HLA Class I Haplotype in Glutamic Acid Decarboxylase Antibody-Associated Neurological Disease

Glutamic acid decarboxylase antibody-associated neurological disease (GADAND) is a rare autoimmune disorder with elusive immunogenetic underpinnings. We aimed to investigate HLA associations with GADAND susceptibility in a Chinese cohort.

We performed HLA genotyping at the HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 loci in 62 Chinese patients with GADAND and compared them with 990 healthy controls. Haplotype frequencies were estimated using the expectation-maximization (EM) algorithm. Allele and haplotype associations with disease susceptibility and clinical phenotypes were assessed.

We identified the HLA class I haplotype A*11:01 ~ B*40:01 ~ C*07:02 as a susceptibility haplotype for GADAND (OR = 10.22, 95% CI 3.86-25.57, p_adj = 0.003), and the association was stronger for the extended haplotype including DQA1*01:03 (OR = 25.61, 95% CI 4.99-89.11, p_adj < 0.001). Three haplotypes showed suggestive but non-significant associations: B*44:02 ~ C*05:01 (OR = 8.32, 95% CI 2.52-24.48, p_adj = 0.069), DQA1*01:03 ~ DQB1*06:01 ~ DRB1*08:03 (OR = 3.15, 95% CI 1.67-5.63, p_adj = 0.066), and DQA1*05:05 ~ DQB1*03:01, which showed a suggestive protective effect (OR = 0.15, 95% CI 0.018-0.556, p_adj = 0.088). T1DM risk haplotypes, including DQA1*03:01 ~ DQB1*03:02 ~ DRB1*04:03 (OR = 5.04, 95% CI 1.18-16.62, p_adj = 0.744) and DQA1*05:01 ~ DQB1*02:01 ~ DRB1*03:01 (OR = 2.50, 95% CI 1.07-5.24, p_adj = 0.829), were more frequent in GADAND patients, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in those with comorbid AITD. No statistically significant associations were identified between HLA haplotypes and clinical phenotypes.

The haplotype A*11:01 ~ B*40:01 ~ C*07:02 was associated with GADAND susceptibility in the Chinese population, implicating T cell involvement. T1DM-associated haplotypes were overrepresented in GADAND, and A*11:01 ~ B*40:01 ~ C*07:02 was enriched in comorbid AITD, suggesting HLA as a shared immunogenetic basis for autoimmune comorbidities. No significant HLA associations with clinical phenotypes were identified, warranting validation in larger cohorts.