The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease

Kuś, Aleksander; Szymański, Konrad M.; Peeters, Robin P.; Miśkiewicz, Piotr; Porcu, Eleonora; Pistis, Giorgio; Naitza, Silvia; Płoski, Rafał; Medici, Marco; Bednarczuk, Tomasz

doi:10.1111/cen.12640

Cited by 30 publications

(21 citation statements)

References 40 publications

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“…A greater understanding of the genetic variants responsible for variation in TSH and thyroid hormone levels is emerging, but only a small proportion (<10%) of the genetic architecture has been explained to date 150,151 . Variants have been identified which increase the risk of Graves' disease 150,152 and also TPO antibody positivity 150 . Greater understanding of the genetic architecture is required particularly in non-Caucasian populations.…”

Section: Resultsmentioning

confidence: 99%

Global epidemiology of hyperthyroidism and hypothyroidism

et al. 2018

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Thyroid hormones are essential for growth, neuronal development, reproduction and regulation of energy metabolism. Hypothyroidism and hyperthyroidism are common conditions with potentially devastating health consequences that affect all populations worldwide. Iodine nutrition is a key determinant of thyroid disease risk; however, other factors, such as ageing, smoking status, genetic susceptibility, ethnicity, endocrine disruptors and the advent of novel therapeutics, including immune checkpoint inhibitors, also influence thyroid disease epidemiology. In the developed world, the prevalence of undiagnosed thyroid disease is likely falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation. However, continued vigilance against iodine deficiency remains essential in developed countries, particularly in Europe. In this report, we review the global incidence and prevalence of hyperthyroidism and hypothyroidism, highlighting geographical differences and the effect of environmental factors, such as iodine supplementation, on these data. We also highlight the pressing need for detailed epidemiological surveys of thyroid dysfunction and iodine status in developing countries.

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Section: Resultsmentioning

confidence: 99%

Global epidemiology of hyperthyroidism and hypothyroidism

et al. 2018

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“…GD is an autoimmune disease characterized by the presence of circulating autoantibodies against the thyroid-stimulating hormone (TSH) receptor. Various factors are involved in GD pathology [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Changes in Serum Immunoglobulin G4 Levels in Patients with Newly Diagnosed Graves’ Disease

Hayashi

Yamada

Itoh

et al. 2018

Exp Clin Endocrinol Diabetes

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Objective Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ. We investigated the association between IgG4-RD and the main characteristics of Graves’ disease (GD) at the time of diagnosis. Additionally, we evaluated whether serum IgG4 levels change during treatment. Design and patients Twenty-eight patients with newly diagnosed GD were enrolled into this longitudinal follow-up study. Serum IgG4 levels and thyroid function were measured in all the participants at the time of diagnosis. Further, the serum IgG4 levels of nine of 28 patients with untreated GD were measured after the achievement of euthyroid state (through the use of methimazole). Results Two (7.1%) of 28 patients with untreated GD had elevated serum IgG4 levels of >135 mg/dL. There was no significant difference in the average IgG4 levels before and after the achievement of euthyroid state (66.2±74.0 mg/dL vs. 50.5±47.3 mg/dL). In two patients, the elevated serum IgG4 levels returned to normal after treatment. However, one patient had an elevated serum IgG4 level of 136.6 mg/dL after treatment. Conclusions This study showed that serum IgG4 levels varied with treatment in patients with GD, independent of thyroid function, suggesting that IgG4 might be indirectly related to GD.

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“…Furthermore, the TPOAb-positivity risk allele of rs3094228 variant is primary associated with an increased expression of MIC-B gene, ligand of CD314 (NKG2D), in thyroid cells. As about 75% of patients with Graves' disease have TPOAb-positivity and rs3094228 that has been associated with TPOAb-positivity and Graves' disease [61,63], it is possible that the association of rs1521 with Graves' disease could be also driven by TPOAb-positivity and, so, associated with its phenotypes. Downregulation of HLA-C gene expression and upregulation of MIC-A and MIC-B gene expression in thyrocytes could activate NK cell functions and the cytokine production against thyrocytes when NK cells and thyrocytes are in contact.…”

Section: The Aitd-associated Genetic Variants Rs1521 and Rs3094228 mentioning

confidence: 99%

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases

Martin

Ilieva

Visconti

et al. 2020

Cells

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The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD.

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The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease

Cited by 30 publications

References 40 publications

Global epidemiology of hyperthyroidism and hypothyroidism

Global epidemiology of hyperthyroidism and hypothyroidism

Changes in Serum Immunoglobulin G4 Levels in Patients with Newly Diagnosed Graves’ Disease

Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases

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