The Science of Gene-Environment Interaction at the Centers for Disease Control and Prevention and Agency for Toxic Substances and Disease Registry

Posted on by Stephanie Foster, Office Of Innovation And Analytics, Agency For Toxic Substances And Disease Registry; Marta Gwinn, Wei Yu, and Muin J. Khoury, Office of Genomics and Precision Public Health, Centers for Disease Control and Prevention

a double helix with different viruses and diseasesNow, more than ever, we are aware that our environment has implications for our health. We are also learning more about the effects of inherited traits, such as blood type, on disease susceptibility and progression. Understanding the interactions between our environment and our genes and how they affect health outcomes offers a multitude of potential opportunities in public health. In addition to the human genome, we are seeing the emergence of other “omic” data (e.g., transcriptomics, epigenomics, and proteomics) in epidemiologic research. Identifying gene-environment interactions can help us identify new or confirm suspected environmental risk factors for disease; aid our understanding of disease natural history, severity and heterogeneity; and stratify disease risks and differentiate interventions for different subgroups of the population.

To explore work on gene-environment interaction (GxE) at the Centers for Disease Control and Prevention (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR), we examined the CDC-Authored Genomics and Precision Health Publications Database (CDC-Authored GPHPD), which includes articles published by CDC/ATSDR authors since 2011. The goal of our search was to identify publications describing the role of specific genes, gene signatures, or molecular pathways and their effects in response to environmental exposures. We defined environment broadly, including infectious agents, toxins, and behavioral risk factors such as alcohol use and smoking. We included articles examining various aspects of gene sequence, expression, and function, including sequence variants, gene-gene interaction, single nucleotide polymorphisms, DNA methylation, molecular methods of cellular function and damage, molecular and cellular signaling pathways, epigenetics, and telomere length. Genetic changes in microbes, animal vectors, and humans were included. Research applying genomic methods to develop treatments or vaccines, to understand antimicrobial mechanisms of resistance, and to examine evolutionary processes were also included.

The CDC-Authored GPHPD was searched using the terms “environment,” “gene environment,” “gene environment interaction,” and others* returning 54 unique articles, of which 15 were excluded because their primary focus was on other topics. Overall, these 39 articles represent 1% of all CDC/ATSDR-authored publications in the database. More than half (23 of 39) of the articles represent epidemiologic studies including candidate gene and genome-wide association studies (GWAS) examining genetic effect modification on disease risk.

Reference information for the 39 papers is provided in the accompanying table.

The articles included a wide range of health outcomes, including birth defects, cancer, and cardiovascular, pulmonary, hepatic, immunologic, and neurologic diseases. The largest subset of articles (22/39) examined the effects of toxic exposures or toxicogenomic effects of chemicals, such as polychlorinated biphenyls, dioxins, heavy metals, and organic solvents. Occupational exposures involving crystalline silica and multiwalled carbon nanotubes were also studied in relation to genetic damage and initiation of disease processes. The next largest category (6 articles) included papers describing evolutionary selection pressures on infectious organisms, either in the natural environment or in host species. The development of treatments and vaccines (5 articles), methods and models for evaluating GxE (5 articles), and recommendations for future research (1 article) complete the remaining topics explored in these publications. Publications originated in 9 of the 16 national Centers or Offices of CDC. The National Institute of Occupational Safety and Health (NIOSH) and the National Center for Emerging Zoonotic and Infectious Disease (NCEZID) contributed the most with 12 and 8 articles, respectively.

In this review, we identified articles aligning with the traditional epidemiologic concept of GxE, as well as several associated with newer biomarkers of exposure, such as DNA methylation (epigenetics) and telomere length. We found some articles related to environmental interactions with inherited genotype and others on environmental exposures that damage genetic material and initiate molecular pathways of pathogenesis.

The relatively small number of CDC/ATSDR GxE publications highlight opportunities to expand GxE research in areas not yet represented in the CDC/ATSDR-authored literature. Expanding GxE research could explore the multifaceted nature of the complex relationships and interactions between genes, the environment, and health.

