title: The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis.
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.
authors: 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.
authors: Qiang
authors: Q
authors: Gang
authors: Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
authors: Conceicao
authors: C
authors: Bettencourt
authors: 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.
authors: Pedro M
authors: PM
authors: Machado
authors: Biomedical Research Centre, UCL and the Education Unit, Institute of Neurology, University College London, London, UK.
authors: Zoe
authors: Z
authors: Fox
authors: 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.
authors: Stefen
authors: S
authors: Brady
authors: Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
authors: Estelle
authors: E
authors: Healy
authors: Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
authors: Matt
authors: M
authors: Parton
authors: Medical Research Council Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
authors: Janice L
authors: JL
authors: Holton
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors: David
authors: D
authors: Hilton-Jones
authors: Neuromuscular Division, Department of Neurology, University of California, Los Angeles Medical Centre, Los Angeles, CA, USA.
authors: Perry B
authors: PB
authors: Shieh
authors: Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
authors: Edmar
authors: E
authors: Zanoteli
authors: Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
authors: Boel
authors: B
authors: De Paepe
authors: Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
authors: Jan
authors: J
authors: De Bleecker
authors: Nerve and Muscle Centre of Texas, Houston, TX, USA.
authors: Aziz
authors: A
authors: Shaibani
authors: Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
authors: Michela
authors: M
authors: Ripolone
authors: Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
authors: Raffaella
authors: R
authors: Violano
authors: Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
authors: Maurizio
authors: M
authors: Moggio
authors: The University of Kansas Medical Centre, Kansas City, USA.
authors: Richard J
authors: RJ
authors: Barohn
authors: The University of Kansas Medical Centre, Kansas City, USA.
authors: Mazen M
authors: MM
authors: Dimachkie
authors: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milan, Italy.
authors: Marina
authors: M
authors: Mora
authors: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milan, Italy.
authors: Renato
authors: R
authors: Mantegazza
authors: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milan, Italy.
authors: Simona
authors: S
authors: Zanotti
authors: 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.
authors: Michael G
authors: MG
authors: Hanna
authors: 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.
authors: Henry
authors: H
authors: Houlden
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018979:Myositis, Inclusion Body / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D012737:Sex Factors
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human
keywords: APOE; Age of onset; Sporadic inclusion body myositis; TOMM40; sIBM