{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T23:16:43Z","timestamp":1780960603238,"version":"3.54.1"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T00:00:00Z","timestamp":1571875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T00:00:00Z","timestamp":1571875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013455","name":"Lady Davis Institute for Medical Research","doi-asserted-by":"publisher","award":["Clinical Research Pilot Project (CLIPP)"],"award-info":[{"award-number":["Clinical Research Pilot Project (CLIPP)"]}],"id":[{"id":"10.13039\/501100013455","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"publisher","award":["Clinical Research Scholar"],"award-info":[{"award-number":["Clinical Research Scholar"]}],"id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["MOP 1303445"],"award-info":[{"award-number":["MOP 1303445"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008762","name":"Genome Canada","doi-asserted-by":"publisher","award":["2017 Bioinformatics"],"award-info":[{"award-number":["2017 Bioinformatics"]}],"id":[{"id":"10.13039\/100008762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood. Increasing evidence suggests that both genetic susceptibilities and changes in DNA methylation influence pivotal biological pathways and thereby contribute to the disease. The role of DNA methylation in SSc has not been fully elucidated, because existing investigations of DNA methylation predominantly focused on nucleotide CpGs within restricted genic regions, and were performed on samples containing mixed cell types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed whole-genome bisulfite sequencing on purified CD4+ T lymphocytes from nine SSc patients and nine controls in a pilot study, and then profiled genome-wide cytosine methylation as well as genetic variations. We adopted robust statistical methods to identify differentially methylated genomic regions (DMRs). We then examined pathway enrichment associated with genes located in these DMRs. We also tested whether changes in CpG methylation were associated with adjacent genetic variation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We profiled DNA methylation at more than three million CpG dinucleotides genome-wide. We identified 599 DMRs associated with 340 genes, among which 54 genes exhibited further associations with adjacent genetic variation. We also found these genes were associated with pathways and functions that are known to be abnormal in SSc, including Wnt\/\u03b2-catenin signaling pathway, skin lesion formation and progression, and angiogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The CD4+ T cell DNA cytosine methylation landscape in SSc involves crucial genes in disease pathogenesis. Some of the methylation patterns are also associated with genetic variation. These findings provide essential foundations for future studies of epigenetic regulation and genome-epigenome interaction in SSc.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-019-0602-8","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T13:06:33Z","timestamp":1572008793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis"],"prefix":"10.1186","volume":"12","author":[{"given":"Tianyuan","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen Oros","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Colmegna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilien","family":"Lora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia M. T.","family":"Greenwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Hudson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,24]]},"reference":[{"issue":"3","key":"602_CR1","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1006\/clin.1997.4412","volume":"84","author":"DL Jacobson","year":"1997","unstructured":"Jacobson DL, et al. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84(3):223\u201343.","journal-title":"Clin Immunol Immunopathol"},{"issue":"3","key":"602_CR2","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S1568-9972(03)00006-5","volume":"2","author":"GS Cooper","year":"2003","unstructured":"Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun Rev. 2003;2(3):119\u201325.","journal-title":"Autoimmun Rev"},{"issue":"4","key":"602_CR3","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.semarthrit.2008.06.002","volume":"39","author":"FF Al-Dhaher","year":"2010","unstructured":"Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum. 2010;39(4):269\u201377.","journal-title":"Semin Arthritis Rheum"},{"issue":"4","key":"602_CR4","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1136\/ard.50.4.267","volume":"50","author":"AJ Silman","year":"1991","unstructured":"Silman AJ. Scleroderma and survival. Ann Rheum Dis. 1991;50(4):267\u20139.","journal-title":"Ann Rheum Dis"},{"key":"602_CR5","doi-asserted-by":"crossref","unstructured":"Ferdowsi N, et al. Development and validation of the scleroderma clinical trials consortium damage index (SCTC-DI): a novel instrument to quantify organ damage in systemic sclerosis. Ann Rheum Dis. 2019.","DOI":"10.1136\/annrheumdis-2018-214764"},{"issue":"9","key":"602_CR6","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1007\/s00109-014-1190-x","volume":"92","author":"B Eckes","year":"2014","unstructured":"Eckes B, et al. Molecular and cellular basis of scleroderma. J Mol Med (Berl). 