RT Journal Article
SR Electronic
T1 Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e1140
DO 10.1212/NXI.0000000000001140
VO 9
IS 2
A1 Vicente Peris Sempere
A1 Sergio Muñiz-Castrillo
A1 Aditya Ambati
A1 Sophie Binks
A1 Anne-Laurie Pinto
A1 Veronique Rogemond
A1 Sean J. Pittock
A1 Divyanshu Dubey
A1 Michael D. Geschwind
A1 Jeffrey Marc Gelfand
A1 Sonam Dilwali
A1 Soon-Tae Lee
A1 Julian Knight
A1 Katherine S. Elliott
A1 Sarosh Irani
A1 Jérôme Honnorat
A1 Emmanuel Mignot
YR 2022
UL http://nn.neurology.org/content/9/2/e1140.abstract
AB Background and Objectives To study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis.Methods 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 χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.Results DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e−50) 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, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequently female (p = 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, p = 4.57 × 10−6 and OR = 8.93, p = 2.50 × 10−3, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = −6.68, p = 9.78 × 10−3). 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.Discussion 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.EPTP=epitempin; FBDS=faciobrachial dystonic seizure; FDR=false discovery rate; HLA=human leukocyte antigen; LGI1=leucine-rich glioma-inactivated 1; LRR=leucine-rich repeat; mRS=modified Rankin score; PCA=principal component analysis