Abstract
Myasthenia gravis (MG) is a rare, treatable antibody-mediated disease which is characterized by muscle weakness. The pathogenic antibodies are most frequently directed at the acetylcholine receptors (AChRs) at the skeletal muscle endplate. An ophthalmoplegic subphenotype of MG (OP-MG), which is characterized by treatment resistant weakness of the extraocular muscles (EOMs), occurs in a proportion of myasthenics with juvenile symptom onset and African genetic ancestry. Since the pathogenetic mechanism(s) underlying OP-MG is unknown, the aim of this study was to use a hypothesis-generating genome-wide analysis to identify candidate OP-MG susceptibility genes and pathways. Whole genome sequencing (WGS) was performed on 25 AChR-antibody positive myasthenic individuals of African genetic ancestry sampled from the phenotypic extremes: 15 with OP-MG and 10 individuals with control MG (EOM treatment-responsive). Variants were called according to the Genome Analysis Toolkit (GATK) best practice guidelines using the hg38 reference genome. In addition to single variant association analysis, variants were mapped to genes (±200 kb) using VEGAS2 to calculate gene-based test statistics and HLA allele group assignment was inferred through “best-match” alignment of reads against the IMGT/HLA database. While there were no single variant associations that reached genome-wide significance in this exploratory sample, several genes with significant gene-based test statistics and known to be expressed in skeletal muscle had biological functions which converge on muscle atrophy signaling and myosin II function. The closely linked HLA-DPA1 and HLA-DPB1 genes were associated with OP-MG subjects (gene-based p < 0.05) and the frequency of a functional A > G SNP (rs9277534) in the HLA-DPB1 3′UTR, which increases HLA-DPB1 expression, differed between the two groups (G-allele 0.30 in OP-MG vs. 0.60 in control MG; p = 0.04). Furthermore, we show that rs9277534 is an HLA-DBP1 expression quantitative trait locus in patient-derived myocytes (p < 1 × 10−3). The application of a SNP to gene to pathway approach to this exploratory WGS dataset of African myasthenic individuals, and comparing dichotomous subphenotypes, resulted in the identification of candidate genes and pathways that may contribute to OP-MG susceptibility. Overall, the hypotheses generated by this work remain to be verified by interrogating candidate gene and pathway expression in patient-derived extraocular muscle.
Highlights
Myasthenia gravis (MG) is a rare, but treatable antibodymediated disease which results in fatigable weakness of skeletal muscles, including extraocular muscles
Though the incidence of acetylcholine receptors (AChR)-antibody positive MG in subSaharan Africa is similar to global figures (Mombaur et al, 2015), and the response to MG therapies overall is similar among populations (Heckmann et al, 2007), we have recognized a subphenotype of treatment-resistant ophthalmoplegia, or OPMG, among a subset of MG subjects of African genetic ancestry (Heckmann et al, 2007; Heckmann and Nel, 2017)
While the sex and ancestry proportions were similar between the whole genome sequencing (WGS) and validation samples, the age at MG onset was significantly higher in the validation sample compared to the WGS sample (p = 4 × 10−8)
Summary
Myasthenia gravis (MG) is a rare, but treatable antibodymediated disease which results in fatigable weakness of skeletal muscles, including extraocular (or eye) muscles. Though the incidence of AChR-antibody positive MG in subSaharan Africa is similar to global figures (Mombaur et al, 2015), and the response to MG therapies overall is similar among populations (Heckmann et al, 2007), we have recognized a subphenotype of treatment-resistant ophthalmoplegia, or OPMG, among a subset of MG subjects of African genetic ancestry (Heckmann et al, 2007; Heckmann and Nel, 2017) This OP-MG subphenotype is characterized by severe, persistent extraocular muscle (EOM) weakness and commonly affects subjects with juvenile onset, but otherwise characteristic AChR-antibody positive MG (i.e., generalized muscle weakness which responds to treatment). This was interesting because the genetic basis of MG has been investigated for more than three decades in individuals of European genetic ancestry and the consistent finding has been the association of the class I and II HLA region with individuals by age at MG onset (Nel and Heckmann, 2018)
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