2014;92(9):913\u201324.","journal-title":"J Mol Med (Berl)"},{"issue":"2","key":"602_CR7","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/sj.gene.6363734","volume":"2","author":"FC Gilchrist","year":"2001","unstructured":"Gilchrist FC, et al. Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP. Genes Immun. 2001;2(2):76\u201381.","journal-title":"Genes Immun"},{"issue":"2\u20134","key":"602_CR8","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3109\/08830189509056707","volume":"12","author":"FC Arnett","year":"1995","unstructured":"Arnett FC. HLA and autoimmunity in scleroderma (systemic sclerosis). Int Rev Immunol. 1995;12(2\u20134):107\u201328.","journal-title":"Int Rev Immunol"},{"issue":"8","key":"602_CR9","first-page":"1481","volume":"32","author":"DD Gladman","year":"2005","unstructured":"Gladman DD, et al. HLA markers for susceptibility and expression in scleroderma. J Rheumatol. 2005;32(8):1481\u20137.","journal-title":"J Rheumatol"},{"key":"602_CR10","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1741-7015-11-9","volume":"11","author":"S Assassi","year":"2013","unstructured":"Assassi S, et al. Genetics of scleroderma: implications for personalized medicine? BMC Med. 2013;11:9.","journal-title":"BMC Med"},{"issue":"6","key":"602_CR11","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1097\/BOR.0b013e328358575b","volume":"24","author":"MD Mayes","year":"2012","unstructured":"Mayes MD. The genetics of scleroderma: looking into the postgenomic era. Curr Opin Rheumatol. 2012;24(6):677\u201384.","journal-title":"Curr Opin Rheumatol"},{"issue":"10","key":"602_CR12","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1093\/rheumatology\/keu155","volume":"54","author":"N Altorok","year":"2015","unstructured":"Altorok N, et al. Epigenetics, the holy grail in the pathogenesis of systemic sclerosis. Rheumatology (Oxford). 2015;54(10):1759\u201370.","journal-title":"Rheumatology (Oxford)"},{"issue":"1","key":"602_CR13","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/1346-8138.13221","volume":"43","author":"T Makino","year":"2016","unstructured":"Makino T, Jinnin M. Genetic and epigenetic abnormalities in systemic sclerosis. J Dermatol. 2016;43(1):10\u20138.","journal-title":"J Dermatol"},{"key":"602_CR14","doi-asserted-by":"publisher","first-page":"438","DOI":"10.3389\/fgene.2014.00438","volume":"5","author":"T Mau","year":"2014","unstructured":"Mau T, Yung R. Potential of epigenetic therapies in non-cancerous conditions. Front Genet. 2014;5:438.","journal-title":"Front Genet"},{"issue":"11","key":"602_CR15","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1016\/j.biochi.2012.06.023","volume":"94","author":"W Pulverer","year":"2012","unstructured":"Pulverer W, et al. The stem cell signature of CHH\/CHG methylation is not present in 271 cancer associated 5'UTR gene regions. Biochimie. 2012;94(11):2345\u201352.","journal-title":"Biochimie"},{"issue":"3","key":"602_CR16","doi-asserted-by":"publisher","first-page":"5629","DOI":"10.18632\/oncotarget.13562","volume":"8","author":"R Tirado-Magallanes","year":"2017","unstructured":"Tirado-Magallanes R, et al. Whole genome DNA methylation: beyond genes silencing. Oncotarget. 2017;8(3):5629\u201337.","journal-title":"Oncotarget"},{"issue":"2","key":"602_CR17","doi-asserted-by":"publisher","first-page":"R31","DOI":"10.1186\/gb-2014-15-2-r31","volume":"15","author":"AE Jaffe","year":"2014","unstructured":"Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014;15(2):R31.","journal-title":"Genome Biol"},{"issue":"7","key":"602_CR18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041361","volume":"7","author":"LE Reinius","year":"2012","unstructured":"Reinius LE, et al. Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One. 2012;7(7):e41361.","journal-title":"PLoS One"},{"issue":"9","key":"602_CR19","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1093\/rheumatology\/kes090","volume":"51","author":"S O'Reilly","year":"2012","unstructured":"O'Reilly S, Hugle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford). 