TSHR as a therapeutic target in Graves’ disease

Smith, Terry J.

doi:10.1080/14728222.2017.1288215

Cited by 30 publications

(29 citation statements)

References 72 publications

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“… 5 , 6 Graves disease is believed to result from a complex interaction between genetic susceptibility (such as polymorphisms in various genes including HLA-DR, CTLA-4, CD45, PTPN22, and TSH-R) which constitute 70% of the attributable risk for the disease and environmental factors (including stress, pregnancy, smoking, selenium deficiency, several drugs, irradiation, infections, allergy, and immune reconstitution). 7 – 9 …”

Section: Introductionmentioning

confidence: 99%

Graves Disease in Central Ghana: Clinical Characteristics and Associated Factors

Sarfo‐Kantanka

Ansah

Kyei

2018

Clin Med Insights Endocrinol Diabetes

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BackgroundGraves disease (GD) has increased in prevalence over the past decade in Africa. Despite this, the condition is not well described, especially in sub-Saharan Africa.ObjectiveWe have described the clinical characteristics and associated factors of GD in a cohort of patients attending a resource-limited setting tertiary hospital.MethodsPatients were examined thoroughly and systematically tested for the degree of clinical and biochemical thyroid status. Thyroid volume, characteristics, and blood flow were assessed at presentation using ultrasonography. Factors associated with an inability to achieve clinical and biochemical thyroid remission were evaluated using multiple logistic regression analysis.ResultsOverall, 182 patients were studied, 152 (83.5%) were women with a female:male ratio of 5.1:1.0. The mean age at presentation was 39.9 ± 14.7 years with women significantly older than men. Thyroid-associated orbitopathy (TAO) was observed in 56% of the participants and pretibial myxoedema in 6%. About 84% of the participants were hyperthyroid at presentation, 9% were euthyroid, 4% were hypothyroid, and 3% had subclinical hyperthyroidism. Inability to achieve biochemical and clinical remission at 24 months was associated with increased thyroid volume (odds ratio [OR]: 2.35, 95% confidence interval [CI]: 1.85-2.52, P < .001), presence of TAO (OR: 2.15, 95% CI: 2.12-2.33, P < .001), increased FT3/FT4 ratio (OR: 1.33, 95% CI: 1.24-2.56, P = .004), and missed clinic appointment (OR: 5.2, 95% CI: 4.55-7.89, P < .001).ConclusionsGraves disease among Ghanaians is associated with significant signs at presentation. Inability to achieve remission within the first 24 months is associated with increased thyroid volume, TAO, an increased FT3/FT4 ratio, as well as missed clinic appointment.

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Section: Introductionmentioning

confidence: 99%

Graves Disease in Central Ghana: Clinical Characteristics and Associated Factors

Sarfo‐Kantanka

Ansah

Kyei

2018

Clin Med Insights Endocrinol Diabetes

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“…The CD74 SNP rs2569103 was located within the upstream region of CD74 and showed the strongest association with the disease, making it a possible target for transcription factors. Indeed, the putative transcription factor-binding sites were predicted using PROMO [ 32 , 33 ]. At SNP rs2569103, the A allele generates motifs for nuclear receptor subfamily 3, group C, member 1 (NR3C1) (TC A GG), whereas the G allele generates a motif for forkhead box P3 (FOXP3) (GTTTC G ).…”

Section: Resultsmentioning

confidence: 99%

Association of variant on the promoter of cluster of differentiation 74 in graves disease and graves ophthalmopathy

2020

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The macrophage migration inhibitory factor (MIF)/cluster of differentiation 74 (CD74) plays a role in immunological functions. This study aims to investigate whether single nucleotide polymorphisms (SNPs) in the MIF and CD74 are risk factors for developing Graves ophthalmopathy (GO) in patients with Graves disease (GD). A case-control study enrolled 484 patients with GD (203 with and 281 without GO) and 1000 healthy individuals. SNPs were discriminated using real-time polymerase chain reaction. Hardy-Weinberg equilibrium, as well as frequencies of allele and genotype between GD patients with and without GO, were estimated using the Chi-square test. The effects of CD74 on adipocyte proliferation and differentiation were evaluated using 3T3-L1 preadipocytes. Quantitative DNA-immunoprecipitation was used to detect the binding capacity of NR3C1 and FOXP3 to A/G oligonucleotides. The results showed that individuals carrying the GG genotype at rs2569103 in the CD74 had a decreased risk of developing GD (p = 3.390 ´ 10-11, odds ratio (OR) = 0.021, 95% confidence interval (CI) = 0.003–0.154); however, patients with GD carrying the AG genotype at rs2569103 in the CD74 had an increased risk of developing GO (p = 0.009, OR = 1.707, 95% CI = 1.168–2.495). The knockdown of CD74 reduced adipocyte proliferation and differentiation. NR3C1 had a higher affinity for A, whereas FOXP3 had a higher affinity for G of rs2569103. The results suggested the existence of a link between the genetic variation of CD74 promoter and the risk for developing GD and GO, which should be considered in clinical practice.

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“…A complete understanding of the pathophysiology of TED has not been delineated, but evidence suggests that disease pathogenesis is related to loss of self-tolerance to thyroid-stimulating hormone receptor (TSH-R) and overexpression of IGF-1R 8,25–27. The autoimmune orbital response occurs in TED because of cross-reactivity against antigens that are present in both the thyroid gland and orbital tissue, although the exact pathophysiology is still unclear 11,28.…”

Section: Molecular Biology Of Thyroid Eye Diseasementioning

confidence: 99%

<p>Thyroid Eye Disease: How A Novel Therapy May Change The Treatment Paradigm</p>

Wang¹,

Patel²,

Douglas³

2019

TCRM

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Thyroid eye disease (TED) is a complex, debilitating autoimmune disease that causes orbital inflammation and tissue remodeling, resulting in proptosis, diplopia, and in severe cases, loss of vision. TED can lead to facial disfigurement and severely impact patients' quality of life. Although the course of TED was identified over 60 years ago, effective treatment options have proved to be challenging. Current treatments such as glucocorticoid therapy and orbital radiation focus on reducing orbital inflammation. However, these therapies fail to modify the disease outcomes, including proptosis and diplopia. Recent advances in the understanding of the molecular basis of TED have facilitated the development of targeted molecular therapies such as teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody. In recent phase 2 and phase 3 randomized placebo-controlled trials, teprotumumab rapidly achieved improvement in clinical endpoints defining TED, including improved proptosis and diplopia. Dramatic improvement in clinical outcomes achieved after teprotumumab therapy during active TED are heretofore singular and comparable only to surgical therapies achieved during the inactive phase of TED. The advent of effective medical therapy can lead to a paradigm shift in the clinical management of TED. This review will provide an overview of TED, its epidemiology, insight into the molecular biology of the disease, clinical characteristics and diagnosis, and current and emerging treatment modalities.

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TSHR as a therapeutic target in Graves’ disease

Cited by 30 publications

References 72 publications

Graves Disease in Central Ghana: Clinical Characteristics and Associated Factors

Graves Disease in Central Ghana: Clinical Characteristics and Associated Factors

Association of variant on the promoter of cluster of differentiation 74 in graves disease and graves ophthalmopathy

<p>Thyroid Eye Disease: How A Novel Therapy May Change The Treatment Paradigm</p>

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