TY - JOUR
T1 - Human Leukocyte Antigen Association Study Reveals DRB1∗04:02 Effects Additional to DRB1∗07:01 in Anti-LGI1 Encephalitis
AU - Peris Sempere, Vicente
AU - Muñiz-Castrillo, Sergio
AU - Ambati, Aditya
AU - Binks, Sophie
AU - Pinto, Anne Laurie
AU - Rogemond, Veronique
AU - Pittock, Sean J.
AU - Dubey, Divyanshu
AU - Geschwind, Michael D.
AU - Gelfand, Jeffrey Marc
AU - Dilwali, Sonam
AU - Lee, Soon Tae
AU - Knight, Julian
AU - Elliott, Katherine S.
AU - Irani, Sarosh
AU - Honnorat, Jérôme
AU - Mignot, Emmanuel
N1 - Publisher Copyright:
© 2022 American Academy of Neurology.
PY - 2022/3/3
Y1 - 2022/3/3
N2 - Background and Objective s : 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.
AB - Background and Objective s : 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.
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U2 - 10.1212/NXI.0000000000001140
DO - 10.1212/NXI.0000000000001140
M3 - Article
C2 - 35115410
AN - SCOPUS:85123972982
SN - 2332-7812
VL - 9
JO - Neurology: Neuroimmunology and NeuroInflammation
JF - Neurology: Neuroimmunology and NeuroInflammation
IS - 2
M1 - e1140
ER -