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

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