2012;51(9):1540\u20139.","journal-title":"Rheumatology (Oxford)"},{"issue":"7","key":"602_CR20","doi-asserted-by":"publisher","first-page":"R61","DOI":"10.1186\/gb-2012-13-7-r61","volume":"13","author":"Y Liu","year":"2012","unstructured":"Liu Y, et al. Bis-SNP: combined DNA methylation and SNP calling for bisulfite-seq data. Genome Biol. 2012;13(7):R61.","journal-title":"Genome Biol"},{"issue":"1","key":"602_CR21","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1093\/ije\/dyr238","volume":"41","author":"AE Jaffe","year":"2012","unstructured":"Jaffe AE, et al. Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. Int J Epidemiol. 2012;41(1):200\u20139.","journal-title":"Int J Epidemiol"},{"issue":"15","key":"602_CR22","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1093\/bioinformatics\/btx183","volume":"33","author":"RG Cavalcante","year":"2017","unstructured":"Cavalcante RG, Sartor MA. annotatr: genomic regions in context. Bioinformatics. 2017;33(15):2381\u20133.","journal-title":"Bioinformatics"},{"issue":"4","key":"602_CR23","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","volume":"30","author":"A Kramer","year":"2014","unstructured":"Kramer A, et al. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 2014;30(4):523\u201330.","journal-title":"Bioinformatics"},{"issue":"5","key":"602_CR24","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1177\/0962280216660128","volume":"27","author":"M Turgeon","year":"2018","unstructured":"Turgeon M, et al. Principal component of explained variance: an efficient and optimal data dimension reduction framework for association studies. Stat Methods Med Res. 2018;27(5):1331\u201350.","journal-title":"Stat Methods Med Res"},{"issue":"1","key":"602_CR25","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.jid.2017.08.024","volume":"138","author":"T Toyama","year":"2018","unstructured":"Toyama T, et al. Therapeutic targeting of TAZ and YAP by dimethyl Fumarate in systemic sclerosis fibrosis. J Invest Dermatol. 2018;138(1):78\u201388.","journal-title":"J Invest Dermatol"},{"issue":"2","key":"602_CR26","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/labinvest.2015.154","volume":"96","author":"C Bergmann","year":"2016","unstructured":"Bergmann C, Distler JH. Canonical Wnt signaling in systemic sclerosis. Lab Investig. 2016;96(2):151\u20135.","journal-title":"Lab Investig"},{"issue":"6","key":"602_CR27","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1002\/art.30312","volume":"63","author":"J Wei","year":"2011","unstructured":"Wei J, et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 2011;63(6):1707\u201317.","journal-title":"Arthritis Rheum"},{"issue":"8","key":"602_CR28","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1002\/art.34424","volume":"64","author":"J Wei","year":"2012","unstructured":"Wei J, et al. Wnt\/beta-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. 2012;64(8):2734\u201345.","journal-title":"Arthritis Rheum"},{"issue":"6","key":"602_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180751","volume":"12","author":"L Cao","year":"2017","unstructured":"Cao L, Lafyatis R, Burkly LC. Increased dermal collagen bundle alignment in systemic sclerosis is associated with a cell migration signature and role of Arhgdib in directed fibroblast migration on aligned ECMs. PLoS One. 2017;12(6):e0180751.","journal-title":"PLoS One"},{"issue":"5","key":"602_CR30","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/art.39575","volume":"68","author":"H Sun","year":"2016","unstructured":"Sun H, et al. Netrin-1 regulates Fibrocyte accumulation in the Decellularized fibrotic Sclerodermatous lung microenvironment and in Bleomycin-induced pulmonary fibrosis. Arthritis Rheumatol. 2016;68(5):1251\u201361.","journal-title":"Arthritis Rheumatol"},{"issue":"12","key":"602_CR31","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1038\/nm.4419","volume":"23","author":"D Lagares","year":"2017","unstructured":"Lagares D, et al. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017;23(12):1405\u201315.","journal-title":"Nat Med"},{"issue":"30","key":"602_CR32","doi-asserted-by":"publisher","first-page":"21546","DOI":"10.1074\/jbc.M604131200","volume":"281","author":"M Koch","year":"2006","unstructured":"Koch M, et al. Expression of type XXIII collagen mRNA and protein. J Biol Chem. 2006;281(30):21546\u201357.","journal-title":"J Biol Chem"},{"issue":"8","key":"602_CR33","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1136\/annrheumdis-2014-205303","volume":"74","author":"N Altorok","year":"2015","unstructured":"Altorok N, et al. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis. 2015;74(8):1612\u201320.","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"602_CR34","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1038\/sj.jid.5701101","volume":"128","author":"J Bayle","year":"2008","unstructured":"Bayle J, et al. Increased expression of Wnt2 and SFRP4 in tsk mouse skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis. J Invest Dermatol. 