Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

Lombardi, Angela; Menconi, Francesca; Greenberg, David A.; Concepcion, Erlinda; Leo, Marenza; Rocchi, Roberto; Marinò, Michele; Keddache, Mehdi; Tomer, Yaron

doi:10.3389/fendo.2016.00021

Cited by 31 publications

(20 citation statements)

References 75 publications

(71 reference statements)

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“…Thus, a well‐designed randomized controlled trial is required to verify these results. Thirdly, genetic factor plays an important role in the pathogenesis of thyroid dysfunction and hypertension . In the present study, we took into consideration the role of genetic background in hypertension by adjusting for family history of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Relationship between thyroid function and elevated blood pressure in euthyroid adults

Zheng

Zhang

et al. 2018

J of Clinical Hypertension

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Thyroid hormones (THs) have profound effects on cardiovascular functions, suggesting that THs may contribute to the development of elevated blood pressure (BP). Few studies, however, have systematically assessed the relationship between THs and elevated BP. We therefore conducted a cross-sectional study to examine how serum THs concentrations are related to the prevalence of elevated BP in a euthyroid population. This study (n = 12 487) was performed in Tianjin, China. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels were measured by chemiluminescence immunoassay. Elevated BP was defined according to the JNC 8 criteria. Analysis of covariance and multiple logistic regression models were used to assess the relationships between FT3, FT4, and TSH quartiles and elevated BP. The multivariable-adjusted odds ratios (95% confidence interval) of elevated BP for gradual increase in the FT3, FT4, and TSH quartiles, when compared to the lowest quartiles were 1.08 (0.97, 1.21), 1.24 (1.12, 1.39), and 1.32 (1.18, 1.47); 1.18 (1.06, 1.32), 1.18 (1.06, 1.31), and 1.24 (1.11, 1.38); 1.06 (0.96, 1.19), 1.06 (0.95, 1.18), and 1.03 (0.93, 1.15), respectively. Our study demonstrated that FT3 and FT4 are positively related to the prevalence of elevated BP in euthyroid adults, but no significant relationship was found between TSH and elevated BP.

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Section: Discussionmentioning

confidence: 99%

Relationship between thyroid function and elevated blood pressure in euthyroid adults

Zheng

Zhang

et al. 2018

J of Clinical Hypertension

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“…Graves’ orbitopathy (GO) is an eye disease occurring mainly in patients with Graves’ disease (GD), in which autoantibodies (TRAB) to the thyrotropin receptor (TSHR) cause hyperthyroidism. GD is associated with considerable genetic susceptibility 16 , including polymorphisms in the TSHR and CD40 genes, with the latter leading to cytokine imbalance in the thyroid 17 . In GO, inflammation with subsequent remodelling and expansion of orbital tissues leads to proptosis accompanied by corneal exposure, diplopia etc., and may even result in blindness.…”

Section: Introductionmentioning

confidence: 99%

Combining micro-RNA and protein sequencing to detect robust biomarkers for Graves’ disease and orbitopathy

Zhang

Masetti

Colucci

et al. 2018

Sci Rep

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Graves’ Disease (GD) is an autoimmune condition in which thyroid-stimulating antibodies (TRAB) mimic thyroid-stimulating hormone function causing hyperthyroidism. 5% of GD patients develop inflammatory Graves’ orbitopathy (GO) characterized by proptosis and attendant sight problems. A major challenge is to identify which GD patients are most likely to develop GO and has relied on TRAB measurement. We screened sera/plasma from 14 GD, 19 GO and 13 healthy controls using high-throughput proteomics and miRNA sequencing (Illumina’s HiSeq2000 and Agilent-6550 Funnel quadrupole-time-of-flight mass spectrometry) to identify potential biomarkers for diagnosis or prognosis evaluation. Euclidean distances and differential expression (DE) based on miRNA and protein quantification were analysed by multidimensional scaling (MDS) and multinomial regression respectively. We detected 3025 miRNAs and 1886 proteins and MDS revealed good separation of the 3 groups. Biomarkers were identified by combined DE and Lasso-penalized predictive models; accuracy of predictions was 0.86 (±0:18), and 5 miRNA and 20 proteins were found including Zonulin, Alpha-2 macroglobulin, Beta-2 glycoprotein 1 and Fibronectin. Functional analysis identified relevant metabolic pathways, including hippo signaling, bacterial invasion of epithelial cells and mRNA surveillance. Proteomic and miRNA analyses, combined with robust bioinformatics, identified circulating biomarkers applicable to diagnose GD, predict GO disease status and optimize patient management.

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“…Genetic predisposition for GO is believed to overlap with Graves’ hyperthyroidism 40 . Immune response modulating genes HLH DR3, CTLA4, FOXP3, CD40L, and thyroid specific genes TSHR has been suggested to predispose for GD and GO 41 – 43 . Also associations between polymorphysms in immunological factors like INFγ, TNFα or ICAM1 and GO were suggested.…”

Section: Discussionmentioning

confidence: 99%

Graves’ orbitopathy occurs sex-independently in an autoimmune hyperthyroid mouse model

Schlüter

Flögel

Díaz‐Cano

et al. 2018

Sci Rep

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Graves’ orbitopathy (GO) is the most common extra thyroidal complication of Graves’ disease (GD) and occurs predominantly in women but more severe in men. The reason for this effect of gender on GO is unknown. Herein we studied the manifestation of GO in both sexes of an induced mouse model in absence of additional risk factors present in patients like advanced age, genetic variabilities or smoking. Male and female mice were immunized with human TSHR A-subunit encoding plasmid. Both sexes comparably developed autoimmune hyperthyroidism characterized by TSHR stimulating autoantibodies, elevated T4 values, hyperplastic thyroids and hearts. Autoimmune mice developed inflammatory eye symptoms and proptosis, although males earlier than females. Serial in vivo 1H/19F-magnetic resonance imaging revealed elevated inflammatory infiltration, increased fat volume and glycosaminoglycan deposition in orbits of both sexes but most significantly in female mice. Histologically, infiltration of T-cells, extension of brown fat and overall collagen deposition were characteristics of GO in male mice. In contrast, female mice developed predominately macrophage infiltration in muscle and connective tissue, and muscle hypertrophy. Apart from sex-dependent variabilities in pathogenesis, disease classification revealed minor sex-differences in incidence and total outcome. In conclusion, sex does not predispose for autoimmune hyperthyroidism and associated GO.

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Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

Cited by 31 publications

References 75 publications

Relationship between thyroid function and elevated blood pressure in euthyroid adults

Relationship between thyroid function and elevated blood pressure in euthyroid adults

Combining micro-RNA and protein sequencing to detect robust biomarkers for Graves’ disease and orbitopathy

Graves’ orbitopathy occurs sex-independently in an autoimmune hyperthyroid mouse model

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