High Frequency of Skewed X-Chromosome Inactivation in Females with Autoimmune Thyroid Disease: A Possible Explanation for the Female Predisposition to Thyroid Autoimmunity

Brix, Thomas Heiberg; Knudsen, Gun Peggy; Kristiansen, Marianne; Kyvik, Kirsten Ohm; Ørstavik, Karen Helene; Hegedűs, László

doi:10.1210/jc.2005-1366

Cited by 182 publications

(143 citation statements)

References 36 publications

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“…[11][12][13] In accordance with these studies, we found a statistically significant positive association between XCI and the serum concentrations of TPOAb in euthyroid subjects (within-cohort analysis). To evaluate whether this association was causal or could be explained by the presence of genetic or environmental confounders, we also analysed the association between XCI and TPOAb within MZ and DZ pairs.…”

Section: Discussionsupporting

confidence: 90%

Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study

et al. 2009

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An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within-twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (b)¼1.45 (95% confidence interval, 0.52-2.38), P¼0.003. The association remained significant in the within-pair analysis; b¼1.74 (0.79-2.69), Po0.001. The relationship was nonsignificant within the 82 monozygotic pairs (b¼0.57 (À0.78-1.92), P¼0.405), whereas the association was significant in the 77 dizygotic pairs (b¼2.17 (0.81-3.53), P¼0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants. Keywords: X-chromosome inactivation; thyroid peroxidase antibodies; thyroid autoantibodies; thyroid autoimmunity; twins; epigenetics INTRODUCTIONClinically overt autoimmune thyroid diseases (AITD) affect around 2% of the female population, whereas prevalence of subclinical disease, reflected by the presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin in euthyroid individuals, is up to 10-fold higher. 1,2 Although common, the aetiology of these diseases is still incompletely understood. However, it is generally assumed that the development of overt as well as subclinical AITD is the net result of environmental triggers 3-5 operating in genetically predisposed individuals. [6][7][8][9] Recently, epigenetic factors such as genetic anticipation 10 and the phenomenon of X-chromosome inactivation (XCI) [11][12][13] have been suggested to have a role in the aetiology of AITD. We 11 and subsequently others 12,13 have reported an association between a skewed XCI pattern and the presence of clinically overt AITD in females. Thus, there is little doubt that an association exists between skewed XCI and overt AITD. The key question, however, is whether it is the skewed XCI per se or other factors such as genes, socioeconomic or environmental conditions that cause the observed association.Because monozygotic (MZ) twin pairs share 100% of their genes and dizygotic (DZ) pairs share 50% (on average), studies of twins offer a unique opportun...

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Section: Discussionsupporting

confidence: 90%

Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study

et al. 2009

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“…These endocrine problems may be related to direct RNA toxicity in the hypothalamic-pituitary axis, or to a direct effect of RNA toxicity on the thyroid-perhaps through an autoimmune mechanism or the induction of apoptosis in the thyroid cells. A skewed AR has been previously reported in patients with thyroid problems related to autoimmune disease [Brix et al, 2005;Ozcelik et al, 2006], but in this study there was no difference in the AR between those with and without thyroid disease. Surprisingly, there was also no difference in the AR in females with and without FXTAS.…”

Section: Discussioncontrasting

confidence: 66%

Expanded clinical phenotype of women with the FMR1 premutation

Coffey

Cook

Tartaglia

et al. 2008

American J of Med Genetics Pt A

297

382

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P ¼ 0.0096), hypertension (P ¼ 0.0020), seizures (P ¼ 0.0077), peripheral neuropathy (P ¼ 0.0040), and fibromyalgia (P ¼ 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P ¼ 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS. ß

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“…Using disease discordant twin pairs, Brix and collaborators have found that the frequency of skewed X chromosome inactivation in female twins with HT was 31% (vs 8% in control population) (Brix et al, 2005). In Tunisian population, findings reported by our team suggest a possible role for X chromosome inactivation mosaicism in the pathogenesis of AITDs (GD and HT) and may, to some extent, explain the female preponderance of these diseases (Chabchoub et al, 2009).…”

Section: Epigenetic Factorssupporting

confidence: 49%

Hashimoto's Disease

Bougacha-Elleuch¹,

Mnif-Feki²,

Charfi-Sellami³

et al. 2012

A New Look at Hypothyroidism

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High Frequency of Skewed X-Chromosome Inactivation in Females with Autoimmune Thyroid Disease: A Possible Explanation for the Female Predisposition to Thyroid Autoimmunity

Abstract: These observations suggest a possible role of XCI in the etiology of AITD and may in part explain the female preponderance of AITD.

Cited by 182 publications

References 36 publications

Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study

Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study

Expanded clinical phenotype of women with the FMR1 premutation

Hashimoto's Disease

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