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

Abstract

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...

Twin studies in autoimmune disease: Genetics, gender and environment

“…Hansen and colleagues [234] indicate that the genetic influence on serum autoantibodies to thyroid peroxidase was greater in females (72%) than in males (61%). Interestingly, no significant association between X chromosome inactivation and anti-thyroid peroxidase antibodies was found in MZ twins, but an association was found with DZ twins [237], and another study has also indicated a higher incidence of X chromosome inactivation in female twins [238]. An interesting study by Phillips and colleagues [236] found a higher MZ (which was also higher in females) compared to DZ concordance for anti-thyroglobulin.…”

“…An earlier study by Lawrence [47] reported a concordance of 30%, whereas a larger Finnish study indicated an MZ pairwise concordance of 12.3%, and a DZ pairwise concordance of 3.5%, based on cohorts of 4136 MZ and 9162 DZ twins [11]. Higher rates of [262] Male and female twins from opposite sex pairs had higher frequency of thyroid antibodies compared to MZ pairs [237] No significant association between X chromosome inactivation and anti-thyroid peroxidase antibodies in female MZ twins Significant association between X chromosome inactivation and anti-thyroid peroxidase antibodies in female DZ twins [263] Higher prevalence of autoantibodies in DZ compared to MZ twins [236] For anti-thyroglobulin: 50 concordance have been reported in an Australian twin cohort, based on a twin registry which contained 3808 pairs of twins as of 1980, when the study occurred [48]. A 0.4% RA prevalence was found in a final cohort of 186 twins in 1990, with MZ and DZ pairwise concordance being 21% and 0% respectively [48].…”

Skewed X-chromosome inactivation in patients with esophageal carcinoma

“…While SXCI occurrence was associated with the autoimmune diseases including autoimmune thyroid diseases [38-40], and systemic sclerosis [41], this phenomenon has been linked to development of a few of malignant solid tumours [33] in females. In 1999, Buller et al reported that patients with invasive ovarian cancer had an increased frequency of SXCI compared to those without a detectable fully malignant ovarian tumor [18].…”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…Finally, [117] 63.6% 3.6% [157] 35% 3% Ulcerative colitis [153] 6.3% 6.3% 0% 0% [154] 16% 3% [155] 14.3% 18.2% 4.5% 4.5% [156] 18.8% 18.8% 0% 0% [157] 16% 2% epigenetic modifications have been investigated, and XCI seems to play a role in clinical autoimmune thyroid diseases pathogenesis in women [134,135]. Moreover, the degree of XCI has been associated to anti-TPO antibodies levels in euthyroid subjects [135], and especially in DZ twins, while in MZ twin pairs became nonsignificant [135].…”