Evaluation of X chromosome inactivation with respect to HLA genetic susceptibility in rheumatoid arthritis and systemic sclerosis

Date
2016
Authors
Kanaan, S. B.
Onat, O. E.
Balandraud, N.
Martin, G. V.
Nelson, J. L.
Azzouz, D. F.
Auger, I.
Arnoux, F.
Martin, M.
Roudier, J.
Advisor
Instructor
Source Title
PLoS ONE
Print ISSN
1932-6203
Electronic ISSN
Publisher
Public Library of Science
Volume
11
Issue
6
Pages
1 - 12
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
Abstract

Background: Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias. Methods: Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome. Results: 110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients. Conclusion: Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity. © 2016 Kanaan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Keywords
HLA DQB1 antigen, HLA DRB1 antigen, Androgen receptor, Autoantibody, HLA antigen, HLA DQ antigen, Autoimmunity, Chromosome mosaicism, Controlled study, Gene locus, Genetic susceptibility, DNA methylation, Genetic epigenesis, Genetic predisposition, Mononuclear cell, Rheumatoid arthritis, Systemic sclerosis, Autoantibodies, Case-Control Studies, DNA Methylation, Genotype, HLA Antigens, HLA-DQ beta-Chains, HLA-DRB1 Chains, Humans, X Chromosome Inactivation
Citation
Published Version (Please cite this version)