Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

Özçelık, Tayfun; Uz, Elif; Akyerli, Cemaliye Boylu; Bağişlar, Sevgi; Mustafa, Chigdem; Gürsoy, Alptekin; Akarsu, Nurten; Toruner, Gokce; Kamel, Nurí; Güllü, Sevim

doi:10.1038/sj.ejhg.5201614

Cited by 105 publications

(89 citation statements)

References 29 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: 77%

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: 77%

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: 51%

Expanded clinical phenotype of women with the FMR1 premutation

Coffey

Cook

Tartaglia

et al. 2008

American J of Med Genetics Pt A

298

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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“…The study revealed a similar age-related frequency of skewed XCI in both cases and controls, thus implying that PBC is not associated with an enhanced rate of skewed XCI in contrast with the data in autoimmune thyroid disease and scleroderma. [30][31][32] However, these latter findings were based on limited numbers of informative subjects and did not include age-matched controls; in fact, although variable prevalence rates of a skewed XCI status have been reported, studies taking into account age as a modifier factor, clearly indicate that as many as 16% of healthy women over the age of 50 are characterized by a severe XCI skewing. 11,12,25,33 Importantly, we also ruled out the possibility that preferential X loss and skewed XCI could be related to each other.…”

Section: Discussionmentioning

confidence: 93%

“…26 In addition, monosomy or major structural abnormalities of the X chromosome, as seen in Turner's syndrome 27,28 and premature ovarian failure, 29 are often characterized by autoimmune features. Following our recent findings of an enhanced monosomy X in peripheral lymphocytes of women with PBC or other autoimmune diseases 8,9 and reports of a frequent skewed XCI in women with non hepatic autoimmune diseases, [30][31][32] we have now investigated the mechanisms of X loss and XCI in 166 women with PBC, 49 with CHC and 177 healthy controls. We speculated that a specific hemizygous status of the monosomic X might unmask peculiar haplotypes responsible for susceptibility to autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis†

et al. 2007

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Recent work has demonstrated enhanced X monosomy in women with primary biliary cirrhosis (PBC) as well as two other female-predominant autoimmune diseases, systemic sclerosis and autoimmune thyroid disease. To further our understanding of these events, we have investigated the mechanisms of X chromosome loss and X chromosome inactivation (XCI) in 166 women with PBC and 226 rigorously age-matched healthy and liver disease controls. X chromosome analysis and determination of loss pattern was performed by quantitative fluorescent polymerase chain reaction (QF-PCR) with 4 X-linked short tandem repeats. Further definition of the XCI was based on analysis of methylation-sensitive restriction sites. Importantly, in PBC the X chromosome loss occurs not only more frequently but also in a preferential fashion. This observation supports our thesis that the enhanced X monosomy involves only one parentally derived chromosome and is not secondary to a constitutive non random pattern of XCI. In fact, in the presence of monosomy, the lost X chromosome is necessarily the inactive homologue. Conclusion: The finding that the X chromosome loss is preferential suggests the critical involvement of X chromosome gene products in the female predisposition to PBC and also emphasizes the need to determine the parental origin of the maintained chromosome to investigate the role of imprinting. (HEPATOLOGY 2007;46:456-462.)

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Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

Cited by 105 publications

References 29 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

Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis†

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