Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/98656
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dc.contributor.author | Richardson, T. | - |
dc.contributor.author | Thomas, E. | - |
dc.contributor.author | Sessions, R. | - |
dc.contributor.author | Lawlor, D. | - |
dc.contributor.author | Tavaré, J. | - |
dc.contributor.author | Day, I. | - |
dc.contributor.editor | Chaturvedi, S. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | PLoS One, 2013; 8(5):e63897-1-e63897-3 | - |
dc.identifier.issn | 1932-6203 | - |
dc.identifier.issn | 1932-6203 | - |
dc.identifier.uri | http://hdl.handle.net/2440/98656 | - |
dc.description.abstract | Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother-offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m(2) (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (χ(2) = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample. | - |
dc.description.statementofresponsibility | Tom G. Richardson, Elaine C. Thomas, Richard B. Sessions, Debbie A. Lawlor, Jeremy M. Tavare, Ian N. M. Day | - |
dc.language.iso | en | - |
dc.publisher | Public Library of Science | - |
dc.rights | © 2013 Richardson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | - |
dc.source.uri | http://dx.doi.org/10.1371/journal.pone.0063897 | - |
dc.subject | GTPase-Activating Proteins | - |
dc.subject | Body Mass Index | - |
dc.subject | Amino Acid Substitution | - |
dc.subject | Gene Frequency | - |
dc.subject | Phenotype | - |
dc.title | Structural and population-based evaluations of TBC1D1 p.Arg125Trp | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1371/journal.pone.0063897 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Lawlor, D. [0000-0002-6793-2262] | - |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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hdl_98656.pdf | Published version | 520.28 kB | Adobe PDF | View/Open |
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