Abstract
Objectives. Inclusion body myositis (IBM) is a progressive inflammatory and degenerative disease of the skeletal muscles that affects individuals over the age of 45 and leads to a gradual loss of mobility. It has been widely reported that a subgroup of 33 to 72% of IBM patients produce self-reactive antibodies that bind cytosolic 5’-nucleotidase 1A (NT5C1A) within the muscles and possibly exacerbate the disease severity. A genetic association between immune-related genes with IBM has been described. This study aimed to deepen our knowledge about the human leukocyte antigen (HLA) genes that alter the risk to develop IBM and to investigate whether specific HLA alleles may contribute to the occurrence of NT5C1A-directed antibodies.
Methods. In this study, we used Illumina next-generation sequencing to resolve the high resolution HLA haplotype of 102 Caucasian IBM patients from the Western Australian cohort. We then compared the frequency and carriage of the identified alleles within the IBM cohort to reference databases of Caucasian cohorts. We additionally compared the HLA allele carriage within the genotypes of anti-NT5C1A-positive and-negative patients within our IBM cohort.
Results. Our results confirmed the previously identified association risk of the 8.1 MHC ancestral haplotype with IBM. We also lifted ambiguities and clarified the identity of the risk-associated alleles that have been previously reported at a lower level of resolution. Additionally, we identified previously unreported risk allele associations with IBM. Furthermore, our analysis validated previously reported protective HLA alleles, and also revealed reduced carriage frequency of additional alleles, suggesting their protective role in the disease. Lastly, our study revealed two alleles, which carriage are associated with anti-NT5C1A antibody production.
Conclusions. Our findings refine and expand on the knowledge of the HLA genetic background of IBM. Stratifying patients based on their HLA genotype provides a genetic basis for new therapeutic intervention strategies early in the disease process to slow down symptom development.