Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis
Vicente Peris Sempere, Sergio Muñiz-Castrillo, Aditya Ambati, Sophie Binks, Anne-Laurie Pinto, Veronique Rogemond, Sean J. Pittock, Divyanshu Dubey, Michael D. Geschwind, Jeffrey Marc Gelfand, Sonam Dilwali, Soon-Tae Lee, Julian Knight, Katherine S. Elliott, Sarosh Irani, Jérôme Honnorat, Emmanuel Mignot
Abstract
<h3>Background and Objectives</h3> To study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis. <h3>Methods</h3> A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ<sup>2</sup>, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable. <h3>Results</h3> DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, <i>p</i> < 10e<sup>−50</sup>) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, <i>p</i> = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (<i>p</i> = 0.003) and more frequently female (<i>p</i> = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, <i>p</i> = 4.57 × 10<sup>−6</sup> and OR = 8.93, <i>p</i> = 2.50 × 10<sup>−3</sup>, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = −6.68, <i>p</i> = 9.78 × 10<sup>−3</sup>). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms. <h3>Discussion</h3> In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.