HLA Associations Differ by Ethnicity and Aquaporin-4 Antibody Status in Patients With Neuromyelitis Optica Spectrum Disorders.

IF 8 1区医学 Q1 CLINICAL NEUROLOGY

Neurology® Neuroimmunology & Neuroinflammation Pub Date : 2026-05-01 Epub Date: 2026-04-16 DOI:10.1212/NXI.0000000000200562

Moritz Niederschweiberer, Georgia Panagiotaropoulou, Marcelo A Fernandez-Viña, Gonzalo Montero-Martin, Kazutoyo Osoegawa, Megan Behne, Andre Franke, Wolfgang Lieb, Sven Jarius, Brigitte Wildemann, Patrick Schindler, Carolin Otto, Friedemann Paul, Eoin P Flanagan, Lawrence J Cook, Jorge Oksenberg, Michael R Yeaman, Stephan Ripke, Klemens Ruprecht

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引用次数: 0

Abstract

Background and objectives: Neuromyelitis optica spectrum disorders (NMOSDs) comprise inflammatory processes of the CNS. Most patients with NMOSD have serum immunoglobulin (Ig) G autoantibodies directed against the astrocytic water channel aquaporin-4 (AQP4-IgG). In this study, we analyzed HLA allelic frequencies in a large cohort of patients with NMOSD, stratified by ethnicity and AQP4-IgG status, compared with healthy controls.

Methods: Next-generation sequencing-based HLA class I and II genotyping was performed in 174 White, 45 Black, and 41 Hispanic AQP4-IgG-positive (AQP4-IgG+) patients with NMOSD; 49 White patients with AQP4-IgG-negative (AQP4-IgG-) NMOSD; and 2,427 White, 244 Black, and 155 Hispanic controls. Correction for multiple testing was performed using the Bonferroni method.

Results: In White AQP4-IgG+ patients with NMOSD, the most significantly associated alleles were HLA-DQA1*05:01:01 (30.1% vs 11.1%, odds ratio 3.43 [95% CI 2.65-4.42], corrected p = 8.95E-17), HLA-DQB1*02:01:01 (29.9% vs 11.3%, 3.34 [2.58-4.31], corrected p = 4.33E-16), and HLA-DRB1*03:01:01 (29.2% vs 11.6%, 3.15 [2.43-4.06], corrected p = 3.66E-14), followed by HLA-B*08:01:01 (26% vs 10.4%, 3.02 [2.3-3.94] corrected p = 8.79E-12), HLA-C*07:01:01 (27.8% vs 14%, 2.36 [1.81-3.04], corrected p = 2.44E-07), and HLA-DRB3*01:01:02 (28% vs 14.7%, 2.27 [1.73-2.95], corrected p = 2.19E-06). The frequency of HLA-DRB1*08:04:01 was higher in Black AQP4-IgG+ patients with NMOSD than in Black controls but did not achieve statistical significance (19.3% vs 5.7%, 3.92 [1.91-7.86], corrected p = 0.08). Nevertheless, when compared with a larger cohort of Black controls (n = 16,178), the frequency of HLA-DRB1*08:04 (19.3% vs 5.1%, 4.46 [2.45-7.66], corrected p = 1.88E-03) was significantly higher in Black AQP4-IgG+ patients with NMOSD. No significant HLA associations were detected in AQP4-IgG+ Hispanic patients or White AQP4-IgG- patients with NMOSD.

Discussion: This study confirms the previously recognized association of HLA-DRB1*03:01 with AQP4-IgG+ NMOSD in White patients and extends this association to the HLA-DRB1*03:01:01∼HLA-DQA1*05:01:01∼HLA-DQB1*02:01:01 haplotype. Furthermore, it identifies an association of HLA-DRB1*08:04 with AQP4-IgG+ NMOSD in Black patients. However, no HLA associations were detected in White AQP4-IgG- patients with NMOSD. The immunogenetic differences between AQP4-IgG+ and AQP4-IgG- NMOSD support pathophysiologic distinctions between these entities.

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视谱神经脊髓炎患者HLA相关性因种族和水通道蛋白-4抗体状态而异

背景和目的：视神经脊髓炎频谱障碍（NMOSDs）包括中枢神经系统的炎症过程。大多数NMOSD患者血清中存在针对星形细胞水通道水通道蛋白4 （AQP4-IgG）的免疫球蛋白G自身抗体。在这项研究中，我们分析了一大批NMOSD患者的HLA等位基因频率，按种族和AQP4-IgG水平分层，并与健康对照组进行了比较。方法：对174名白人、45名黑人和41名西班牙裔AQP4-IgG阳性（AQP4-IgG+）的NMOSD患者进行基于新一代测序的HLA I和II类基因分型；AQP4-IgG阴性（AQP4-IgG-） NMOSD患者49例；2427名白人，244名黑人和155名西班牙裔对照。采用Bonferroni法对多重检验进行校正。结果:白色AQP4-IgG + NMOSD患者最显著相关的等位基因是HLA-DQA1 * 05:01:01 (30.1% vs 11.1%,优势比为3.43 (95% CI 2.65 - -4.42),纠正p = 8.95 e-17), HLA-DQB1 * 02:01:01 (29.9% vs 11.3%, 3.34(2.58 - -4.31),纠正p = 4.33 e-16),和HLA-DRB1 * 03:01:01 (29.2% vs 11.6%, 3.15(2.43 - -4.06),纠正p = 3.66 e-14),其次是HLA-B * 08:01:01 (26% vs 10.4%, 3.02[2.3 - -3.94]纠正p = 8.79 e-12), HLA-C * 07:01:01 (27.8% vs 14%, 2.36(1.81 - -3.04),纠正p = 2.44 e-07),HLA-DRB3*01:01:02 （28% vs 14.7%, 2.27[1.73-2.95]，修正p = 2.19E-06）。黑人AQP4-IgG+ NMOSD患者HLA-DRB1*08:04:01的频率高于黑人对照组，但差异无统计学意义（19.3% vs 5.7%, 3.92[1.91-7.86]，校正p = 0.08）。然而，与黑人对照（n = 16178）相比，黑人AQP4-IgG+ NMOSD患者HLA-DRB1*08:04的频率（19.3% vs 5.1%, 4.46[2.45-7.66]，校正p = 1.88E-03）显著高于黑人。在AQP4-IgG阳性的西班牙裔患者或AQP4-IgG阳性的白人NMOSD患者中未检测到明显的HLA关联。讨论：本研究证实了先前在白人患者中发现的HLA-DRB1*03:01与AQP4-IgG+ NMOSD的关联，并将这种关联扩展到HLA-DRB1*03:01:01 ~ HLA-DQA1*05:01:01 ~ HLA-DQB1*02:01:01单倍型。此外，研究还发现HLA-DRB1*08:04与黑人患者AQP4-IgG+ NMOSD存在关联。然而，在白色AQP4-IgG阳性的NMOSD患者中未检测到HLA关联。AQP4-IgG+和AQP4-IgG- NMOSD之间的免疫遗传学差异支持了这些实体之间的病理生理差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurology® Neuroimmunology & Neuroinflammation Neuroscience-Neurology

CiteScore

15.60

自引率

2.30%

发文量

219

审稿时长

8 weeks

期刊介绍： Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.