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A genome-wide association study of myasthenia gravis.

Publication ,  Journal Article
Renton, AE; Pliner, HA; Provenzano, C; Evoli, A; Ricciardi, R; Nalls, MA; Marangi, G; Abramzon, Y; Arepalli, S; Chong, S; Hernandez, DG ...
Published in: JAMA Neurol
April 2015

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

April 2015

Volume

72

Issue

4

Start / End Page

396 / 404

Location

United States

Related Subject Headings

  • United States
  • Polymorphism, Single Nucleotide
  • Myasthenia Gravis
  • Middle Aged
  • Male
  • Humans
  • HLA-DQ alpha-Chains
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
 

Citation

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Chicago
ICMJE
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Renton, A. E., Pliner, H. A., Provenzano, C., Evoli, A., Ricciardi, R., Nalls, M. A., … Traynor, B. J. (2015). A genome-wide association study of myasthenia gravis. JAMA Neurol, 72(4), 396–404. https://doi.org/10.1001/jamaneurol.2014.4103
Renton, Alan E., Hannah A. Pliner, Carlo Provenzano, Amelia Evoli, Roberta Ricciardi, Michael A. Nalls, Giuseppe Marangi, et al. “A genome-wide association study of myasthenia gravis.JAMA Neurol 72, no. 4 (April 2015): 396–404. https://doi.org/10.1001/jamaneurol.2014.4103.
Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R, Nalls MA, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015 Apr;72(4):396–404.
Renton, Alan E., et al. “A genome-wide association study of myasthenia gravis.JAMA Neurol, vol. 72, no. 4, Apr. 2015, pp. 396–404. Pubmed, doi:10.1001/jamaneurol.2014.4103.
Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R, Nalls MA, Marangi G, Abramzon Y, Arepalli S, Chong S, Hernandez DG, Johnson JO, Bartoccioni E, Scuderi F, Maestri M, Gibbs JR, Errichiello E, Chiò A, Restagno G, Sabatelli M, Macek M, Scholz SW, Corse A, Chaudhry V, Benatar M, Barohn RJ, McVey A, Pasnoor M, Dimachkie MM, Rowin J, Kissel J, Freimer M, Kaminski HJ, Sanders DB, Lipscomb B, Massey JM, Chopra M, Howard JF, Koopman WJ, Nicolle MW, Pascuzzi RM, Pestronk A, Wulf C, Florence J, Blackmore D, Soloway A, Siddiqi Z, Muppidi S, Wolfe G, Richman D, Mezei MM, Jiwa T, Oger J, Drachman DB, Traynor BJ. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015 Apr;72(4):396–404.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

April 2015

Volume

72

Issue

4

Start / End Page

396 / 404

Location

United States

Related Subject Headings

  • United States
  • Polymorphism, Single Nucleotide
  • Myasthenia Gravis
  • Middle Aged
  • Male
  • Humans
  • HLA-DQ alpha-Chains
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease