Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.
Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.
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DOI：
10.1371/journal.pgen.1002216
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Todd JA
中科院分区：
文献类型：
--
作者：
Plagnol V;Howson JM;Smyth DJ;Walker N;Hafler JP;Wallace C;Stevens H;Jackson L;Simmonds MJ;Type 1 Diabetes Genetics Consortium;Bingley PJ;Gough SC;Todd JA
除了主要组织相容性复合体(MHC)人类白细胞抗原(HLA)区域的关联外，自身抗体产生的遗传基础在很大程度上是未知的。这项研究的目的是利用全基因组关联扫描单核苷酸多态性(SNP)数据，通过自身抗体测量发现1型糖尿病(T1D)患者自身抗体阳性的新的遗传关联。我们检测了两种与自身免疫性胃炎相关的抗胰岛自身抗体，谷氨酸脱羧酶(GADA，n = 2,506)，胰岛素瘤相关抗原2(IA-2A，n = 2,498)，自身免疫性甲状腺疾病(Graves‘病)自身抗原甲状腺过氧化物酶(TpoA，n = 8,300)和胃壁细胞抗体(Pca，n = 4,328)。有两个座位通过了严格的全基因组显著水平(p<；10−10)：1q23/FCRL3与IA-2A和9q34/ABO与Pca。在52个非MHC T1D基因座中，有11个座位的假发现率为16%：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。对2477例Graves病患者的TPOA相关基因座进行分析，发现两个新的AITD基因座(BACH2和UBASH3A)。自身抗体是自身免疫性疾病的重要标志，如1型糖尿病和Graves病。然而，人们对控制它们生产的遗传因素知之甚少。为了提高我们对这一遗传基础的理解，我们在多达8300例1型糖尿病患者的血浆样本中测量了四种自身抗体。我们将这些测量结果与全基因组的基因数据结合起来，进行了四项独立的全基因组相关性研究。有两个基因座显示出自身抗体关联的明确证据：FCRL3基因座和ABO血型基因座。FCRL3基因的变异以前曾被认为与自身免疫性疾病有关，但这种相关性在ABO血型基因型中还没有报道。此外，我们发现1型糖尿病和自身抗体基因座之间存在广泛的重叠，这些发现提供了关于这些风险变量作用的新信息。最后，我们假设与甲状腺自身抗体相关的基因是与甲状腺自身免疫性疾病相关的候选基因。我们通过在一组独立的Graves病病例中对这些变异进行基因分型，证实了这一假设，并发现了两个新的Graves病基因座的证据。
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). Autoantibodies are important markers for autoimmune diseases such as type 1 diabetes and Graves' disease. However, little is known about the genetic factors that control their production. To improve our understanding of this genetic basis, we measured four autoantibodies in a collection of up to 8,300 type 1 diabetes cases plasma samples. We combined these measurements with genome-wide genotype data to conduct four independent genome-wide association studies. Two loci showed unequivocal evidence of autoantibody association: the FCRL3 locus and the ABO blood group locus. Variants in the FCRL3 gene have been previously associated with autoimmune diseases, but such associations have not been reported for ABO blood group genotypes. In addition, we found extensive overlap between type 1 diabetes and autoantibody loci, and these findings provide new information about the role of these risk variants. Lastly, we hypothesized that loci associated with thyroid autoantibodies are strong candidates for association with thyroid autoimmune disorders. We confirmed this hypothesis by genotyping these variants in an independent cohort of Graves' disease cases, and we found evidence for two new Graves' disease loci.
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影响因子：
1.8
作者：
Kordonouri, O.;Hartmann, R.;Ilonen, J.
通讯作者：
Ilonen, J.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.182.3.1541
发表时间：
2009-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Maier LM;Anderson DE;Severson CA;Baecher-Allan C;Healy B;Liu DV;Wittrup KD;De Jager PL;Hafler DA
通讯作者：
Hafler DA
影响因子：
24.5
作者：
CALLENDER, S;LANGMAN, MJS;NIELSEN, KR
通讯作者：
NIELSEN, KR