Quantification of HLA Allele and Haplotype Frequencies in ALS and ALS-FTD (P8-8.005)

Abstract

<h3>Objective:</h3> To explore the role of human leukocyte (HLA) alleles and haplotypes in pathophysiology of amyotrophic lateral sclerosis (ALS) and ALS-frontotemporal dementia (ALS-FTD). <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Pandya has nothing to disclose. Kory Johnson, 2962 has nothing to disclose. Dr. Phatnani has nothing to disclose. Dr. Nath has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Nath has received research support from National Institutes of Health. The institution of Dr. Nath has received research support from ALS Association.