Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.
PLoS Genet. 2011 Aug;7(8):e1002216. doi: 10.1371/journal.pgen.1002216. Epub 2011 Aug 4.
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).
自身抗体产生的遗传基础在主要组织相容性复合体 (MHC) 人类白细胞抗原 (HLA) 区域之外的关联中很大程度上是未知的。本研究的目的是使用 1 型糖尿病 (T1D) 患者的全基因组关联扫描单核苷酸多态性 (SNP) 数据，发现与自身抗体阳性相关的新遗传关联，这些患者具有自身抗体测量值。我们测量了两种抗胰岛自身抗体，谷氨酸脱羧酶 (GADA，n = 2,506)、胰岛素瘤相关抗原 2 (IA-2A，n = 2,498)、自身免疫性甲状腺 (格雷夫斯') 疾病 (AITD) 自身抗原甲状腺过氧化物酶 (TPOA，n = 8,300) 和针对胃壁细胞 (PCA，n = 4,328) 的抗体，这些抗体与自身免疫性胃炎有关。两个位点通过了严格的全基因组显著性水平 (p<10(-10)): 1q23/FCRL3 与 IA-2A 和 9q34/ABO 与 PCA。在假发现率为 16%的情况下，52 个非 MHC T1D 位点中有 11 个显示与至少一种自身抗体相关的证据：16p11/IL27-IA-2A、2q24/IFIH1-IA-2A 和 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 和 12q24/SH2B3-GADA 和 TPOA。在 2477 例格雷夫斯病患者中对 TPOA 相关位点进行分析，确定了两个新的 AITD 位点 (BACH2 和 UBASH3A)。
