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Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis
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 as...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Lippincott Williams & Wilkins
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815287/ https://www.ncbi.nlm.nih.gov/pubmed/35115410 http://dx.doi.org/10.1212/NXI.0000000000001140 |
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author | Peris Sempere, Vicente Muñiz-Castrillo, Sergio Ambati, Aditya Binks, Sophie Pinto, Anne-Laurie Rogemond, Veronique Pittock, Sean J. Dubey, Divyanshu Geschwind, Michael D. Gelfand, Jeffrey Marc Dilwali, Sonam Lee, Soon-Tae Knight, Julian Elliott, Katherine S. Irani, Sarosh Honnorat, Jérôme Mignot, Emmanuel |
author_facet | Peris Sempere, Vicente Muñiz-Castrillo, Sergio Ambati, Aditya Binks, Sophie Pinto, Anne-Laurie Rogemond, Veronique Pittock, Sean J. Dubey, Divyanshu Geschwind, Michael D. Gelfand, Jeffrey Marc Dilwali, Sonam Lee, Soon-Tae Knight, Julian Elliott, Katherine S. Irani, Sarosh Honnorat, Jérôme Mignot, Emmanuel |
author_sort | Peris Sempere, Vicente |
collection | PubMed |
description | 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 χ(2), 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. |
format | Online Article Text |
id | pubmed-8815287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-88152872022-02-04 Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis Peris Sempere, Vicente Muñiz-Castrillo, Sergio Ambati, Aditya Binks, Sophie Pinto, Anne-Laurie Rogemond, Veronique Pittock, Sean J. Dubey, Divyanshu Geschwind, Michael D. Gelfand, Jeffrey Marc Dilwali, Sonam Lee, Soon-Tae Knight, Julian Elliott, Katherine S. Irani, Sarosh Honnorat, Jérôme Mignot, Emmanuel Neurol Neuroimmunol Neuroinflamm Article 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 χ(2), 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. Lippincott Williams & Wilkins 2022-02-03 /pmc/articles/PMC8815287/ /pubmed/35115410 http://dx.doi.org/10.1212/NXI.0000000000001140 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , 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. |
spellingShingle | Article Peris Sempere, Vicente Muñiz-Castrillo, Sergio Ambati, Aditya Binks, Sophie Pinto, Anne-Laurie Rogemond, Veronique Pittock, Sean J. Dubey, Divyanshu Geschwind, Michael D. Gelfand, Jeffrey Marc Dilwali, Sonam Lee, Soon-Tae Knight, Julian Elliott, Katherine S. Irani, Sarosh Honnorat, Jérôme Mignot, Emmanuel Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title | Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title_full | Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title_fullStr | Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title_full_unstemmed | Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title_short | Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis |
title_sort | human leukocyte antigen association study reveals drb1*04:02 effects additional to drb1*07:01 in anti-lgi1 encephalitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815287/ https://www.ncbi.nlm.nih.gov/pubmed/35115410 http://dx.doi.org/10.1212/NXI.0000000000001140 |
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