Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1
Vicente Peris Sempere1, Sergio Muñiz-Castrillo1, Aditya Ambati1
1From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.
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.
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