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Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies

Abstract

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01–DQB1*02:01–DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54–10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40–8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02–0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

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Acknowledgements

We thank NeuroBioTec Hospices Civils de Lyon BRC (AC-2013-1867, NFS96-900) for banking DNA samples. This study is supported by research Grants from ANR (ANR-14-CE15-0001-MECANO) and FRM (Fondation pour la recherche médicale) DQ20170336751. This work has been developed within the BETPSY project, which is supported by a public Grant overseen by the French National Research Agency (ANR), as part of the second “Investissements d´Avenir” program (reference ANR-18-RHUS-0012). SM-C is supported by a research grant from Fundación Alfonso Martín Escudero (Spain). We thank Philip Robinson for help in manuscript preparation (Direction de la Recherche Clinique, Hospices Civils de Lyon).

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Correspondence to Jérôme Honnorat.

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All procedures were performed in accordance with the institutional ethics committee and the Declaration of Helsinki.

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Supplementary Fig.

The first two (C1 and C2) genetic principal components (PC) scatter plot. PC analysis is a statistical tool that reduces data dimension, describing a large amount of data as new, un-correlated variables, labeled PC. Genotypes of patients (GAD) and controls were converted in 9 PC based on single nucleotide polymorphisms. Comparing PC by scatter plot enabled to guide case–control ethnical matching. (TIFF 11720 kb)

Supplementary file2 (DOCX 22 kb)

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Muñiz-Castrillo, S., Ambati, A., Dubois, V. et al. Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies. J Neurol 267, 1906–1911 (2020). https://doi.org/10.1007/s00415-020-09782-8

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Keywords

  • HLA
  • Glutamic acid decarboxylase
  • Limbic encephalitis
  • Cerebellar ataxia
  • Stiff person syndrome