High-resolution HLA genotyping in inclusion body myositis refines 8.1 ancestral haplotype association to DRB103:01:01 and highlights pathogenic role of arginine-74 of DRβ1 chain

• Published in: Journal of autoimmunity Vol. 142; p. 103150
• Main Authors: Slater, Nataliya, Sooda, Anuradha, McLeish, Emily, Beer, Kelly, Brusch, Anna, Shakya, Rakesh, Bundell, Christine, James, Ian, Chopra, Abha, Mastaglia, Frank L., Needham, Merrilee, Coudert, Jerome D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2024
• Subjects: Alleles; Arginine; Australia; Autoimmunity genetic association; Genotype; Haplotypes; HLA Antigens; HLA-DRB1 Chains - genetics; Human leukocyte antigens; Humans; Inclusion body myositis; Myositis; Myositis, Inclusion Body - genetics; Next generation sequencing; Australia; Inclusion body myositis; Autoimmunity genetic association; Next generation sequencing; Human leukocyte antigens
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2023.103150

Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5′-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRβ1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis. •HLA-DRB1*03:01:01 of the 8.1 ancestral haplotype is a genetic risk factor for Inclusion Body Myositis (IBM) in Caucasians.•HLA-DRB4*01:01:01 and DQA1*01:02:01 are found at lower frequencies in Caucasian IBM patients and therefore are protective.•Carriers of DRB1*03:01:01 but not DRB4*01:01:01 or DQA1*01:02:01 are 14x more at risk of IBM, with a 5 years earlier onset.•An arginine in position 74 of the DRβ1 protein confers the allelic risk, while a glutamine at this position is protective.•We found no HLA association with the production of anti-cN1A antibodies in IBM.