Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

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, = 1.06 × 10, 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-DQB105:02 ( = 1.43 × 10; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A11:01 ( = 4.36 × 10; OR, 1.52; 95% CI 1.29-1.79) and HLA-A02:07 ( = 1.28 × 10; 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 ( = 1.43 × 10; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R ( = 3.40 × 10; 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 DQB105:02.

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.