Possible link of genetic variants to autoimmunity in GAD-antibody-associated neurological disorders

• Published in: Journal of the neurological sciences Vol. 413; p. 116860
• Main Authors: Thaler, Franziska S., Bangol, Barbara, Biljecki, Michelle, Havla, Joachim, Schumacher, Adrian-Minh, Kümpfel, Tania
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2020
• Subjects: Autoantibodies; Autoimmune Diseases; Autoimmunity - genetics; Diabetes Mellitus, Type 1; Female; GAD65; Genetic variants; Glutamate Decarboxylase - genetics; Humans; Male; Nervous System Diseases - genetics; Neurological disorders; Autoantibodies; Genetic variants; GAD65; Neurological disorders
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2020.116860

In patients with GAD-antibody (ab) associated neurological disorders coexistence of other autoimmune disorders is observed. In this exploratory study we analysed variations in 33 candidate genes involved in autoimmunity or representing immunological check-points using next-generation sequencing. We performed haplotype-analysis of HLA-DRB1 and HLA-DQB1. Additionally, we analysed levels of sFasL, IL10, and IL18 in serum of patients and healthy controls. 19 patients (3 males, 16 females; mean age at onset: 46.4 years) with positive GAD-ab and the following neurological phenotypes were included: n = 8 cerebellar ataxia, n = 6 limbic encephalitis, n = 4 stiff person syndrome, n = 1 demyelinating CNS disease with recurrent optic neuritis. 15 patients exhibited at least one other autoimmune disorder and/or showed other auto-ab. We identified several variations in genes linked to autoimmunity or representing check-point proteins. Most frequently (14/19 patients, allele frequency: 42.1%), we observed an amino acid exchange in the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene. Two of the observed variants are known to cause alterations of protein function (Y446C in caspase-10, K750N in protein-tyrosin-phosphatase, non-receptor type 22). These latter variants were detected in two related patients (mother and daughter) who both present with GAD-ab-associated neurological disorders but with different clinical phenotypes. The rare haplotype DRB1*15:01:01 ~ DQA1*01:02:01 ~ DQB1*05:02:01 previously described in patients with GAD-ab-associated neurological disorders was not observed in any of our patients. No elevated serum levels of sFasL, IL18 or IL10 were observed in patients indicating no typical phenotype of autoimmune lymphoproliferate syndrome. These findings suggest genetic risk factors in patients with GAD-ab-associated neurological disorders. •In patients with GAD-antibody associated disorders.•Autoimmune disorders co-occur suggesting genetic risk factors.•Haplotype DRB1*15:01:01 ~ DQA1*01:02:01 ~ DQB1*05:02:01 was not detected in our cohort.•No typical phenotype of autoimmune lymphoproliferative syndrome was observed.•Validation of observed genetic variants in genome wide studies is recommended.