Additional benefits could be reaped by promoting collaborative research among CDC/ATSDR programs and with academic partners. For example, the National Health and Nutrition Examination Survey (NHANES) Biospecimen Program collects and stores DNA samples; however, none of the publications in this CDC/ATSDR-authored literature review presented work utilizing this resource. Evidence related to genotoxicity is evaluated and presented for more than 200 hazardous substances in ATSDR Toxicological Profiles. Similarly, collaborations with the Geospatial Research, Analysis and Services Program (GRASP) may offer other unique opportunities to advance GxE research through the application of geostatistical and temporal methods to visualize and evaluate the impact of, and relationships among, place and human, animal, and pathogen genomes. Such partnerships could provide opportunities to leverage both expertise and resources.

*Search conducted 9/11/2021. Additional search terms: alcohol, chemical, exposure, hazard, hazardous, host response, human genome, human genome and chemical, interaction, particulate matter, pollution, smoking, toxicity, and VOC. We recognize that articles focusing on other, specific environmental exposures could have been missed by limiting our search to these terms.

PubMed ID Title Authors (CDC/ATSDR Authors in bold) Journal Year
33602020 Lung toxicity and gene expression changes in response to whole-body inhalation exposure to cellulose nanocrystal in rats Pius Joseph, Christina M Umbright, Jenny R Roberts, Jared L Cumpston, Marlene S Orandle, Walter G McKinney, Tina M Sager Inhalation Toxicology 2021
34474067 Systemic toxicity induced by topical application of heptafluorobutyric acid (PFBA) in a murine model. Lisa M Weatherly, Hillary L Shane, Ewa Lukomska, Rachel Baur, Stacey E Anderson Food and Chemical Toxicology 2021
32449871 Potential classification of chemical immunologic response based on gene expression profiles Stacey E Anderson, Rachel Baur, Michael Kashon, Ewa Lukomska, Lisa Weatherly, Hillary L Shane Journal of Immunotoxicology 2020
32881478 HMG-CoA reductase inhibitors as Drug Leads against Naegleria fowleri Hye Jee Hahn, Ruben Abagyan, Larissa M Podust, Shantanu Roy, Ibne Karim M Ali, Anjan Debnath ACS Chemical Neuroscience 2020
32629249 Dioxin-like compound exposures and DNA methylation in the Anniston Community Health Survey Phase II Gary S Pittman, Xuting Wang, Michelle R Campbell, Sherry J Coulter, James R Olson , Marian Pavuk, Linda S Birnbaum, Douglas A Bell The Science of the Total Environment 2020
31901242 Viruses in the Built Environment (VIBE) meeting report Aaron J Prussin 2nd, Jessica A Belser, Werner Bischoff, Scott T Kelley, Kaisen Lin, William G Lindsley, Jean Pierre Nshimyimana, Michael Schuit, Zhenyu Wu, Kyle Bibby, Linsey C Marr Microbiome 2020
31851354 Exploring mechanistic toxicity of mixtures using PBPK modeling and computational systems biology Patricia Ruiz, Claude Emond, Eva D McLanahan, Shivanjali Joshi-Barr, Moiz Mumtaz Toxicological Sciences 2020
31549720 On the Fly: Interactions Between Birds, Mosquitoes, and Environment That Have Molded West Nile Virus Genomic Structure Over Two Decades Nisha K Duggal, Kate E Langwig, Gregory D Ebel, Aaron C Brault Journal of Medical Entomology 2019
31487287 Burkholderia pseudomallei, the causative agent of melioidosis, is rare but ecologically established and widely dispersed in the environment in Puerto Rico Carina M Hall, Sierra Jaramillo, Rebecca Jimenez, Nathan E Stone, Heather Centner, Joseph D Busch, Nicole Bratsch, Chandler C Roe, Jay E Gee, Alex R Hoffmaster, Sarai Rivera-Garcia, Fred Soltero, Kyle Ryff, Janice Perez-Padilla, Paul Keim, Jason W Sahl, David M Wagner Neglected Tropical Diseases 2019
