A Genome-Wide Association Study of Myasthenia Gravis

Renton, Alan E.; Pliner, Hannah A.; Provenzano, Carlo; Evoli, Amelia; Ricciardi, Rocco; Nalls, Michael A.; Marangi, Giuseppe; Abramzon, Yevgeniya; Arepalli, Sampath; Chong, Sean; Hernandez, Dena G.; Johnson, Janel O.; Bartoccioni, Emanuela; Scuderi, Flavia; Maestri, Michelangelo; Gibbs, J. Raphael; Errichiello, Edoardo; Chiò, Adriano; Restagno, Gabriella; Sabatelli, Mario; Macek, Mark D.; Scholz, Sonja W.; Corse, Andrea M.; Chaudhry, Vinay; Benatar, Michael; Barohn, Richard J.; McVey, April; Pasnoor, Mamatha; Dimachkie, Mazen M.; Rowin, Julie; Kissel, John T.; Freimer, Miriam; Kaminski, Henry J.; Sanders, Donald B.; Lipscomb, Bernadette; Massey, Janice M.; Chopra, Manisha; Howard, James F.; Koopman, Wilma J.; Nicolle, Michael W.; Pascuzzi, Robert M.; Pestronk, Alan; Wulf, Charlie; Florence, Julaine; Blackmore, Derrick; Soloway, Aimee; Siddiqi, Zaeem A.; Muppidi, Srikanth; Wolfe, Gil I.; Richman, David P.; Mezei, Michelle M.; Jiwa, Theresa; Oger, Joél; Drachman, Daniel B.; Traynor, Bryan J.

doi:10.1001/jamaneurol.2014.4103

Cited by 136 publications

(127 citation statements)

References 50 publications

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“…We also found suggestive evidence for associations in eight disparate regions (Table 2); they include the same R620W variant of PTPN22 noted previously, and one for the tumor necrosis factor receptor superfamily, member 11a, NFKB activator (TNFRSF11A, alias RANK and its particular SNP, rs4574025), reported recently in LOMG (16). For each of the loci achieving at least suggestive significance (P < 10 -5 ), odds ratios (ORs) were similar for the more stringent cutoff age (≥60 years) ( Table 2 and Supplementary Table S4).…”

Section: More Precise Imputation Of Potentially Associated Locisupporting

confidence: 82%

“…These include TNIP1 and such possible candidates as STAT4, IKZF1, IRF5, NKX2-3, ORMDL3, CD226 and PPG1 (15). We also found no firm evidence for the CTLA4 associations previously reported in MG (5,16). Similarly, for the LOMG-associated genes, ZBTB10 and TNFRSF11A, there was no suggestion of association in our previous EOMG study (15).…”

contrasting

confidence: 89%

“…Although not supporting all of the previously reported associations (see Discussion), this study provided strong evidence for an association with TNFRSF11A (alias RANK) in the LOMG subset defined by age of onset >40 years (16). The current study was undertaken to further define genetic associations in stringently defined LOMG patients (onset ≥50 and ≥60 years), again focusing on Northern Europeans, using population substructure matching of publicly available control genotypes, and imputation methods extending to specific HLA variants and amino acids (AAs).…”

contrasting

confidence: 79%

“…Recently, another group reported a GWAS in EOMG (n = 235) and LOMG patients (n = 737), both separately and combined (16). Although not supporting all of the previously reported associations (see Discussion), this study provided strong evidence for an association with TNFRSF11A (alias RANK) in the LOMG subset defined by age of onset >40 years (16).…”

contrasting

confidence: 49%

See 3 more Smart Citations

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Seldin

Alkhairy

Lee

et al. 2015

Mol Med

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Section: More Precise Imputation Of Potentially Associated Locisupporting

confidence: 82%

contrasting

confidence: 89%

contrasting

confidence: 79%

contrasting

confidence: 49%

See 2 more Smart Citations

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Seldin

Alkhairy

Lee

et al. 2015

Mol Med

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“…There is additional evidence that CTLA-4 expression on T cells may be altered in MG [64]. Furthermore, a recent genome-wide association study in patients with AChR-positive MG identified an association signal at the CTLA-4 gene, suggesting that aberrant cellular mechanisms involving CTLA-4 may predispose to MG and that therapies targeting this pathway should be considered [65]. The above findings also suggest that there are genetically defined patients with MG that may be differentially responsive to abatacept or other related compounds.…”

Section: T-cell Signaling Pathways and Tregsmentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

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Epigenome‐wide DNA methylation analysis of myasthenia gravis

et al. 2023

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Myasthenia gravis (MG) is a common neuromuscular junction disorder and autoimmune disease mediated by several antibodies. Several studies have shown that genetic factors play an important role in MG pathogenesis. To gain insight into the epigenetic factors affecting MG, we report here genome‐scale DNA methylation profiles of MG. DNA was extracted from eight MG patients and four healthy controls for genome‐wide DNA methylation analysis using the Illumina HumanMethylation 850K BeadChip. Verification of pyrosequencing was conducted based on differential methylation positions. Subsequently, C2C12 and HT22 cell lines (derived from mouse) were treated with demethylation drugs. Transcribed mRNA of the screened differential genes was detected using quantitative real‐time PCR. The control and MG group were compared, and two key probe positions were selected. The corresponding genes were CAMK1D and CREB5 (P < 0.05). Similarly, the myasthenic crisis (MC) and non‐MC group were compared and four key probe positions were selected. The corresponding genes were SAV1, STK3, YAP1, and WWTR1 (P < 0.05). Subsequently, pyrosequencing was performed for verification, revealing that hypomethylation of CAMK1D was significantly different between the MG and control group (P < 0.001). Moreover, transcription of CREB5, PKD, YAP1, and STK3 genes in the C2C12 cells was downregulated (P < 0.05) after drug treatment, but only YAP1 mRNA was downregulated in HT22 cells (P < 0.05). This is the first study to investigate genome‐scale DNA methylation profiles of MG using 850 K BeadChip. The identified molecular markers of methylation may aid in the prevention, diagnosis, treatment, and prognosis of MG.

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A Genome-Wide Association Study of Myasthenia Gravis

Cited by 136 publications

References 50 publications

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Epigenome‐wide DNA methylation analysis of myasthenia gravis

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