Volume 22, Issue 1, March 2006

Table of Contents 22-1

X-Chromosome Inactivation and Autoimmune Thyroid Disease

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Brix and colleagues examined X-chromosome inactivation as a possible explanation for the female predominance in the prevalence of autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The rationale is based on the Lyon hypothesis: to avoid gene overdosing, one of the two X-chromosomes in female embryos becomes inactivated in a presumably random fashion; thus roughly half the cells express genes from the maternally derived X-chromosome and the rest from the paternally derived X. Thus, females are essentially X-mosaics. Should the inactivation be skewed, so alleles from one parent are expressed in the periphery but not in sufficient quantities in the thymus to permit the induction of tolerance, then those self-antigens in the periphery will be treated as foreign.

X-chromosome phenotype was determined by extracting DNA from peripheral blood cells, digesting the DNA with a methylation-sensitive restriction endonuclease, and analyzing the digestion products by PCR of a polymorphic repeat within the X-linked gene for the androgen receptor ( AR ); PCR will amplify the product from only the inactivated X-chromosome. The authors defined skewed X-chromosome inactivation (XCI) as inactivation of the same X-chromosome in at least 80% of cells, and extremely skewed as at least 90% of cells.

Subjects were female twin individuals in the Danish Twin Register with AITD who were identified from their response to a mailed questionnaire as having AITD; medical records were then used to confirm the diagnosis. Forty of these 69 women had DNA available for testing, and 32 were heterozygous, and hence informative, for the AR polymorphism. For each subject with AITD, three age- and zygosity-matched, healthy, biochemically euthyroid controls were selected from the Register. Compared to these controls, the subjects with AITD had a higher prevalence of skewed XCI (34% vs 11%; P =0,003) and severely skewed XCI (16% vs 1% over-all; 16% of women with GD vs. 0%; and 15% of women with HT vs 3% of their controls). The subjects with AITD were also compared to their healthy co-twins. The prevalence of skewed XCI in the subjects (42%) exceeded that of their healthy twin co-population (12%; P =0.03), and provided an overall odds ratio for risk of developing AITD of 9.0 (95% CI, 1.64-49.4).

The authors used their results to explain why concordance rates of AITD in monozygotic twin pairs is only 30 - 50%. About one-third of monozygotic twins are dichorionic, with a twinning event that occurs within the first 4 days after conception (the remaining two-thirds of twins later and are monochorionic). The late blastocyst stage (about 5 days after conception) is when XCI occurs. Thus, monochorionic twins have highly similar X-inactivation patterns but dichorionic twins do not. Without data on placental anatomy, the authors were not able to test this hypothesis directly.

Brix TH, Knudsen GPS, Kristiansen M, Kyvik O, Ørstavik KH, Hegedüs L. High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: A possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endocrinol Metab. 2005; 90:5949 - 5953.

Editor’s Comment: It is interesting that explanations for the female predominance of AITD have turned to genetic and epigenetic phenomena, rather than to hormonal effects as had been postulated previously (estrogen exacerbates while androgens inhibit AITD activity).^1,2 What do we know more specifically about the X-chromosome? Firstly, the phenotype of skewed XCI has itself been linked to loci on the X-chromosome.³ Although AITD is more common among women with Turner syndrome, it is especially so for those harboring an Xq-isochromosome (lack a short arm but have two long arms of the X-chromosome).⁴ Several immune-modulating genes are located on the X-chromosome, and X-chromosome loci may show linkage with AITD.⁵ A new polyendocrine syndrome has been mapped to chromosome Xp11.23-q13.3 and attributed to mutations of the FOXP3 gene. Called IPEX ( Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked), it is characterized by intractable diarrhea (autoimmune enteropathy), eczema, hemolytic anemia, diabetes mellitus, or thyroid autoimmunity.⁶ The evidence shown by the authors is very intriguing. Incidentally, AR, the gene these investigators used as their X-chromosome marker, is mapped to chromosome Xq11-q12.⁷

Adda Grimberg, MD

References - (linked to )

1. Estienne V, Duthoit C, Reichert M, et al. Androgen-dependent expression of FcgammaRIIB2 by thymocytes from patients with autoimmune Graves’ disease: A Possible molecular clue for sex dependence of autoimmune disease. FASEB J. 2002;16:1087 - 1092.
2. Cutolo M, Sulli A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus. 2004;13:635 - 638.
3. Naumova AK, Olien L, Bird LM, et al. Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet. 1998;6:552 - 562.
4. Stratakis CA , Rennert OM. Turner syndrome: Molecular and cytogenetics, dysmorphology, endocrine, and other clinical manifestations and their management. The Endocrinologist. 1994;4:442 - 453.
5. Tomer Y, Davies TF. Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev. 2003;24:694 - 717.
6. OMIM #304790.
7. OMIM *313700.

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