Association of the HLA-DRB1 epitope LA67, 74 with rheumatoid arthritis and citrullinated vimentin binding
Association of the HLA-DRB1 epitope LA67, 74 with rheumatoid arthritis and citrullinated vimentin binding
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DOI：
10.1002/art.30636
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发表时间：
2011-12-01
影响因子：
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通讯作者：
Aubrey, Michael T.
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文献类型：
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作者：
Freed, Brian M.;Schuyler, Ronald P.;Aubrey, Michael T.
目的 尽管类风湿性关节炎 (RA) 长期以来一直与 HLADRB1 共享表位相关，但从未对其他表位进行系统搜索。此外，尚未研究这些表位与瓜氨酸自身抗原的结合之间的关系。我们开发了一个程序，可以分析最多 5 个氨基酸的所有可能表位的 HLA 数据，并使用该程序来评估 RA.Methods 中的共享表位假设。我们分析了来自国际组织相容性工作组的高分辨率数据，该工作组包括 488 名 RA 患者和 448 名种族和族裔平衡的对照受试者，针对多态性 HLA-DRB1 位置 8-93 中最多 5 个氨基酸的所有组合。统计显着性通过卡方和费舍尔精确检验确定，并进行错误发现率校正。结果。三个残基（V11、H13 和 L67）被发现与 RA 易感性具有最高程度的关联（P < 10-11），并且发现 D70 与 RA 耐药性相关性最好（P = 2 x 10(-11)）。在检查的 > 200 万个表位中，LA67、74 表现出与 RA 易感性最高的相关性（P = 2 x 10(-20)；比值比 4.07 [ 95% 置信区间 3.07-5.39]）。含有 LA67、74 表位的 HLA 等位基因与含有 D70 的等位基因相比，与瓜氨酸波形蛋白 65-77 的结合显着更强。仅 1 个等位基因 (DRB1* 16: 02) 同时包含 LA67、74 和 D70；它与瓜氨酸波形蛋白的结合较弱并且与RA无关。结论。这些研究的结果证实了第 4 袋中的 HLA-DRB1 氨基酸对于瓜氨酸自身抗原的结合和 RA 易感性的重要性。
Objective Although rheumatoid arthritis (RA) has long been associated with an HLADRB1 shared epitope, a systematic search for other epitopes has never been conducted. In addition, the relationship between these epitopes and the binding of citrullinated autoantigens has not been investigated. We developed a program that can analyze HLA data for all possible epitopes of up to 5 amino acids and used this program to assess the shared epitope hypothesis in RA.Methods. We analyzed high-resolution data from the International Histocompatibility Working Group, which included a group of 488 patients with RA and a group of 448 racially and ethnically balanced control subjects, for all combinations of up to 5 amino acids among polymorphic HLA-DRB1 positions 8-93. Statistical significance was determined by chi-square and Fisher's exact tests, with a false discovery rate correction.Results. Three residues (V11, H13, and L67) were found to have the highest degree of association with RA susceptibility (P < 10-11), and D70 was found to correlate best with RA resistance (P = 2 x 10(-11)). Of > 2 million epitopes examined, LA67, 74 exhibited the highest correlation with RA susceptibility (P = 2 x 10(-20); odds ratio 4.07 [ 95% confidence interval 3.07-5.39]). HLA alleles containing the LA67, 74 epitope exhibited significantly greater binding to citrullinated vimentin65-77 than did alleles containing D70. Only 1 allele (DRB1* 16: 02) contained both LA67, 74 and D70; it bound citrullinated vimentin weakly and was not associated with RA.Conclusion. The findings of these studies confirm the importance of HLA-DRB1 amino acids in pocket 4 for the binding of citrullinated autoantigens and susceptibility to RA.