Using Genetic Epidemiologic Methods to Explore the Influence of Gene-Environment Interactions on Colorectal Adenoma Recurrence

Persistent Link:
http://hdl.handle.net/10150/193888
Title:
Using Genetic Epidemiologic Methods to Explore the Influence of Gene-Environment Interactions on Colorectal Adenoma Recurrence
Author:
Lowe, Kimberly Anne
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
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 (p(inter)=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.
Type:
text; Electronic Dissertation
Keywords:
genetic epidemiology; gene-environment interactions; colorectal adenoma recurrence
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Epidemiology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Martinez, M. Elena
Committee Chair:
Martinez, M. Elena

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleUsing Genetic Epidemiologic Methods to Explore the Influence of Gene-Environment Interactions on Colorectal Adenoma Recurrenceen_US
dc.creatorLowe, Kimberly Anneen_US
dc.contributor.authorLowe, Kimberly Anneen_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractIntroduction: 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 (p(inter)=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.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectgenetic epidemiologyen_US
dc.subjectgene-environment interactionsen_US
dc.subjectcolorectal adenoma recurrenceen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineEpidemiologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMartinez, M. Elenaen_US
dc.contributor.chairMartinez, M. Elenaen_US
dc.contributor.committeememberRanger-Moore, Jamesen_US
dc.contributor.committeememberSherrill, Duaneen_US
dc.contributor.committeememberGuerra, Stefanoen_US
dc.contributor.committeememberThompson, Patriciaen_US
dc.identifier.proquest2556en_US
dc.identifier.oclc659748484en_US
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