Strong genetic predisposition with direct functional implications reported in autoimmune 2 neurological syndromes

The findings of a genome-wide association study (GWAS) published in Brain reported the association of genes in supplying neural structure and immune function in anti-glutamic acid decarboxylase (GAD65) autoimmune neurological syndromes (AINS), mainly contributed by genomic regions outside the classical HLA alleles.

The study considered a German cohort of 1,214 subjects, which included 167 patients with anti-GAD65 AINS and 1,047 subjects without the neurological or endocrine disease (controls). GWAS recognized 16 genome-wide significant loci for the susceptibility to anti-GAD65 AINS with localization of a top variant rs2535288 to a mid HLA class I region intergenic segment.

Moreover, >90% of variants of these loci were mapped to non-coding regions of the genome. Nearly 40% of the variants were found to have regulatory functions on the expression of 48 genes in disease-associated cells and tissues, especially CD4+ T cells and the cerebral cortex. Network analysis of the aforementioned protein-coding genes helped to understand the role of protein kinase C beta (PRKCB) and the enrichment of numerous biological pathways involved in immunity and neural function.

Robust associations were noted for DQA1*03:01-DQB1*03:02- DRB1*04:01HLA haplotype (p=4.39×10-4 25, OR=2.5, 95%CI= 1.499-4.157), and DRB1*04:01 allele (p=8.3×10-5 26, OR=2.4, 95%CI = 1.548-3.682) in the study cohort. GWAS conducted in the CSF proteome of anti-GAD65 AINS demonstrated differential expression of five proteins (HLA-A/B, C4A, ATG4D, and NEO1) of eQTL genes.

Christine Strippel and co-researchers concluded that various immune cell types and the brain itself are involved in the anti-GAD65 AINS pathogenesis. The poor response towards treatment can be explained by a bidirectional interaction in subjects vulnerable to impaired immune responses, and altered neuronal structure and function.

Reference: Strippel C, Herrera-Rivero M, Wendorff M, et al. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies [published online ahead of print, 2022 Mar 28]. Brain. 2022;awac119.