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Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis
Xu Liu1, Xiaodong Zheng1, Yaqing Shu1
1From the Department of Neurology (X. Liu, F.-Y.H., D.Z., Z.H.), West China Hospital, Sichuan University, Chengdu; Department of Dermatology (X.Z., L.S.), the First Affiliated Hospital of Anhui Medical University; Key Laboratory of Dermatology (Anhui Medical University) (X.Z., L.S.), Ministry of Education; Anhui Province Laboratory of Inflammation and Immune Mediated Diseases (X.Z.); Anhui Provincial Institute of Translational Medicine (X.Z.), Hefei; Department of Neurology (Y.S., W.Q.), The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou; Genesky Biotechnologies Inc. (X.Q., C.L.), Shanghai; Department of Neurology (Q.W., X. Liu), Beijing Tiantan Hospital, Capital Medical University; Department of Neurology (J.L., B.-M.H.), Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu; Department of Neurology (Y.L.), First Affiliated Hospital of Zhengzhou University; Institute of Brain Science and Brain-Inspired Technology of West China Hospital (D.Z.), Sichuan University, Chengdu; North China University of Science and Technology Affiliated Hospital (L.S.); Health Science Center (L.S.), North China University of Science and Technology; School of Public Health (L.S.), North China University of Science and Technology, Tangshan; Inflammation and Immune Diseases Laboratory of North China University of Science and Technology (L.S.); and Department of Neurology (Z.H.), Chengdu Shangjin Nanfu Hospital, China.
Background And Objectives:
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population.
Methods:
We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls.
Results:
Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQβ1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02.
Discussion:
Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.
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