30374291 A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation Travis J A Craddock, Lindsay T Michalovicz, Kimberly A Kelly, Mark A Rice Jr, Diane B Miller, Nancy G Klimas, Mariana Morris, James P O’Callaghan, Gordon Broderick Frontiers in Cellular Neuroscience 2018
29925854 Avian influenza surveillance in domestic waterfowl and environment of live bird markets in Bangladesh, 2007–2012 Salah Uddin Khan, Emily S Gurley, Nancy Gerloff, Md Z Rahman, Natosha Simpson, Mustafizur Rahman, Najmul Haider, Sukanta Chowdhury, Amanda Balish, Rashid Uz Zaman, Sharifa Nasreen, Bidhan Chandra Das, Eduardo Azziz-Baumgartner, Katharine Sturm-Ramirez, C Todd Davis, Ruben O Donis, Stephen P Luby Scientific Reports 2018
28886414 Serum polychlorinated biphenyls and leukocyte telomere length in a highly-exposed population: The Anniston Community Health Survey Catherine L Callahan, Marian Pavuk, Linda S Birnbaum, Xuefeng Ren, James R Olson, Matthew R Bonner Environment International 2017
29071735 Impact of sample collection participation on the validity of estimated measures of association in the National Birth Defects Prevention Study when assessing gene-environment interactions Mary M Jenkins, Jennita Reefhuis, Amy H Herring, Margaret A Honein Genetic Epidemiology 2017
28720289 Transcriptomics in toxicology Pius Joseph Food and Chemical Toxicology 2017
29244000 Identification of recent cases of hepatitis C virus infection using physical-chemical properties of hypervariable region 1 and a radial basis function neural network classifier James Lara, Mahder Teka, Yury Khudyakov BMC Genomics 2017
27304166 Genotyping and Axenic Growth of Coxiella burnetii Isolates Found in the United States Environment Gilbert J Kersh, Rachael A Priestley, Heidie M Hornstra, Joshua S Self, Kelly A Fitzpatrick, Brad J Biggerstaff, Paul Keim, Talima Pearson, Robert F Massung Vector-Borne and Zoonotic Diseases 2016
27551784 Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors Oksana Lockridge, Robert B Norgren Jr, Rudolph C Johnson, Thomas A Blake Chemical Research in Toxicology 2016
28035981 Potential Inhibitory Influence of miRNA 210 on Regulatory T Cells during Epicutaneous Chemical Sensitization Carrie Mae Long, Ewa Lukomska, Nikki B Marshall, Ajay Nayak, Stacey E Anderson Genes 2016
25137520 Heavy metals, organic solvents and multiple sclerosis: an exploratory look at gene-environment interactions Melanie D Napier , Charles Poole, Glen A Satten, Allison Ashley-Koch, Ruth Ann Marrie, Dhelia M Williamson Archives of Environmental  and Occupational Health 2016
27587008 Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction Xiaojun Xu , Hong Thai , Kathryn M Kitrinos, Guoliang Xia, Anuj Gaggar, Matthew Paulson, Lilia Ganova-Raeva, Yury Khudyakov, James Lara BMC Bioinformatics 2016
26150536 Borrelia burgdorferi RevA Significantly Affects Pathogenicity and Host Response in the Mouse Model of Lyme Disease Rebecca Byram, Robert A Gaultney, Angela M Floden, Christopher Hellekson, Brandee L Stone, Amy Bowman, Brian Stevenson, Barbara J B Johnson, Catherine A Brissette Infection and Immunity 2015
26345256 Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents Jie Dong, Xiaoqing Yu, Dale W Porter, Lori A Battelli, Michael L Kashon, Qiang Ma Archives of Toxicology 2015
