Abstract/Details

Using genetic epidemiologic methods to explore the influence of gene-environment interactions on colorectal adenoma recurrence


2008 2008

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Abstract (summary)

Introduction. There is evidence to suggest that common genetic polymorphisms can modify the effect of environmental risk factors on colorectal neoplasia.

Methods. Data on 1430 individuals were obtained from two chemoprevention trials, the Wheat Bran Fiber Trial (WBF) (1) and the Effects of Ursodeoxycholic Acid on Adenomatous Polyp Recurrence Trial (URSO) (2). Data were analyzed to test for gene-environment interactions between allelic variation in PPAR-γ (Pro12Ala, C1431T), body mass index (BMI) and waist circumference, and the biochemical biomarkers of metabolic syndrome. Simulated data were then used to determine if the sample size required to formally test the relationship between gene-exposure interactions could be reduced by using a genetically enriched study population. For this simulation aspect of the work, an established gene-drug interaction (i.e.: flavin monooxygenase 3 (FMO3) and sulindac) was used as a model system.

Results. There was a borderline significant interaction between BMI and PPAR-γ for the Pro12Ala genotype (p inter = 0.11) and significant interactions between BMI and the C1431T genotype (pinter = 0.09). Results from the recursive partition model identified BMI (p = 0.007) and baseline fasting glucose levels (p = 0.033) as significant predictors of colorectal adenoma recurrence for carriers of Ala12 and waist circumference as a significant predictor for the Pro12Pro12 carriers (p = 0.002). Results from the simulated studies indicated that using genetically pre-screened and enriched populations can result in a 50% savings in the number of subjects required to test the candidate gene-drug interaction.

Conclusions. These findings provide evidence that the effect of allelic variation in PPAR-γ on colorectal adenoma recurrence is modified by BMI and that component traits of metabolic syndrome differentially affect the risk of colorectal adenoma recurrence depending on genotype. In addition, using genotype as an inclusion criterion in future studies of adenoma recurrence will result in a smaller sample size required to test gene-environment interactions.

Indexing (details)


Subject
Epidemiology
Classification
0766: Epidemiology
Identifier / keyword
Health and environmental sciences; Body mass index; Colorectal adenoma; PPARgamma
Title
Using genetic epidemiologic methods to explore the influence of gene-environment interactions on colorectal adenoma recurrence
Author
Lowe, Kimberly Anne
Number of pages
245
Publication year
2008
Degree date
2008
School code
0009
Source
DAI-B 69/01, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549434986
Advisor
Martinez, M. Elena
University/institution
The University of Arizona
Department
Epidemiology
University location
United States -- Arizona
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3299609
ProQuest document ID
304685115
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304685115
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