The influence of gene polymorphisms, modifiable lifestyle factors, and toxicants on the protective effects of the paraoxonase genes

The paraoxonase gene family consists of three members (PON1, PON2, and PON3) with both distinct and overlapping roles in human health. These enzymes influence oxidative stress, inflammation, and bacterial infections, along with a large number of diseases and disorders, such as atherosclerosis. The wide-reaching effects of the PON gene family make them an important and highly advantageous subject of study. Their ability to be modified by diet, lifestyle, and environmental exposures, as well as various polymorphisms and genetic influences, provide for a complex, highly modifiable internal form of individual protection. The overall goal of this project was to determine what factors affect individual variations in paraoxonase activity, as well as the influence of individual PON members on health and exposure outcomes. The initial study in this project provided the first data about intra-individual PON1 variations over a time of about 15 years, showing levels remain relatively stable in an agricultural population. This study also contributed data regarding the polymorphic distributions of influential PON SNPs and the influence of lifestyle factors on PON1 activity. The use of a twin population for the next study allowed for examination of the heritability of PON1 activity and antioxidant capacity, and provided novel data regarding the influence of genetic variations on PON1 activity. To further attempt to eliminate the complexity of influences on these genes and individual polymorphisms, the third study in this project characterized an innovative transgenic Drosophila melanogaster model with the goal of analyzing the influence of individual PON family members on exposure and disease outcomes without the effects of compensation from other PONs. By further elucidating the effects of the PONs at the individual level, human populations will be able to be advised regarding the most at-risk individuals and modifiable changes to improve PON levels, and therefore overall health.