26001754 Quantitative analysis of the relative mutagenicity of five chemical constituents of tobacco smoke in the mouse lymphoma assay Xiaoqing Guo, Robert H Heflich, Stacey L Dial, Patricia A Richter, Martha M Moore, Nan Mei Mutagenesis 2015
26454015 The Dynamics of Genetic Interactions between Vibrio metoecus and Vibrio cholerae, Two Close Relatives Co-Occurring in the Environment Fabini D Orata, Paul C Kirchberger, Raphaël Méheust, E Jed Barlow, Cheryl L Tarr, Yan Boucher Genome Biology and Evolution 2015
26330309 Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells Xing Xin, P K Senthilkumar, Jerald L Schnoor, Gabriele Ludewig Environmental Science and Pollution Research International 2015
25011450 Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data Michael V Holmes, Caroline E Dale, Luisa Zuccolo, Richard J Silverwood, Yiran Guo, Zheng Ye, David Prieto-Merino, Abbas Dehghan, Stella Trompet, Andrew Wong, Alana Cavadino, Dagmar Drogan, Sandosh Padmanabhan, Shanshan Li, Ajay Yesupriya, Maarten Leusink, Johan Sundstrom, Jaroslav A Hubacek, Hynek Pikhart, Daniel I Swerdlow, Andrie G Panayiotou, Svetlana A Borinskaya, Chris Finan, Sonia Shah, Karoline B Kuchenbaecker, Tina Shah, Jorgen Engmann, Lasse Folkersen, Per Eriksson, Fulvio Ricceri, Olle Melander, Carlotta Sacerdote, Dale M Gamble, Sruti Rayaprolu, Owen A Ross, Stela McLachlan, Olga Vikhireva, Ivonne Sluijs, Robert A Scott, Vera Adamkova, Leon Flicker, Frank M van Bockxmeer, Christine Power, Pedro Marques-Vidal, Tom Meade, Michael G Marmot, Jose M Ferro, Sofia Paulos-Pinheiro, Steve E Humphries, Philippa J Talmud, Irene Mateo Leach, Niek Verweij, Allan Linneberg, Tea Skaaby, Pieter A Doevendans, Maarten J Cramer, Pim van der Harst, Olaf H Klungel, Nicole F Dowling, Anna F Dominiczak, Meena Kumari, Andrew N Nicolaides, Cornelia Weikert, Heiner Boeing, Shah Ebrahim, Tom R Gaunt, Jackie F Price, Lars Lannfelt, Anne Peasey, Ruzena Kubinova, Andrzej Pajak, Sofia Malyutina, Mikhail I Voevoda, Abdonas Tamosiunas, Anke H Maitland-van der Zee, Paul E Norman, Graeme J Hankey, Manuela M Bergmann, Albert Hofman, Oscar H Franco, Jackie Cooper, Jutta Palmen, Wilko Spiering, Pim A de Jong, Diana Kuh, Rebecca Hardy, Andre G Uitterlinden, M Arfan Ikram, Ian Ford, Elina Hyppönen, Osvaldo P Almeida, Nicholas J Wareham, Kay-Tee Khaw, Anders Hamsten, Lise Lotte N Husemoen, Anne Tjønneland, Janne S Tolstrup, Eric Rimm, Joline W J Beulens, W M Monique Verschuren, N Charlotte Onland-Moret, Marten H Hofker, S Goya Wannamethee, Peter H Whincup, Richard Morris, Astrid M Vicente, Hugh Watkins, Martin Farrall, J Wouter Jukema, James Meschia, L Adrienne Cupples, Stephen J Sharp, Myriam Fornage, Charles Kooperberg, Andrea Z LaCroix, James Y Dai, Matthew B Lanktree, David S Siscovick, Eric Jorgenson, Bonnie Spring, Josef Coresh, Yun R Li, Sarah G Buxbaum, Pamela J Schreiner, R Curtis Ellison, Michael Y Tsai, Sanjay R Patel, Susan Redline, Andrew D Johnson, Ron C Hoogeveen, Hakon Hakonarson, Jerome I Rotter, Eric Boerwinkle, Paul I W de Bakker, Mika Kivimaki, Folkert W Asselbergs, Naveed Sattar, Debbie A Lawlor, John Whittaker, George Davey Smith, Kenneth Mukamal, Bruce M Psaty, James G Wilson, Leslie A Lange, Ajna Hamidovic, Aroon D Hingorani, Børge G Nordestgaard, Martin Bobak, David A Leon, Claudia Langenberg, Tom M Palmer, Alex P Reiner, Brendan J Keating, Frank Dudbridge, Juan P Casas, The InterAct Consortium British Medical Journal 2014
