The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

Qiang Gang¹, Conceicao Bettencourt², Pedro M Machado¹, Zoe Fox³, Stefen Brady⁴, Estelle Healy⁵, Matt Parton⁵, Janice L Holton⁵, David Hilton-Jones⁶, Perry B Shieh⁷, Edmar Zanoteli⁸, Boel De Paepe⁹, Jan De Bleecker⁹, Aziz Shaibani¹⁰, Michela Ripolone¹¹, Raffaella Violano¹¹, Maurizio Moggio¹¹, Richard J Barohn¹², Mazen M Dimachkie¹², Marina Mora¹³, Renato Mantegazza¹³, Simona Zanotti¹³, Michael G Hanna¹, Henry Houlden¹⁴; Muscle Study Group and the International IBM Genetics Consortium(#)

Affiliations

¹ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
² Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
³ Biomedical Research Centre, UCL and the Education Unit, Institute of Neurology, University College London, London, UK.
⁴ Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵ Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁷ Neuromuscular Division, Department of Neurology, University of California, Los Angeles Medical Centre, Los Angeles, CA, USA.
⁸ Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
⁹ Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
¹⁰ Nerve and Muscle Centre of Texas, Houston, TX, USA.
¹¹ Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
¹² The University of Kansas Medical Centre, Kansas City, USA.
¹³ Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milan, Italy.
¹⁴ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK. Electronic address: h.houlden@ucl.ac.uk.

PMID: 25670332
PMCID: PMC4378665
DOI: 10.1016/j.neurobiolaging.2014.12.039

The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

Qiang Gang et al. Neurobiol Aging. 2015 Apr.

. 2015 Apr;36(4):1766.e1-1766.e3.

doi: 10.1016/j.neurobiolaging.2014.12.039. Epub 2015 Jan 14.

Authors

Affiliations

¹ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
² Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
³ Biomedical Research Centre, UCL and the Education Unit, Institute of Neurology, University College London, London, UK.
⁴ Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵ Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁷ Neuromuscular Division, Department of Neurology, University of California, Los Angeles Medical Centre, Los Angeles, CA, USA.
⁸ Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
⁹ Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
¹⁰ Nerve and Muscle Centre of Texas, Houston, TX, USA.
¹¹ Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
¹² The University of Kansas Medical Centre, Kansas City, USA.
¹³ Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milan, Italy.
¹⁴ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK. Electronic address: h.houlden@ucl.ac.uk.

PMID: 25670332
PMCID: PMC4378665
DOI: 10.1016/j.neurobiolaging.2014.12.039

Abstract

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in "translocase of outer mitochondrial membrane 40" (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3.

Keywords: APOE; Age of onset; Sporadic inclusion body myositis; TOMM40; sIBM.

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References

1. Gang Q., Bettencourt C., Machado P., Hanna M.G., Houlden H. Sporadic inclusion body myositis: the genetic contributions to the pathogenesis. Orphanet J. Rare Dis. 2014;9:88. - PMC - PubMed
1. Machado P.M., Dimachkie M.M., Barohn R.J. Sporadic inclusion body myositis: new insights and potential therapy. Curr. Opin. Neurol. 2014;27:591–598. - PMC - PubMed
1. Mastaglia F.L., Rojana-Udomsart A., James I., Needham M., Day T.J., Kiers L., Corbett J.A., Saunders A.M., Lutz M.W., Roses A.D., Alzheimer's Disease Neuroimaging Initiative Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms. Neuromuscul. Disord. 2013;23:969–974. - PubMed
1. Needham M., Hooper A., James I., van Bockxmeer F., Corbett A., Day T., Garlepp M.J., Mastaglia F.L. Apolipoprotein epsilon alleles in sporadic inclusion body myositis: a reappraisal. Neuromuscul. Disord. 2008;18:150–152. - PubMed
1. Roses A.D., Lutz M.W., Amrine-Madsen H., Saunders A.M., Crenshaw D.G., Sundseth S.S., Huentelman M.J., Welsh-Bohmer K.A., Reiman E.M. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2010;10:375–384. - PMC - PubMed

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The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

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The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis

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