HLA genotyping and clinical characteristics of early-onset and late-onset anti-LGI1 encephalitis: a single-center cohort study in China

Objectives To investigate the human leukocyte antigen (HLA) associations and clinical characteristics of anti-Leucine-rich glioma-inactivated 1 (LGI1) encephalitis in a Chinese cohort, focusing on potential differences between early-onset and late-onset patients. Methods Eighty patients diagnosed with anti-LGI1 encephalitis at Peking Union Medical College Hospital between the years 2016 and 2024 were included. Patients were stratified into early-onset (<50 years, n=22) and late-onset (≥50 years, n=58) groups for clinical features analysis. High-resolution NGS HLA genotyping was performed and compared with 984 healthy controls. Logistic and linear regressions were used to analyze disease susceptibility, age of onset associations, and prognostic factors. Results Compared with the late-onset group, the early-onset group more frequently presented with generalized tonic-clonic seizures (GTCS) as the initial symptom (45.5% vs . 10.3%, post-hoc p = 0.001), and a lower frequency of psychiatric symptoms ( p = 0.047) and amnesia ( p = 0.002) during the disease course, presenting with lower mRS scores at onset ( p = 0.020). Genetically, DRB1*07:01 was confirmed as the primary risk allele (OR = 10.4, 95% CI 6.01-18.02, p c = 6.78×10 −15 ). DRB1*09:01(OR = 3.67, 95% CI 2.17-6.20, p c = 1.16×10 -5 ) and DQB1*03:03 (OR = 3.25, 95% CI 1.98-5.33, p c = 1.32×10 -5 ) were identified as novel secondary risk alleles in this Chinese cohort. Importantly, specific HLA genotypes were significantly associated with the age of onset. A*02:01 was linked to an earlier onset (β = -9.26; p c = 0.019) and served as a risk factor for the early-onset group, while DRB1*07:01 was associated with a later onset (β = 13.44, p c = 0.006). Diagnostic delay (OR = 1.01, 95% CI 1.00-1.02, p = 0.037) and GTCS (OR = 5.01, 95% CI 1.11-22.66, p = 0.036) were independent predictors of poor prognosis. Conclusions This study suggests that early-onset and late-onset anti-LGI1 encephalitis may possess differential immunogenetic and clinical profiles. In addition to the broad susceptibility conferred by DRB1*07:01, the presence of A*02:01 is significantly associated with an earlier onset age. These findings provide insights into the role of HLA genotyping in accounting for the observed differences between early-onset and late-onset patients.