Recent progress in the genetics and epigenetics of paraoxonase: why it is relevant to children's environmental health

Abstract

Purpose of review: Children are more susceptible to exposures in utero and during early childhood that may result in developmental problems and chronic diseases. Novel discoveries in the field of molecular epidemiology that can help explain susceptibility to exposures and disease will be demonstrated using the multifunctional enzyme paraoxonase 1 (PON1) as an example.

Recent findings: The broad PON1 variability in humans, partly due to differences in genetics and age, can confer differential susceptibility because this enzyme can detoxify organophosphate pesticides and has antioxidant properties. Epigenetics plays a significant role in the mediation of the effects of environmental exposure on human health and is hypothesized to be a major contributing factor to the early-life origins of adult disease. Studies highlighted in this review demonstrate the relationship of PON1 polymorphisms with microRNA binding in addition to a link between DNA methylation in the transcriptional regulatory region with changes in PON1 enzyme levels. Other important methodologies such as ancestry informative markers and lactonase activity can enhance studies involving PON1.

Summary: This PON1 model demonstrates that integrating genetic and epigenetic factors, as well as other novel methodologies, can improve our understanding of important susceptibility factors linked to pediatric disease.

Figure 1

Figure 1A shows that if differences in ancestry are associated both with genotype and the outcome of interest, genetic ancestry can act as a source of genetic confounding. Bar plot of genetic ancestry esimates generated by STRUCTURE software. Estimates were expressed as proportion of European, African and Native American ancestry in B) Mexican-American CHAMACOS children (n=375) and C) GALA II participants of Hispanic origin (; n=6021). Each vertical bar represents the ancestral distribution in 1 subject. For each subject, the proportions of: A) Native American (blue), African (green), and European (red) ancestry and B) Native American (red), African (blue), and European (tan) ancestry are displayed. There is substantial variability in individual ancestry both within and between Hispanic ethnic subgroups. Particularly for studies involving admixed populations, it is important to control for the potential bias introduced by population stratification. This is vital in PON1 genetic studies because allele frequencies of many common PON1 SNPs vary between ethnic groups and health outcomes of interest such as obesity and cardiovascular disease also differ by ethnic group. Figure 1B is reproduced with permission from [15**] and Figure 1C is reproduced with permission from [33].

Figure 2. Map of PON1 CpG sites putative miRNA binding sites

PON1 contains 2 CpG islands, one in the promoter region and one in exon 7. It has 278 CpG sites spread across the CpG islands, shores, shelves, and open seas. In silico analyses using the most recent version of miRbase (version 21) has identified 25 putative miRNA binding sites in PON1. However, thus far, none of these sites has been functionally validated with PON1.