Primary biliary cirrhosis (PBC) is an uncommon autoimmune disease with a homogeneous clinical phenotype that reflects incomplete disease concordance in monozygotic (MZ) twins. We have taken advantage of a unique collection consisting of genomic DNA and mRNA from peripheral blood cells of female MZ twins (n = 3 sets) and sisters of similar age (n = 8 pairs) discordant for disease. We performed a genome-wide study to investigate differences in (i) DNA methylation (using a custom tiled four-plex array containing tiled 50-mers 19,084 randomly chosen methylation sites), (ii) copy number variation (CNV) (with a chip including markers derived from the 1000 Genomes Project, all three HapMap phases, and recently published studies), and/or (iii) gene expression (by whole-genome expression arrays). Based on the results obtained from these three approaches we utilized quantitative PCR to compare the expression of candidate genes. Importantly, our data support consistent differences in discordant twins and siblings for the (i) methylation profiles of 60 gene regions, (ii) CNV of 10 genes, and (iii) the expression of 2 interferon-dependent genes. Quantitative PCR analysis showed that 17 of these genes are differentially expressed in discordant sibling pairs. In conclusion, we report that MZ twins and sisters discordant for PBC manifest particular epigenetic differences and highlight the value of the epigenetic study of twins.
Keywords: autoimmune cholangitis, epigenetics, environment
Citation: Selmi C, Cavaciocchi F, Lleo A, Cheroni C, De Francesco R, Lombardi SA, De Santis M, Meda F, Raimondo MG, Crotti C, Folci M, Zammataro L, Mayo MJ, Bach N, Shimoda S, Gordon SC, Miozzo M, Invernizzi P, Podda M, Scavelli R, Martin MR, LaSalle JM and Gershwin ME (2014) Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis. Front. Immunol. 5:128. doi: 10.3389/fimmu.2014.00128
Received: 01 November 2013; Accepted: 13 March 2014;
Published online: 28 March 2014.
Edited by:Paola Zanovello, University of Padova, Italy
Reviewed by:Giovanni Vazza, University of Padova, Italy
Copyright: © 2014 Selmi, Cavaciocchi, Lleo, Cheroni, De Francesco, Lombardi, De Santis, Meda, Raimondo, Crotti, Folci, Zammataro, Mayo, Bach, Shimoda, Gordon, Miozzo, Invernizzi, Podda, Scavelli, Martin, LaSalle and Gershwin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Carlo Selmi, Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, via A. Manzoni 56, 20089 Rozzano, Milan, Italy e-mail: email@example.com