Genetic polymorphisms in disease susceptibility: Gene-gene and gene-environment interactions

Abstract

Genetic polymorphisms within genes encoding biotransformation enzymes can alter the biotransformation process of exogenous and endogenous chemicals. The purpose of this thesis is to review and evaluate the associations between genetic polymorphisms of biotransformation enzymes, including microsomal epoxide hydrolase (mEH), NAD(P)H quinone oxidoreductase (NQO1), glutathione S-transferase (GST) mu 1 (GSTM1), GST theta 1 (GSTT1), and GST pi 1 (GSTP1), and the transcription factor, nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), and diseases of the liver, bladder, and lung, and Parkinson's disease (PD). This evaluation will provide an analysis of the overall associations between the polymorphisms and disease and how and these associations are dependent on gene-gene and gene-environment interactions.

Overall, genetic polymorphisms within the biotransformation enzymes evaluated in this thesis, alone, are unlikely to be significant susceptibility or protective factors in the development of disease. Rather, their role as susceptibility or protective factors ultimately depends on gene-gene and gene-environment interactions. Also, dose, length of exposure, the type of xenobiotic, diet, and other factors can be the difference between a polymorphism being a susceptibility or protective factor. Given this differential susceptibility, associations between polymorphisms and disease risk will have to be evaluated on a chemical-specific and mechanistic basis.