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Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases

Plagnol, V; Howson, JMM; Smyth, DJ; Walker, N; Hafler, JP; Wallace, C; ... Type 1 Diabet Genetics Consortium,; + view all (2011) Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases. PLOS GENET , 7 (8) , Article e1002216. 10.1371/journal.pgen.1002216. Green and gold open access

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Abstract

The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).

Type:Article
Title:Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases
Open access status:An open access publication. A version is also available from UCL Discovery.
DOI:10.1371/journal.pgen.1002216
Publisher version:http://dx.doi.org/10.1371/journal.pgen.1002216
Language:English
Additional information:© 2011 Plagnol et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Wellcome Trust (WT061858), the Juvenile Diabetes Research Foundation (JDRF 9-2005-25), and the UK National Institute for Health Research (NIHR, RG52731). We acknowledge use of the DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council and Wellcome Trust. The Cambridge Institute for Medical Research is the recipient of a Wellcome Trust Strategic Award (079895). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords:SYSTEMIC-LUPUS-ERYTHEMATOSUS, GENETIC RISK MARKERS, ABO BLOOD GROUPS, BETA-CELL, DISEASE SUSCEPTIBILITY, HELICOBACTER-PYLORI, PERNICIOUS ANEMIA, GASTRIC CARCINOMA, CROHNS-DISEASE, HLA-RISK
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute

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