24668907 Maternal Smoking, Xenobiotic Metabolizing Enzyme Gene Variants, and Gastroschisis Risk Mary M Jenkins, Jennita Reefhuis, Margaret L Gallagher, Jennifer G Mulle, Thomas J Hoffmann, Deborah A Koontz, Cynthia Sturchio, Sonja A Rasmussen, John S Witte, Patricia Richter, Margaret A Honein, National Birth Defects Prevention Study American Journal of Medical Genetics Part A 2014
25112188 Population‐Based Association and Gene by Environment Interactions in Genetic Analysis Workshop 18 Glen A Satten, Swati Biswas, Charalampos Papachristou, Asuman Turkmen, Inke R König Genetic Epidemiology. 2014
23737943 Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species Reuben Thomas, Russell S Thomas, Scott S Auerbach, Christopher J Portier PLoS ONE 2013
25741530 Interaction of HLA-DRB1*1501 and TNF-Alpha in a Population-based Case-control Study of Multiple Sclerosis Dhelia M Williamson, Ruth Ann Marrie, Allison Ashley-Koch, Glen A Satten Immunology and Infectious Diseases 2013
22749914 Joint toxicity of alkoxyethanol mixtures: contribution of in silico applications H R Pohl, P Ruiz, F Scinicariello, M Mumtaz Regulatory Toxicology and Pharmacology 2012
21606948 Varenicline for Smoking Cessation: Nausea Severity and Variation in Nicotinic Receptor Genes G E Swan, H S Javitz, L M Jack, J Wessel, M Michel, D A Hinds, R P Stokowksi, J B McClure, S L Catz, J Richards, S M Zbikowski, M Deprey, T McAfee, D V Conti, A W Bergen Pharmacogenomics Journal 2012
22825454 A smoking-associated 7-gene signature for lung cancer diagnosis and prognosis Ying-Wooi Wan, Rebecca A Raese, James E Fortney, Changchang Xiao, Dajie Luo, John Cavendish, Laura F Gibson, Vincent Castranova, Yong Qian, Nancy Lan Guo International Journal of Oncology. 2012
20980515 Reverse Genetics Generation of Chimeric Infectious Junin/Lassa Virus Is Dependent on Interaction of Homologous Glycoprotein Stable Signal Peptide and G2 Cytoplasmic Domains César G Albariño, Brian H Bird, Ayan K Chakrabarti, Kimberly A Dodd, David M White, Eric Bergeron, Punya Shrivastava-Ranjan, Stuart T Nichol Journal of Virology 2011
20941551 Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association Virginia R Falkenberg, Brian M Gurbaxani, Elizabeth R Unger, Mangalathu S Rajeevan Neuromolecular Medicine 2011
21658235 Assessing causal relationships in genomics: From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs Sara Geneletti, Valentina Gallo, Miquel Porta, Muin J Khoury, Paolo Vineis Emerging Themes in Epidemiology 2011
22081859 Multiwalled Carbon Nanotubes Induce a Fibrogenic Response by Stimulating Reactive Oxygen Species Production, Activating NF-κB Signaling, and Promoting Fibroblast-to-Myofibroblast Transformation Xiaoqing He, Shih-Houng Young, Diane Schwegler-Berry, William P Chisholm, Joseph E Fernback, Qiang Ma Chemical Research in Toxicology 2011
21295098 The impact of CYP2E1 genetic variability on risk assessment of VOC mixtures Hana R Pohl, Franco Scinicariello Regulatory Toxicology and Pharmacology 2011
21602193 Blood gene expression profiling detects silica exposure and toxicity Rajendran Sellamuthu, Christina Umbright, Jenny R Roberts, Rebecca Chapman, Shih-Houng Young, Diana Richardson, Howard Leonard, Walter McKinney, Bean Chen, David Frazer, Shengqiao Li, Michael Kashon, Pius Joseph Toxicological Sciences 2011
Posted on by Stephanie Foster, Office Of Innovation And Analytics, Agency For Toxic Substances And Disease Registry; Marta Gwinn, Wei Yu, and Muin J. Khoury, Office of Genomics and Precision Public Health, Centers for Disease Control and PreventionTags
Page last reviewed: April 9, 2024
Page last updated: April 9, 2024