title: A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution.
abstract: Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Marie-Abele
authors.initials: MA
authors.lastname: Bind
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Brent
authors.initials: B
authors.lastname: Coull
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Suh
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Wright
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Baccarelli
authors.affiliation: VA Normative Aging Study, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Pantel
authors.initials: P
authors.lastname: Vokonas
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Schwartz
mesh_terms: D000368:Aged; D000393:Air Pollutants / Q000378:metabolism / Q000633:toxicity*; D000397:Air Pollution; D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D053263:Gene Regulatory Networks; D059647:Gene-Environment Interaction; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D008670:Metals / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000235:genetics*; D052638:Particulate Matter / Q000378:metabolism / Q000633:toxicity*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D000393:Air Pollutants; D015415:Biomarkers; D008670:Metals; D052638:Particulate Matter; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D002097:C-Reactive Protein
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