Rank Wise Effect of HLA-DQ5 Explains Risk for the Development of Anti-IgLON5 Disease

Abstract

Objective To better characterize the genetic association between human leukocyte antigen (HLA) and anti-IgLON5 disease and to explore auto-antigen binding to associated HLA molecules and their functional involvement in pathophysiology. Background Anti-IgLON5 disease is a rare, but likely underdiagnosed type of autoantibody encephalitis with a heterogeneous clinical phenotype, including sleep, movement and brainstem dysfunction. Its pathophysiology remains elusive, although dominant association with HLA-DRB1*10:01-DQB1*05:01 strongly supports an autoimmune basis. Design/Methods A multicentric cohort of 62 patients and 433 controls matched by principal component analysis was included. Genome-wide association analysis was performed with 4-digit resolution HLA imputation and selected 8-digit resolution validation typing. A generalized logistic model was used to determine the association with individual alleles and haplotype counts to establish haplotype associations. Furthermore, we computationally predicted binding of IgLON5-derived peptides to risk-associated HLA-molecules. Results Our results indicate a rank wise effect of HLA-DQA1*01:05∼DQB1*05:01 (heterozygotes: OR 46.6), HLA-DQA1*01:01∼DQB1*05:01 (homozygotes: OR 26.9; heterozygotes: OR 2.5) and HLA-DQA1*01:04-∼DQB1*05:03 (homozygotes: OR 30.9; heterozygotes: OR 5.6), in order of descending relative risk predisposition. Differences between encoded heterodimers are minimal (a few amino acids outside the main HLA sequence binding region), suggesting a common function. Computational binding predictions support similar, high binding affinity for IgLON5275-283 in a post-translationally modified (N-deglycosylated) form by all three of these HLA-DQ molecules and other common binders. In contrast, association analysis suggests that effects of HLA-DR are likely explained by linkage disequilibrium. Conclusions This study is the, so far, largest genetic study on anti-IgLON5 disease. Our results strongly suggest HLA-DQ over HLA-DR association, with higher reactivity against post-translationally modified versus physiological peptides, in line with reduced T cell priming against these epitopes. Further studies should address the functional implications of these HLA associations.