Abstract
BackgroundThe cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The histopathologic hallmark of IMM is lymphocytic infiltration of myofibers. The purpose of this study was to identify putative functional variants associated with equine IMM.MethodsA genome-wide association (GWA) study was performed on 36 IMM QHs and 54 breed matched unaffected QHs from the same environment using the Equine SNP50 and SNP70 genotyping arrays.ResultsA mixed model analysis identified nine SNPs within a ~ 2.87 Mb region on chr11 that were significantly (Punadjusted < 1.4 × 10− 6) associated with the IMM phenotype. Associated haplotypes within this region encompassed 38 annotated genes, including four myosin genes (MYH1, MYH2, MYH3, and MYH13). Whole genome sequencing of four IMM and four unaffected QHs identified a single segregating nonsynonymous E321G mutation in MYH1 encoding myosin heavy chain 2X. Genotyping of additional 35 IMM and 22 unaffected QHs confirmed an association (P = 2.9 × 10− 5), and the putative mutation was absent in 175 horses from 21 non-QH breeds. Lymphocytic infiltrates occurred in type 2X myofibers and the proportion of 2X fibers was decreased in the presence of inflammation. Protein modeling and contact/stability analysis identified 14 residues affected by the mutation which significantly decreased stability.ConclusionsWe conclude that a mutation in MYH1 is highly associated with susceptibility to the IMM phenotype in QH-related breeds. This is the first report of a mutation in MYH1 and the first link between a skeletal muscle myosin mutation and autoimmune disease.
Highlights
The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown
The first objective of this study was to identify associated genomic regions underlying risk for developing equine IMM by performing a genome-wide association (GWA) study of QHs and related breeds with and without IMM that were housed in the same environment and exposed to the same risk factors that may result in the IMM phenotype
The mean percentage of type 2X fibers in IMM E321G horse muscle without inflammatory infiltrates (4 semimembranosus, 2 gluteal) was 45%, ranging from 30 to 56%, as compared to control samples (3 semimembranosus, 2 gluteal), where the mean percentage of type 2X fibers was 60%, ranging from 43–87%. This is the first report of a mutation in MYH1 gene associated with susceptibility to a specific myopathy
Summary
The cause of immune-mediated myositis (IMM), characterized by recurrent, rapid-onset muscle atrophy in Quarter Horses (QH), is unknown. The purpose of this study was to identify putative functional variants associated with equine IMM. Common clinical features include malaise, muscle atrophy, and weakness with a histopathologic hallmark of inflammatory infiltrates, lymphocytes, surrounding blood. The first objective of this study was to identify associated genomic regions underlying risk for developing equine IMM by performing a genome-wide association (GWA) study of QHs and related breeds with and without IMM that were housed in the same environment and exposed to the same risk factors that may result in the IMM phenotype. The second objective was to evaluate the region of association from the GWA using whole genome sequencing to identify a putative functional variant associated with the equine IMM phenotype. The third objective was to determine if the alteration encoded by the putative functional variant altered protein structure and was targeted by inflammation
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