2008;128(4):871\u201381.","journal-title":"J Invest Dermatol"},{"issue":"4","key":"602_CR35","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/nrrheum.2009.26","volume":"5","author":"J Varga","year":"2009","unstructured":"Varga J, Pasche B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol. 2009;5(4):200\u20136.","journal-title":"Nat Rev Rheumatol"},{"key":"602_CR36","doi-asserted-by":"publisher","first-page":"226","DOI":"10.2741\/s22","volume":"1","author":"J Varga","year":"2009","unstructured":"Varga J, Whitfield ML. Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed). 2009;1:226\u201335.","journal-title":"Front Biosci (Schol Ed)"},{"issue":"4","key":"602_CR37","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.4049\/jimmunol.174.4.2071","volume":"174","author":"SC McKarns","year":"2005","unstructured":"McKarns SC, Schwartz RH. Distinct effects of TGF-beta 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3. J Immunol. 2005;174(4):2071\u201383.","journal-title":"J Immunol"},{"issue":"5","key":"602_CR38","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/j.jid.2017.12.003","volume":"138","author":"W Ding","year":"2018","unstructured":"Ding W, et al. Genome-wide DNA methylation analysis in systemic sclerosis reveals Hypomethylation of IFN-associated genes in CD4(+) and CD8(+) T cells. J Invest Dermatol. 2018;138(5):1069\u201377.","journal-title":"J Invest Dermatol"},{"issue":"2","key":"602_CR39","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1086\/422507","volume":"75","author":"K Freude","year":"2004","unstructured":"Freude K, et al. Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation. Am J Hum Genet. 2004;75(2):305\u20139.","journal-title":"Am J Hum Genet"},{"key":"602_CR40","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13059-015-0618-0","volume":"16","author":"F Yang","year":"2015","unstructured":"Yang F, et al. The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome Biol. 2015;16:52.","journal-title":"Genome Biol"},{"issue":"5880","key":"602_CR41","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1126\/science.1153252","volume":"320","author":"M Chahrour","year":"2008","unstructured":"Chahrour M, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008;320(5880):1224\u20139.","journal-title":"Science"},{"issue":"8","key":"602_CR42","first-page":"1208","volume":"77","author":"Y He","year":"2018","unstructured":"He Y, et al. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Ann Rheum Dis. 2018;77(8):1208\u201318.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"602_CR43","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1111\/j.1365-2249.2012.04621.x","volume":"169","author":"C Selmi","year":"2012","unstructured":"Selmi C, et al. X chromosome gene methylation in peripheral lymphocytes from monozygotic twins discordant for scleroderma. Clin Exp Immunol. 2012;169(3):253\u201362.","journal-title":"Clin Exp Immunol"},{"key":"602_CR44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13069-015-0028-7","volume":"8","author":"R Lee","year":"2015","unstructured":"Lee R, et al. Enhanced chemokine-receptor expression, function, and signaling in healthy African American and scleroderma-patient monocytes are regulated by caveolin-1. Fibrogenesis Tissue Repair. 2015;8:11.","journal-title":"Fibrogenesis Tissue Repair"},{"issue":"4","key":"602_CR45","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1084\/jem.20160247","volume":"214","author":"T Takahashi","year":"2017","unstructured":"Takahashi T, et al. Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma. J Exp Med. 2017;214(4):1129\u201351.","journal-title":"J Exp Med"},{"issue":"2","key":"602_CR46","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00109-014-1213-7","volume":"93","author":"T Zhu","year":"2015","unstructured":"Zhu T, et al. The anti-angiogenic role of discoidin domain receptor 2 (DDR2) in laser-induced choroidal neovascularization. J Mol Med (Berl). 2015;93(2):187\u201398.","journal-title":"J Mol Med (Berl)"},{"issue":"4","key":"602_CR47","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1002\/path.4311","volume":"232","author":"S Zhang","year":"2014","unstructured":"Zhang S, et al. A host deficiency of discoidin domain receptor 2 (DDR2) inhibits both tumour angiogenesis and metastasis. J Pathol. 2014;232(4):436\u201348.","journal-title":"J Pathol"},{"issue":"1","key":"602_CR48","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/jid.2012.252","volume":"133","author":"K Makino","year":"2013","unstructured":"Makino K, et al. Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts. J Invest Dermatol. 2013;133(1):110\u20139.","journal-title":"J Invest Dermatol"},{"key":"602_CR49","doi-asserted-by":"crossref","unstructured":"Brena, R.M. and J.F. Costello, Genome-epigenome interactions in cancer. Hum Mol Genet, 2007. 