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PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes

Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene par...

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Autores principales: Huen, Karen, Yousefi, Paul, Street, Kelly, Eskenazi, Brenda, Holland, Nina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762373/
https://www.ncbi.nlm.nih.gov/pubmed/26913202
http://dx.doi.org/10.1093/eep/dvv003
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author Huen, Karen
Yousefi, Paul
Street, Kelly
Eskenazi, Brenda
Holland, Nina
author_facet Huen, Karen
Yousefi, Paul
Street, Kelly
Eskenazi, Brenda
Holland, Nina
author_sort Huen, Karen
collection PubMed
description Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1(-108,) was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1(-108) genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1.
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spelling pubmed-47623732016-02-22 PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes Huen, Karen Yousefi, Paul Street, Kelly Eskenazi, Brenda Holland, Nina Environ Epigenet Research Article Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1(-108,) was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1(-108) genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1. Oxford University Press 2015-09-11 /pmc/articles/PMC4762373/ /pubmed/26913202 http://dx.doi.org/10.1093/eep/dvv003 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Research Article
Huen, Karen
Yousefi, Paul
Street, Kelly
Eskenazi, Brenda
Holland, Nina
PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title_full PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title_fullStr PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title_full_unstemmed PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title_short PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
title_sort pon1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762373/
https://www.ncbi.nlm.nih.gov/pubmed/26913202
http://dx.doi.org/10.1093/eep/dvv003
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