X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma

• Published in: Clinical and experimental immunology Vol. 169; no. 3; pp. 253 - 262
• Main Authors: Selmi, C., Feghali‐Bostwick, C. A., Lleo, A., Lombardi, S. A., De Santis, M., Cavaciocchi, F., Zammataro, L., Mitchell, M. M., LaSalle, J. M., Medsger Jr, T., Gershwin, M. E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2012; Blackwell; Oxford University Press; Blackwell Science Inc
• Subjects: Adult; Analytical, structural and metabolic biochemistry; Apoptosis; Biological and medical sciences; Cell proliferation; Chromosome Mapping; Chromosomes; Chromosomes, Human, X - chemistry; Chromosomes, Human, X - genetics; Connective tissue diseases; CpG Islands; Diseases in Twins - genetics; DNA; DNA Methylation; Environmental factors; epigenetics; Female; Fibrosis; Fundamental and applied biological sciences. Psychology; Genes, X-Linked - genetics; Genetic Association Studies; Genetic Predisposition to Disease; genome‐wide; Humans; Immunoprecipitation; Inflammation; Interleukin 1; Lymphocytes; Lymphocytes - chemistry; Medical sciences; MeDIP; Middle Aged; Oligonucleotide Array Sequence Analysis; Original; Oxidative stress; Peripheral blood mononuclear cells; Promoter Regions, Genetic - genetics; Promoters; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma; Scleroderma, Systemic - genetics; Sex chromosomes; surface antigens; systemic autoimmunity; Transcription factors; Twins; Twins, Monozygotic - genetics; X chromosome; Autoimmunity; Immunopathology; Connective tissue disease; Skin disease; Autoimmune disease; Biochemistry; genome-wide; Gene; Systemic disease; Epigenetics; Genetics; X-Chromosome; Genome; Methylation; Scleroderma; Monozygotic twin; Lymphocyte; MeDIP; systemic autoimmunity
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2012.04621.x

Summary Scleroderma (SSc) is a rare connective tissue disease characterized by fibrosis, microvasculopathy and autoimmune features. The role of genetics is limited in SSc, as suggested by similar concordance rates in monozygotic and dizygotic twin pairs, while environmental factors may act through epigenetic changes, as demonstrated for specific genes. Further, sex chromosome changes have been reported in SSc and may explain the female preponderance. In the present study we compared the methylation profile of all X chromosome genes in peripheral blood mononuclear cells from monozygotic twins discordant (n = 7) and concordant (n = 1) for SSc. Methylated DNA immunoprecipitations from each discordant twin pair were hybridized to a custom‐designed array included 998 sites encompassing promoters of all X chromosome genes and randomly chosen autosomal genes. Biostatistical tools identified sites with an elevated probability to be consistently hypermethylated (n = 18) or hypomethylated (n = 25) in affected twins. Identified genes include transcription factors (ARX, HSFX1, ZBED1, ZNF41) and surface antigens (IL1RAPL2, PGRMC1), and pathway analysis suggests their involvement in cell proliferation (PGK1, SMS, UTP14A, SSR4), apoptosis (MTM1), inflammation (ARAF) and oxidative stress (ENOX2). In conclusion, we propose that X chromosome genes with different methylation profiles in monozygotic twin pairs may constitute candidates for SSc susceptibility.