16 Spec No 1: p. R96\u2013105.","DOI":"10.1093\/hmg\/ddm073"},{"key":"602_CR50","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1186\/1471-2164-15-487","volume":"15","author":"G Almouzni","year":"2014","unstructured":"Almouzni G, et al. Relationship between genome and epigenome--challenges and requirements for future research. BMC Genomics. 2014;15:487.","journal-title":"BMC Genomics"},{"issue":"12","key":"602_CR51","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1136\/annrheumdis-2012-202742","volume":"72","author":"FD Carmona","year":"2013","unstructured":"Carmona FD, et al. New insight on the Xq28 association with systemic sclerosis. Ann Rheum Dis. 2013;72(12):2032\u20138.","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"602_CR52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033560","volume":"7","author":"A Piha-Gossack","year":"2012","unstructured":"Piha-Gossack A, Sossin W, Reinhardt DP. The evolution of extracellular fibrillins and their functional domains. PLoS One. 2012;7(3):e33560.","journal-title":"PLoS One"},{"issue":"3","key":"602_CR53","doi-asserted-by":"publisher","DOI":"10.4081\/pr.2013.e15","volume":"5","author":"F Tocchioni","year":"2013","unstructured":"Tocchioni F, et al. Pectus excavatum and heritable disorders of the connective tissue. Pediatr Rep. 2013;5(3):e15.","journal-title":"Pediatr Rep"},{"issue":"37","key":"602_CR54","doi-asserted-by":"publisher","first-page":"22423","DOI":"10.1074\/jbc.M115.642710","volume":"290","author":"C Dai","year":"2015","unstructured":"Dai C, et al. Transcriptional activation of human CDCA8 gene regulated by transcription factor NF-Y in embryonic stem cells and cancer cells. J Biol Chem. 2015;290(37):22423\u201334.","journal-title":"J Biol Chem"},{"issue":"5","key":"602_CR55","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1038\/jid.2011.472","volume":"132","author":"SA Pendergrass","year":"2012","unstructured":"Pendergrass SA, et al. Intrinsic gene expression subsets of diffuse cutaneous systemic sclerosis are stable in serial skin biopsies. J Invest Dermatol. 2012;132(5):1363\u201373.","journal-title":"J Invest Dermatol"},{"issue":"7635","key":"602_CR56","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nature20784","volume":"541","author":"S Wahl","year":"2017","unstructured":"Wahl S, et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature. 2017;541(7635):81\u20136.","journal-title":"Nature"},{"issue":"7549","key":"602_CR57","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/nature14125","volume":"520","author":"L Liang","year":"2015","unstructured":"Liang L, et al. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature. 2015;520(7549):670\u20134.","journal-title":"Nature"},{"issue":"4","key":"602_CR58","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.ajhg.2017.09.003","volume":"101","author":"TG Richardson","year":"2017","unstructured":"Richardson TG, et al. Mendelian randomization analysis identifies CpG sites as putative mediators for genetic influences on cardiovascular disease risk. Am J Hum Genet. 2017;101(4):590\u2013602.","journal-title":"Am J Hum Genet"},{"issue":"11","key":"602_CR59","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41584-018-0099-0","volume":"14","author":"C Angiolilli","year":"2018","unstructured":"Angiolilli C, et al. New insights into the genetics and epigenetics of systemic sclerosis. Nat Rev Rheumatol. 2018;14(11):657\u201373.","journal-title":"Nat Rev Rheumatol"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-019-0602-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12920-019-0602-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-019-0602-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T23:55:26Z","timestamp":1695340526000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-019-0602-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,24]]},"references-count":59,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["602"],"URL":"https:\/\/doi.org\/10.1186\/s12920-019-0602-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.12858\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.12858\/v2","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.12858\/v3","asserted-by":"object"}]},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,24]]},"assertion":[{"value":"5 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethics approval for this study was obtained from the Institutional Review Board at McGill University, Montreal, Canada. Every study subject signed an informed consent.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All study subjects gave consent to publish WGBS data and de-identified demographic features.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"144"}}