机构：[1]Department of Neurology,West China Hospital, Sichuan University, Chengdu, China.四川大学华西医院[2]Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, China.[3]Key Laboratory of Dermatology (Anhui Medical University) , Ministry of Education, China.[4]Anhui Province Laboratory of Inflammation and Immune Mediated Diseases, China.[5]Anhui Provincial Institute of Translational Medicine, Hefei, China.[6]Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou中山大学附属第三医院[7]Genesky Biotechnologies Inc., Shanghai, China.[8]Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China.首都医科大学附属天坛医院[9]Department of Neurology , Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.四川省人民医院[10]Department of Neurology, First Affiliated Hospital of Zhengzhou University, China.[11]Institute of Brain Science and Brain-Inspired Technology of West China Hospital, Sichuan University, Chengdu, China.[12]North China University of Science and Technology Affiliated Hospital, China.[13]Health Science Center, North China University of Science and Technology, China.[14]School of Public Health, North China University of Science and Technology, Tangshan, China.[15]Inflammation and Immune Diseases Laboratory of North China University of Science and Technology, China.[16]Department of Neurology,Chengdu Shangjin Nanfu Hospital, China.
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.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.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.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.
基金：
This work was supported by the National Key R&D Programof China (2022YFC2503800, Project 2022YFC2503806), theNational Natural Science Foundation of China (81971213),the 1.3.5 Talent Excellence Development Project-West ChinaHospital of Sichuan University (ZYGD20011), and theClinical Research Incubation program, West China Hospital,Sichuan University (2022HXFH022).
第一作者机构：[1]Department of Neurology,West China Hospital, Sichuan University, Chengdu, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology,West China Hospital, Sichuan University, Chengdu, China.[2]Department of Dermatology, the First Affiliated Hospital of Anhui Medical University, China.[3]Key Laboratory of Dermatology (Anhui Medical University) , Ministry of Education, China.[12]North China University of Science and Technology Affiliated Hospital, China.[13]Health Science Center, North China University of Science and Technology, China.[14]School of Public Health, North China University of Science and Technology, Tangshan, China.[15]Inflammation and Immune Diseases Laboratory of North China University of Science and Technology, China.[16]Department of Neurology,Chengdu Shangjin Nanfu Hospital, China.
推荐引用方式(GB/T 7714)：
Liu Xu,Zheng Xiaodong,Shu Yaqing,et al.Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis[J].Neurology(R) Neuroimmunology & Neuroinflammation.2024,11(3):e200221.doi:10.1212/NXI.0000000000200221.
APA：
Liu Xu,Zheng Xiaodong,Shu Yaqing,Qu Xiao,Wang Qun...&Hong Zhen.(2024).Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.Neurology(R) Neuroimmunology & Neuroinflammation,11,(3)
MLA：
Liu Xu,et al."Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis".Neurology(R) Neuroimmunology & Neuroinflammation 11..3(2024):e200221
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