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The relationship between skewed X chromosome inactivation and the prognosis of Graves' and Hashimoto's diseases.

ABSTRACT: Autoimmune thyroid diseases (AITDs) predominantly develop in females. One of two X chromosomes is randomly inactivated by methylation in each female cell, but it has been reported that skewed X chromosome inactivation (XCI) may be associated with the development of autoimmune diseases. To clarify the significance of skewed XCI in the prognosis and development of AITD, we investigated the proportion of skewed XCI in female patients with AITD.We analyzed the degree of XCI skewing in 120 female patients with AITD (77 patients with Graves' disease [GD] and 43 patients with Hashimoto's disease [HD]) and 49 female controls in DNA from peripheral blood mononuclear cells (PBMC). We performed XCI analysis by digesting inactive DNA with a methylation-sensitive restriction enzyme (HpaII) followed by a polymerase chain reaction (PCR) assay for the polymorphic CAG repeat of the androgen receptor gene and electrophoresis of the PCR products.The proportion of skewed XCI (?65% skewing) was not significantly different between AITD patients and control subjects but was higher in patients with intractable GD (66.7%) than those with GD in remission (25.0%, p=0.0033) and control subjects (32.6%, p=0.0038). When the cutoff value for XCI skewing was relaxed, the proportion of skewed XCI (?60% skewing) was higher in patients with severe HD (76.5%) than in those with mild HD (41.2%, p=0.0342).Skewed XCI is related to the prognosis of AITD, particularly the intractability of GD.

SUBMITTER: Ishido N

PROVIDER: S-EPMC4322037 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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The relationship between skewed X chromosome inactivation and the prognosis of Graves' and Hashimoto's diseases.

Ishido Naoko N Inoue Naoya N Watanabe Mikio M Hidaka Yoh Y Iwatani Yoshinori Y

Thyroid : official journal of the American Thyroid Association 20141210 2

<h4>Background</h4>Autoimmune thyroid diseases (AITDs) predominantly develop in females. One of two X chromosomes is randomly inactivated by methylation in each female cell, but it has been reported that skewed X chromosome inactivation (XCI) may be associated with the development of autoimmune diseases. To clarify the significance of skewed XCI in the prognosis and development of AITD, we investigated the proportion of skewed XCI in female patients with AITD.<h4>Methods</h4>We analyzed the degr ...[more]

PMID: 25338305

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Project description:BackgroundX chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia.MethodsA total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups.ResultsFirst, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ? 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers.LimitationsThe XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease.ConclusionOur study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.

Project description:BackgroundAgeing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of 46, XX females to balance the gene expression with 46, XY males. Age acquired XCI-skew describes the preferential selection of cells across a tissue resulting in an imbalance of XCI, which is particularly prevalent in blood tissues of ageing females, and yet its clinical consequences are unknown.MethodsWe assayed XCI in 1575 females from the TwinsUK population cohort using DNA extracted from whole blood. We employed prospective, cross-sectional, and intra-twin study designs to characterise the relationship of XCI-skew with molecular and cellular measures of ageing, cardiovascular disease risk, and cancer diagnosis.ResultsWe demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10 year follow-up study, XCI-skew is predictive of future cancer incidence.ConclusionsOur study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk.FundingKSS acknowledges funding from the Medical Research Council [MR/M004422/1 and MR/R023131/1]. JTB acknowledges funding from the ESRC [ES/N000404/1]. MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London.

Dataset Information

The relationship between skewed X chromosome inactivation and the prognosis of Graves' and Hashimoto's diseases.

Publications

The relationship between skewed X chromosome inactivation and the prognosis of Graves' and Hashimoto's diseases.

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