Neurology(R) neuroimmunology & neuroinflammation · 2026
HLA Associations Differ by Ethnicity and Aquaporin-4 Antibody Status in Patients With Neuromyelitis Optica Spectrum Disorders.
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Niederschweiberer Moritz, Panagiotaropoulou Georgia, Fernandez-Viña Marcelo A, Montero-Martin Gonzalo, Osoegawa Kazutoyo, Behne Megan, Franke Andre, Lieb Wolfgang, Jarius Sven, Wildemann Brigitte, Schindler Patrick, Otto Carolin, Paul Friedemann, Flanagan Eoin P, Cook Lawrence J, Oksenberg Jorge, Yeaman Michael R, Ripke Stephan, Ruprecht Klemens, Guthy-Jackson Charitable Foundation CIRCLES Study Group
Аннотация
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.
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.