Skewed X Chromosome Inactivation and Female Preponderance in Autoimmune Thyroid Disease: An Association Study and Meta-Analysis

Simmonds, Matthew J.; Kavvoura, Fotini K.; Brand, Stephan; Newby, Paul; Jackson, Laura E.; Hargreaves, Chantal E.; Franklyn, Jayne A.; Gough, Stephen

doi:10.1210/jc.2013-2667

Cited by 76 publications

(56 citation statements)

References 18 publications

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“…Several studies have shown that skewed XCI is associated with an increased risk of developing AITD. A meta-analysis confirmed significant skewing of XCI in women with Graves' disease (OR, 2.54; 95% CI, 1.58-4.10) and Hashimoto's disease (OR, 2.40; 95% CI, 1.10-5.26) (14). The epigenetic phenomenon of skewed XCI may, in part, explain the strong female preponderance in AITD.…”

Section: X-chromosome Inactivationmentioning

confidence: 86%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Effraimidis

Wiersinga

2014

European Journal of Endocrinology

289

196

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The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained -at least in part -by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers -as well known -are at increased risk for Graves' disease, but -surprisingly -at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.

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Section: X-chromosome Inactivationmentioning

confidence: 86%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Effraimidis

Wiersinga

2014

European Journal of Endocrinology

289

196

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“…Skewed XCI has been proposed as a potential mechanism explaining the female preponderance of AITD (184). Previous studies have proven the increased frequency of skewed XCI in AITD patients (182, 184–187).…”

Section: Epigenetics In Aitdmentioning

confidence: 99%

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

et al. 2017

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Autoimmune thyroid diseases (AITD) are a group of both B cell- and T cell-mediated organ-specific autoimmune diseases. Graves’ disease and Hashimoto thyroiditis are the two main clinical presentations of AITD. Both genetic and environmental factors have important roles in the development of AITD. Epigenetics have been considered to exert key roles in integrating those genetic and environmental factors, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD. Recent studies on the epigenetics of AITD have provided some novel insights into the pathogenesis of AITD. The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, such as DNA methylation, histone modifications, and non-coding RNAs. This review highlights the key roles of epigenetics in the pathogenesis of AITD and potential clinical utility. However, the epigenetic roles in AITD are still not fully elucidated, and more researches are needed to provide further deeper insights into the roles of epigenetics in AITD and to uncover new therapeutic targets. Although there are many studies assessing the epigenetic modifications in AITD patients, the clinical utility of epigenetics in AITD remains poorly defined. More studies are needed to identify the underlying epigenetic modifications that can contribute to accurate diagnosis of AITD, adequate choice of treatment approach, and precise prediction of treatment outcomes.

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“…There is a balance maintained between Th1 and Th2 effects, but dysregulation can result in diseases. More recently, balance among Th17 cell subsets have come under suspicion since they control self-reactive T-cell proliferation [42][43][44][45][46] Skewed X inactivation One of the two X chromosomes in female cells may have genetic abnormalities or the X inactivation process cannot be established or maintained with the result that there is expression of abnormal X-linked proteins or abnormal protein levels due to improper X-linked dosage compensation that leads to an autoimmune response [51,53,54] Molecular mimicry Viral proteins or molecules in the diet that provoke an immune reaction could have epitopes similar to endogenous material. The immune reaction then spreads to an autoimmune reaction targeting the endogenous material.…”

Section: Hypotheses Of Autoimmune Diseasesmentioning

confidence: 99%

“…Familial skewing of X inactivation has been linked to a high rate of spontaneous abortions [49]. As far as ADs, skewed X inactivation has been reported for autoimmune thyroid disease [50,51] and systemic sclerosis [52,53], and there is a report of increased skewing in MS patients as they go from relapsing/remitting MS to progressive MS, but otherwise MS patients in general did not appear to have any significant variance from controls with regards to skewing [54]. Studies on other ADs have not yet shown skewing to be of significance although more studies are needed.…”

Section: The Bcytokine Polarization^hypothesesmentioning

confidence: 99%

A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis

Brooks

2016

Clinic Rev Allerg Immunol

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Numerous hypotheses have been proposed in order to explain the complexity of autoimmune diseases. These hypotheses provide frameworks towards understanding the relations between triggers, autoantigen development, symptoms, and demographics. However, testing and refining these hypotheses are difficult tasks since autoimmune diseases have a potentially overwhelming number of variables due to the influence on autoimmune diseases from environmental factors, genetics, and epigenetics. Typically, the hypotheses are narrow in scope, for example, explaining the diseases in terms of genetics without defining detailed roles for environmental factors or epigenetics. Here, we present a brief review of the major hypotheses of autoimmune diseases including a new one related to the consequences of abnormal nucleolar interactions with chromatin, the "nucleolus" hypothesis which was originally termed the "inactive X chromosome and nucleolus nexus" hypothesis. Indeed, the dynamic nucleolus can expand as part of a cellular stress response and potentially engulf portions of chromatin, leading to disruption of the chromatin. The inactive X chromosome (a.k.a. the Barr body) is particularly vulnerable due to its close proximity to the nucleolus. In addition, the polyamines, present at high levels in the nucleolus, are also suspected of contributing to the development of autoantigens.

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Skewed X Chromosome Inactivation and Female Preponderance in Autoimmune Thyroid Disease: An Association Study and Meta-Analysis

Abstract: Convincing evidence exists to support a role for skewed XCI in female subjects with AITD, which may, in part, explain the strong female preponderance observed in this disease.

Cited by 76 publications

References 18 publications

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

The Emerging Role of Epigenetics in Autoimmune Thyroid Diseases

A Review of Autoimmune Disease Hypotheses with Introduction of the “Nucleolus” Hypothesis

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