title: Genome-wide analysis of DNA methylation, copy number variation, and gene expression in monozygotic twins discordant for primary biliary cirrhosis.
abstract: 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.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy ; Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis , Davis, CA , USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy ; BIOMETRA Department, University of Milan , Milan , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavaciocchi
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Lleo
authors.affiliation: National Institute of Molecular Genetics (INGM) , Milan , Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.affiliation: National Institute of Molecular Genetics (INGM) , Milan , Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Lombardi
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy ; BIOMETRA Department, University of Milan , Milan , Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: De Santis
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Meda
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Raimondo
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Crotti
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folci
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.affiliation: University of Texas Southwestern , Dallas, TX , USA.
authors.forename: Marlyn J
authors.initials: MJ
authors.lastname: Mayo
authors.affiliation: Mt. Sinai University , New York, NY , USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bach
authors.affiliation: Clinical Research Center, National Nagasaki Medical Center , Nagasaki , Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.affiliation: Henry Ford Hospital , Detroit, MI , USA.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan , Milan , Italy ; Division of Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico , Milan , Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Miozzo
authors.affiliation: Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center , Milan , Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Podda
authors.affiliation: National Institute of Molecular Genetics (INGM) , Milan , Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Scavelli
authors.affiliation: Genome Center and M.I.N.D. Institute, University of California Davis , Davis, CA , USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Martin
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA; Department of Internal Medicine, University of California at Davis, Davis, CA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Genome Center and M.I.N.D. Institute, University of California Davis , Davis, CA , USA.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lasalle
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis , Davis, CA , USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
keywords: autoimmune cholangitis; environment; epigenetics
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):411-9
references.pmid: 20215007
references.citation: Eur J Immunol. 1999 Jun;29(6):2037-45
references.pmid: 10382767
references.citation: Epigenetics. 2011 Jan;6(1):95-102
references.pmid: 20864813
references.citation: PLoS Genet. 2011 Sep;7(9):e1002300
references.pmid: 21980303
references.citation: N Engl J Med. 2009 Jun 11;360(24):2544-55
references.pmid: 19458352
references.citation: Genes Immun. 2010 Oct;11(7):554-60
references.pmid: 20463746
references.citation: J Autoimmun. 2012 Dec;39(4):259-71
references.pmid: 22739348
references.citation: PLoS One. 2013;8(3):e57886
references.pmid: 23526956
references.citation: BMC Genomics. 2012 Nov 17;13:636
references.pmid: 23157493
references.citation: Genes Immun. 2012 Jun;13(4):328-35
references.pmid: 22257840
references.citation: Autoimmun Rev. 2012 Dec;12(2):300-4
references.pmid: 22634708
references.citation: Hepatology. 2012 Jan;55(1):153-60
references.pmid: 21898485
references.citation: Nucleic Acids Res. 2010 May;38(9):e105
references.pmid: 20142258
references.citation: Arthritis Res Ther. 2005;7(5):R1001-13
references.pmid: 16207316
references.citation: Nat Genet. 2010 Aug;42(8):658-60
references.pmid: 20639880
references.citation: Am J Hum Genet. 2012 Jul 13;91(1):38-55
references.pmid: 22726847
references.citation: Nat Rev Rheumatol. 2011 May;7(5):263-71
references.pmid: 21343899
references.citation: Autoimmun Rev. 2010 Mar;9(5):A247-50
references.pmid: 20144744
references.citation: Int Immunol. 2000 Sep;12(9):1285-92
references.pmid: 10967023
references.citation: Carcinogenesis. 2001 Oct;22(10):1615-23
references.pmid: 11577000
references.citation: Am J Hum Genet. 2007 Jan;80(1):91-104
references.pmid: 17160897
references.citation: Lancet. 2011 May 7;377(9777):1600-9
references.pmid: 21529926
references.citation: Int J Cancer. 1999 Feb 9;80(4):573-80
references.pmid: 9935159
references.citation: Gastroenterology. 2004 Aug;127(2):485-92
references.pmid: 15300581
references.citation: J Clin Gastroenterol. 2004 Mar;38(3):264-71
references.pmid: 15128074
references.citation: Oncogene. 2009 Apr 9;28(14):1653-68
references.pmid: 19234488
references.citation: Tissue Antigens. 2011 Jul;78(1):65-8
references.pmid: 21506939
references.citation: Science. 2007 Feb 9;315(5813):848-53
references.pmid: 17289997
references.citation: J Autoimmun. 2012 May;38(2-3):J177-86
references.pmid: 22137891
references.citation: J Exp Med. 1985 May 1;161(5):1135-51
references.pmid: 2580935
references.citation: Genes Immun. 2010 Mar;11(2):155-60
references.pmid: 19741716
references.citation: J Autoimmun. 2012 Dec;39(4):272-84
references.pmid: 22749494
references.citation: Clin Exp Immunol. 2012 Sep;169(3):253-62
references.pmid: 22861365
references.citation: PLoS One. 2011;6(8):e23634
references.pmid: 21886806
references.citation: J Autoimmun. 2012 Dec;39(4):253-8
references.pmid: 22771005
references.citation: Nat Genet. 2011 Mar 13;43(4):329-32
references.pmid: 21399635
references.citation: Genome Res. 2010 Feb;20(2):170-9
references.pmid: 20028698
references.citation: J Autoimmun. 2012 Dec;39(4):285-93
references.pmid: 22748431
references.citation: Nat Genet. 2010 Aug;42(8):655-7
references.pmid: 20639879
references.citation: Nature. 2010 Apr 29;464(7293):1351-6
references.pmid: 20428171
references.citation: Am J Hum Genet. 2012 Oct 5;91(4):721-8
references.pmid: 23000144
references.citation: Genes Immun. 2013 Apr;14(3):179-86
references.pmid: 23392275
references.citation: Hum Mol Genet. 2012 Dec 1;21(23):5209-21
references.pmid: 22936693
references.citation: Am J Hum Genet. 2008 Mar;82(3):763-71
references.pmid: 18304490