Myositis Genetics Consortium. Genome-Wide Association Study of Dermatomyositis Reveals Shared Genetic Risk Factors with Other Autoimmune Diseases

H. Chinoy, F.W. Miller, R.G. Cooper, J. Vencovsky, L.G. Rider, K. Danko, L.R. Wedderburn, I.E. Lundberg, L.M. Pachman, A.M. Reed, S.R. Ytterberg, L. Padyukov, O’Callaghan A. Selva, T. Radstake, D.A. Isenberg, WER Ollier, T. O’Hanlon, B. Peng, P. Scheet, A.T. LeeJ. Lamb, W. Chen, C. Amos, P.K. Gregersen

Research output: Contribution to conferenceOther

Abstract

Background/Purpose: Genetic risk factors for adult dermatomyositis(DM) and juvenile DM outside of the major histocompatibility complex(MHC) have been difficult to identify, although family studies have suggestedthat DM shares genetic risk factors with other autoimmune diseases.Methods: We performed a genome-wide association study (GWAS) onadult DM and juvenile DM subjects of European ancestry meeting probableor definite Bohan and Peter criteria using the Illumina platform. DM cases(n_1178: 705 with adult DM and 473 with juvenile DM) were compared togeographically- and race-matched controls (n_4724). Ingenuity SystemsPathway Analyses were performed based on the genes identified by GWAS.Results: As expected, we observed a strong signal in the MHC locusacross the class II region (maximum p_2.79 10_29) but no other locusreached genome-wide significance in this dataset. To assess for possibleshared genes with other autoimmune diseases, however, we examined theassociation signals in 140 non-MHC loci that have been associated withautoimmune diseases. Strikingly, seven SNPs from six genes had p values _0.01, thus substantially exceeding expectation. These included: B lymphocytekinase (BLK: rs2736340, p_6.53 10_5); chemokine (C-C motif) ligand 21(CCL21: rs2492358, p_2.10 10_4; and rs951005, p_3.17 10_5); proteintyrosine phosphatase non-receptor type 2 (PTPN2: rs1893217, p_0.0029);signal transducer and activator of transcription 4 (STAT4: rs7574865,p_0.0050); interleukin 2 receptor alpha (IL2RA: rs7072793, p_0.0073); anda gene encoding a 153–amino acid protein with four putative transmembranedomains (ORMDL3: rs2290400, p_0.0010). Based on the associated genesfrom the entire GWAS, canonical pathways that seemed particularly importantin DM were those relating to antigen presentation (p_9.49 10_23),cytotoxic T cell-mediated apoptosis of target cells (p_1.44 10_17), allograftrejection signaling (p_1.44 10_17), the OX40 (CD134) signaling pathway(p_5.9 10_17) and autoimmune thyroid disease signaling (p_5.0 10_13).Conclusion: Our findings indicate that DM shares many genetic featuresand canonical pathways with other autoimmune diseases. This first identificationof these common autoimmune disease genetic predispositions thatpromote the development of DM suggests potential novel therapeutic approachesfor this disorder.
Original languageEnglish
PagesS656
Publication statusPublished - Nov 2011
EventAmerican College of Rheumatology -
Duration: 1 Jan 1824 → …

Conference

ConferenceAmerican College of Rheumatology
Period1/01/24 → …

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