665-kb LD block harbouring the strongest TSHR association, corroborating intron 1 rs12101261 and rs179243 SNPs as independent GD susceptibility variants in the replication stage and in combined populations (5 300 GD cases and 4 916 controls) [83]. Intron 7 SNPs described by Hiratani et al [82] were not significantly associated with GD in this large Chinese cohort.…”

supporting

confidence: 68%

“…It was suggested that these 3 amino acid changes could constitute GD specific mutations but their frequent presence in healthy individuals ruled them out. Despite the positive results of some association studies [73][74][75], subsequent case-control reports largely rejected an association with GD for either of these TSHR SNPs in both Caucasian [76][77][78][79][80] However, the main associated SNPs were unexpectedly located between introns 7 and 8 of the TSHR [82]. Several studies in Caucasians failed to confirm this association [87][88][89].…”

mentioning

confidence: 99%

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Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

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As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.

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supporting

confidence: 68%

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confidence: 99%

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

et al. 2015

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“…Strongest SNP associations were rs179247 (OR = 1.53) and rs12101255 (OR = 1.55), which were replicated in Polish-Caucasian cohorts. A different study showed that two SNPs (rs12101261, rs179243) in intron 1 are associated with GD in Chinese population [37]. However these polymorphisms are in linkage disequilibrium with SNP's previously reported in Caucasian populations.…”

Section: Discussionmentioning

confidence: 88%

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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“…Dopamine-secreting PPGL are even rarer entities and can evade this strongly reassuring test. To date, their incidence is limited to case reports and only 53 have been described in the literature 1, 2, 3, 4, 5. Eisenhofer et al 2 defines dopamine secreting PPGL as tumors that produce dopamine (or its metabolite 3-methoxytyramine) greater than the combined concentrations of noradrenaline and adrenaline (or their metabolites), and corresponds to the biochemical findings in this case.…”

Section: Introductionmentioning

confidence: 92%

“…The sensitivity of plasma and urine metanephrines is close to 100% according to Van Berkel et al 1 . Metanephrine-negative PPGL is rare.…”

Section: Introductionmentioning

confidence: 97%

Pheochromocytoma with Negative Metanephrines: A Rarity and the Significance of Dopamine Secreting Tumors

Bozin

Lamb

Putra

2017

Urology Case Reports

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We describe a case of a 25-year-old female with a dopamine secreting PPGL diagnosed retrospectively with biochemical analysis. This finding resulted in change in approach to investigation and management, given their important clinical implications. There are important differences in management of dopamine secreting PPGL compared to classical noradrenaline and adrenaline-secreting PPGL. This includes the risk of peri-operative cardiovascular collapse peri-operatively with alpha/beta blockade, risk of malignancy/recurrence, and associated genetic abnormalities.

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Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population

Cited by 11 publications

References 32 publications

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

Genetics of Graves’ Disease: Special Focus on the Role of TSHR Gene

Association between Polymorphisms in the TSHR Gene and Graves' Orbitopathy

Pheochromocytoma with Negative Metanephrines: A Rarity and the Significance of Dopamine Secreting Tumors

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