Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/98656
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Type: Journal article
Title: Structural and population-based evaluations of TBC1D1 p.Arg125Trp
Author: Richardson, T.
Thomas, E.
Sessions, R.
Lawlor, D.
Tavaré, J.
Day, I.
Citation: PLoS One, 2013; 8(5):e63897-1-e63897-3
Publisher: Public Library of Science
Issue Date: 2013
ISSN: 1932-6203
1932-6203
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Tom G. Richardson, Elaine C. Thomas, Richard B. Sessions, Debbie A. Lawlor, Jeremy M. Tavare, Ian N. M. Day
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.
Keywords: GTPase-Activating Proteins; Body Mass Index; Amino Acid Substitution; Gene Frequency; Phenotype
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.
RMID: 0030042789
DOI: 10.1371/journal.pone.0063897
Appears in Collections:Medicine publications

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