Journal article
Human Leukocyte Antigen Association Study Reveals DRB1*04:02 effects additional to DRB1*07:01 in anti-LGI1 encephalitis
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 212.2KB, Terms of use)
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- Publisher copy:
- 10.1212/nxi.0000000000001140
Authors
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 104079/Z/14/Z
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V007173/1
+ National Institute of Allergy and Infectious Diseases
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- Funder identifier:
- https://ror.org/043z4tv69
- Grant:
- U01 AI125250
- Publisher:
- Lippincott, Williams & Wilkins
- Journal:
- Neurology, Neuroimmunology and Neuroinflammation More from this journal
- Volume:
- 9
- Issue:
- 2
- Article number:
- e1140
- Place of publication:
- United States
- Publication date:
- 2022-02-03
- Acceptance date:
- 2021-12-27
- DOI:
- EISSN:
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2332-7812
- Pmid:
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35115410
- Language:
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English
- Keywords:
- Pubs id:
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1238615
- Local pid:
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pubs:1238615
- Deposit date:
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2025-02-07
- ARK identifier:
Terms of use
- Copyright holder:
- Peris Sempere et al
- Copyright date:
- 2022
- Rights statement:
- © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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