Objectives: Antibodies against contactin-associated protein-like 2 (CASPR2) are associated with three neurological phenotypes: limbic encephalitis (LE), acquired neuromyotonia and Morvan syndrome. We analyzed human leukocyte antigen (HLA) subtypes in these three phenotypes versus controls.
Methods: Four-digit resolution HLA genotypes were imputed from available Genome Wide Association data, and carrier frequencies compared between anti-CASPR2 patients (n=61) and controls (n=338), stratified by phenotype (LE=45, Morvan=9, neuromyotonia=7). Fisher exact tests and logistic regressions controlled by principal component analysis were used.
Results: No HLA association was observed in neuromyotonia and Morvan syndrome. In contrast, LE was strongly associated with DQA1*05:05 (OR=5.4, 95% CI 2.5-11.5, p=1.5e-04), DQB1*03:01 (OR=4.3, 95% CI 2.0-9.4, p= 2.1e-03), DRB1*11:01 (OR= 8.5, 95% CI 3.9-18.7, corrected p=1.7e-06), and DRB3*02:02 (OR= 4.9, 95% CI 2.2-11.4, corrected p=3.4e-04) in the context of the common DR11~DQ3 haplotype. Importantly however, DQA1*05:05, DQB1*03:01 and DRB3*02:02 were no longer significant after controlling for DRB1*11:01, whereas DRB1*11:01 was still significant after controlling for DQB1*03:0 and DRB3*02:02, but not DQA1*05:05, indicating a primary DRB1*11:01 association. No secondary associations were found in non-DRB1*11:01 carriers or across DRB1*11:01 heterozygotes. DRB1*11:01 homozygosity was associated with a 10.9-fold increased risk versus heterozygotes (p=1.3e-03).
Conclusions: HLA association is specific to DRB1*11:01 and to patients with LE, with a strong effect of homozygocity. DRB1*11:04, another frequent subtype with only one aminoacid difference, is not associated. The specific association to LE suggests a different pathogenesis versus other anti-CASPR2 phenotypes.
