Please use this identifier to cite or link to this item:
https://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 |
Editor: | Chaturvedi, S. |
Statement of Responsibility: | 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. |
DOI: | 10.1371/journal.pone.0063897 |
Published version: | http://dx.doi.org/10.1371/journal.pone.0063897 |
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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