Whole-genome analysis in Korean patients with autoimmune myasthenia gravis

Abstract

Background: Myasthenia gravis (MG) is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigability. The underlying cause of myasthenia gravis is unknown, although there is probably a genetic component to it. However, no common genetic variants have been unequivocally linked to autoimmune myasthenia gravis. We sought to identify the genetic variants associated with an increased or decreased risk of developing myasthenia gravis in the Korean Multicenter MG Cohort samples. Methods: To find new genetic targets that are related to autoimmune myasthenia gravis, a whole genome-based SNP analysis was performed using an Axiom™ Genome-Wide ASI 1 Array plate containing 598,375 SNPs and samples from 109 MG patients and 150 neurologically normal controls. The SNP selection criteria were: 1) minor allele frequency > 0.01, 2) genotyping success rate > 0.90, and 3) P > 1E-07 in the Hardy-Weinberg Equilibrium test from QQ plot. Results: The p values of association between these SNPs and autoimmune myasthenia gravis were calculated in all the available genetic modes such as allele, dominant, recessive, and co-dominant mode using 1) MG & Control, 2) AChR-antibody positive MG & Control, 3) AChR-antibody negative MG & Control, 4) Ocular MG & Control, and 5) Generalized MG & Control samples, respectively. A total of 641 SNPs from 5 case-control associations showed p values of less than 0.00001. From regional analysis, we selected 7 genes (RYR3, CACNA1S, SLAMF1, SOX5, FHOD3, GABRB1, SACS) for further analysis. Conclusion and comment: Myasthenia gravis (MG) is an autoimmune disease with impaired neuromuscular transmission mainly due to the effect of autoantibodies to acetylcholine receptor (AChR). Dysregulation of sarcoplasmic reticulum (SR) Ca2+ release has been associated with muscle fatigue. Fatigue in MG patients was caused not only by abnormal

neuromuscular transmission but also by the impairment of excitation–contraction (E–C) coupling. In the process of E–C coupling in skeletal muscle, ryanodine receptor (RyR) and dihydropyridine receptor (DHPR/CACNA1S) function as Ca2+ channels. SLAMF1 is an important genetic susceptibility locus for autoantibody production. SLAMF1 leads to IFN-γ production of CD4+ T cells. IFN-γ production of CD4+ T cells is associated with pathogenesis and immunoregulation of MG. However, speculating the plausibility and the biological significance of these candidate loci is premature because additional genetic data is needed to confirm the notion that these E-C coupling gene or SLAMF1 gene are associated with autoimmune MG. The present study suggests that some genetic polymorphisms might be related to autoimmune myasthenia gravis. Our findings also encourage further studies, particularly confirmatory studies with larger samples, to validate and analyze the association between these SNPs and autoimmune myasthenia gravis.