Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.
Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.
复制标题
DOI：
10.1038/ng.3353
复制
发表时间：
2015-08
期刊：
影响因子：
30.8
通讯作者：
Raychaudhuri S
中科院分区：
文献类型：
--
作者：
Hu X;Deutsch AJ;Lenz TL;Onengut-Gumuscu S;Han B;Chen WM;Howson JM;Todd JA;de Bakker PI;Rich SS;Raychaudhuri S
人类白细胞抗原(HLA)基因变异占1型糖尿病(T1D)遗传风险的一半。人类白细胞抗原-DR和人类白细胞抗原-DQ分子中的氨基酸变化介导了大部分风险，但广泛的连锁不平衡使独立效应的定位复杂化。利用18,832例病例对照样本，我们将信号定位于人类白细胞抗原-DQ和人类白细胞抗原-DR的3个氨基酸位置。β-DQ第1位57位(已知，P=1×10−1,355)本身可解释总表型变异的15.2%。HLADRβ1基因第13位(P=1×10−721)和71位(P=1×10−95)的独立效应使变异解释比例增加到26.9%。这三个位点共同解释了人类白细胞抗原-DRB1-人类白细胞抗原-DQA1-人类白细胞抗原-DQB1基因座表型变异的90%。此外，我们还观察到21对常见的HLADRB1-HLADQA1-HLADQB1单倍型中的11对存在显著的交互作用(P=1.6×10−)。HL A-DRβ1第13位和第71位涉及抗原结合沟中的P4口袋，从而指出除了HLADQ P9口袋外，另一个与T1D风险有关的关键蛋白质结构。
Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10−1,355) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10−721) and 71 (P = 1 × 10−95) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1–HLA-DQA1–HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1–HLA-DQA1–HLA-DQB1 haplotypes (P = 1.6 × 10−64). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.