2023 American Academy of Neurology Abstract Website

Objective:

To explore the role of human leukocyte (HLA) alleles and haplotypes in pathophysiology of amyotrophic lateral sclerosis (ALS) and ALS-frontotemporal dementia (ALS-FTD).

Background:

HLA antigens modulate immune responses and cellular function and thus could serve as a link between neurodegeneration and immune dysfunction noted in ALS and ALS-FTD. A recent meta-analysis revealed increased frequency of B*35 in ALS albeit in studies with small sample sizes. HLA allele combinations such as ancestral haplotype AH8.1 (A*01/Cw*07/B*08/DRB1*03/DQA1*05/DQB1*02) may also play a role in immune-mediated diseases.

Design/Methods:

RNA-Seq data from ALS spinal cord tissue (174 subjects, 348 total alleles), ALS-FTD (22 subjects, 44 total alleles), and non-neurological control (44 subjects, 88 total alleles) was obtained from the NY Genome Center and genotyped for HLA class I and class II genes using the “arcasHLA” tool. Allele and haplotype frequencies were calculated. Fisher’s exact test was employed for statistical analysis.

Results:

Compared to controls, the frequency of B*35 in ALS (8.9% vs 2.3%, p=0.04) and ALS-FTD (13.6% vs 2.3%, p=0.02) was increased. DPB1*04 in ALS (37.1% vs 52.3%, p=0.01) was decreased. AH8.1 haplotype was more frequent in ALS (14.9% vs 6.8%, p=0.22), as was haplotype A*03/B*35/C*04/DPB1*04/DQA1*01 (8.1% vs 0.0%, p=0.08). No significant gender differences were found in the analysis. 100% of AH8.1 and A*03/B*35/C*04/DPB1*04/DQA1*01 haplotypes were of predominantly European ancestry.

Conclusions:

The increased frequency of the B*35 allele in ALS and ALS-FTD patients may be important as it causes ER stress and unfolded protein response which is implicated in ALS pathophysiology. B*35 along with C*04 have been implicated with rapid HIV/AIDS progression and are both components of the A*03/B*35/C*04/DPB1*04/DQA1*01 haplotype increased in ALS. Given the suspected role of endogenous retroviruses in ALS, this may be pertinent. The pathophysiological role of these haplotypes requires further investigation.