title: A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging.
abstract: The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12-18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age.
authors.affiliation: Human Communication and Deafness, School of Psychological Sciences, The University of Manchester, Manchester, UK. Electronic address: tony.payton@manchester.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Payton
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: P
authors.initials: P
authors.lastname: Sindrewicz
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pessoa
authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, The University of Manchester, Manchester, UK.
authors.forename: H
authors.initials: H
authors.lastname: Platt
authors.affiliation: Centre for Clinical and Cognitive Neuroscience, Salford Royal NHS Hospital, The University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Horan
authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, The University of Manchester, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Ollier
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: V J
authors.initials: VJ
authors.lastname: Bubb
authors.affiliation: Centre for Clinical and Cognitive Neuroscience, Salford Royal NHS Hospital, The University of Manchester, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Pendleton
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Quinn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001057:Apolipoproteins E / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018626:Retroelements; D013997:Time Factors; D014825:Vocabulary
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018626:Retroelements; C400783:TOMM40 protein, human; D008156:Luciferases
keywords: APOE; Aging; Cognition; Expression; Retrotransposon; TOMM40