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JAMA Neurol. 2015 Apr;72(4):396-404. doi: 10.1001/jamaneurol.2014.4103.

A genome-wide association study of myasthenia gravis.

Author information

1
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
2
Institute of General Pathology, Catholic University, Rome, Italy.
3
Institute of Neurology, Catholic University, Rome, Italy.
4
Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy.
5
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
6
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland6Institute of Medical Genetics, Catholic University, Rome, Italy.
7
Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
8
Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
9
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland9Rita Levi Montalcini Department of Neuroscience, University of Turin, Tu.
10
Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
11
Molecular Genetics Unit, Department of Clinical Pathology, ASO OIRM-S Anna, Turin, Italy.
12
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
13
Department of Neurology, University of Miami, Miami, Florida.
14
Department of Neurology, University of Kansas Medical Center, Kansas City.
15
Department of Neurology, University of Illinois College of Medicine, Chicago.
16
Department of Neurology, Ohio State University Medical Center, Columbus.
17
Department of Neurology, George Washington University, Washington, DC.
18
Department of Neurology, Duke University Medical Center, Durham, North Carolina.
19
Department of Neurology, University of North Carolina, Chapel Hill.
20
Department of Clinical Neurosciences, London Health Sciences Centre, London, Ontario, Canada.
21
Department of Neurology, Indiana University-Purdue University, Indianapolis.
22
Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
23
Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.
24
Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo.
25
Department of Neurology, University of California, Davis Medical Center.
26
Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
27
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland11Department of Neurology, Johns Hopkins School of Medicine, Baltimore, M.

Abstract

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.

PMID:
25643325
PMCID:
PMC4856525
DOI:
10.1001/jamaneurol.2014.4103
[Indexed for MEDLINE]
Free PMC Article

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