Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A.
Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A.
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DOI：
10.1111/j.1463-1326.2008.01001.x
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发表时间：
2009-02
期刊：
影响因子：
--
通讯作者：
Type 1 Diabetes Genetics Consortium
中科院分区：
文献类型：
--
作者：
Howson JM;Walker NM;Clayton D;Todd JA;Type 1 Diabetes Genetics Consortium
直到最近，由于图谱覆盖范围不足、统计方法不充分以及跨越整个 MHC 的强连锁不平衡，人类白细胞抗原 (HLA) II 类独立与主要组织相容性复合物 (MHC) 区域中 1 型糖尿病 (T1D) 的关联尚未得到充分表征。在这里，我们使用 1 型糖尿病遗传学联盟 (T1DGC) 生成的精细图谱数据测试 MHC 中 HLA II 类独立关联。我们将递归分区应用于 II 类基因座的建模，并使用逐步条件逻辑回归来测试染色体 6p21 上 29 至 34 Mb 之间的约 1534 个基因座，这些基因座分型于 2240 个受影响的同胞对 (ASP) 家族。初步分析证实，HLA-B（31.4 Mb）、HLA-A（30.0 Mb）与 T1D 相关，独立于 II 类基因 HLA-DRB1 和 HLA-DQB1（P 分别 = 6.0 × 10−17 和 8.8 × 10−13）。此外，包含单核苷酸多态性 (SNP)、rs439121 和 II 类基因座 HLA-DPB1 的第二 II 类关联区域被鉴定为 T1D 易感性效应，该效应独立于 HLA-DRB1、HLA-DQB1 和 HLA-B (P = 9.2 × 10−8)。 HLA-B*39 的 T1D 诊断年龄较年轻 (P = 7.6 × 10−6)，而 HLA-B*38 对 T1D 有保护作用。 T1DGC 家族的这些分析重复了我们之前在约 2000 个病例和对照以及 850 个家庭中获得的结果。将这两项研究放在一起，有证据表明 30.0 Mb (HLA-A)、31.4 Mb (HLA-B)、32.5 Mb (rs9268831/HLA-DRA) 和 33.2 Mb (rs439121/HLA-DPB1) 处的四个 T1D 相关区域独立于 HLA-DRB1/HLA-DQB1。两项研究均未发现 HLA-C、HLA-DQA1 基因座以及 UBD/MAS1L 或 ITPR3 基因区域独立关联的证据。这些研究表明，为了找到真正的 II 类独立效应，需要大量、强大的样本集合，并使用密集的标记图谱进行基因分型。此外，需要一种能够完全模拟 II 类效应的稳健统计方法。递归分区是对这些多等位基因系统进行建模的有用工具。
Until recently, human leucocyte antigen (HLA) class II-independent associations with type 1 diabetes (T1D) in the Major Histocompatibility Complex (MHC) region were not adequately characterized owing to insufficient map coverage, inadequate statistical approaches and strong linkage disequilibrium spanning the entire MHC. Here we test for HLA class II-independent associations in the MHC using fine mapping data generated by the Type 1 Diabetes Genetics Consortium (T1DGC). We have applied recursive partitioning to the modelling of the class II loci and used stepwise conditional logistic regression to test ~1534 loci between 29 and 34 Mb on chromosome 6p21, typed in 2240 affected sibpair (ASP) families. Preliminary analyses confirm that HLA-B (at 31.4 Mb), HLA-A (at 30.0 Mb) are associated with T1D independently of the class II genes HLA-DRB1 and HLA-DQB1 (P = 6.0 × 10−17 and 8.8 × 10−13, respectively). In addition, a second class II region of association containing the single-nucleotide polymorphism (SNP), rs439121, and the class II locus HLA-DPB1, was identified as a T1D susceptibility effect which is independent of HLA-DRB1, HLA-DQB1 and HLA-B (P = 9.2 × 10−8). A younger age-at-diagnosis of T1D was found for HLA-B*39 (P = 7.6 × 10−6), and HLA-B*38 was protective for T1D. These analyses in the T1DGC families replicate our results obtained previously in ~2000 cases and controls and 850 families. Taking both studies together, there is evidence for four T1D-associated regions at 30.0 Mb (HLA-A), 31.4 Mb (HLA-B), 32.5 Mb (rs9268831/HLA-DRA) and 33.2 Mb (rs439121/HLA-DPB1) that are independent of HLA-DRB1/HLA-DQB1. Neither study found evidence of independent associations at HLA-C, HLA-DQA1 loci nor in the UBD/MAS1L or ITPR3 gene regions. These studies show that to find true class II-independent effects, large, well-powered sample collections are required and be genotyped with a dense map of markers. In addition, a robust statistical methodology that fully models the class II effects is necessary. Recursive partitioning is a useful tool for modelling these multiallelic systems.
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