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Genetics, Epigenetics and Public Health: a Primer

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Genetics, Epigenetics and Public Health: a Primer Genetics, Epigenetics and Public Health: A Primer Muin J. Khoury MD, PhD CDC Office of Public Health Genomics Outline Public health in the genomics era Genetics and epigenetics 101 Using epigenetics in public health: opportunities and challenges What is the Role of Public Health in Translating Genomics into Health Impact? Assessment- Policy- Assurance CDC Office of Public Health Genomics Mission Provides timely and credible information for the effective and responsible translation of genome-based discoveries into public health & health care 1. Identify evidence-based applications 2. Inform & communicate 3. Integrate into practice & programs Public Health Genomics Has Come of Age CDC Home Page September 3, 2014 CDC Horizon Scanning for Genomics and Health Impact Public Health Genomics Priorities 2012-2017 2012 Public Health Genomics 2012 3-Tiered Classification of Evidence for Action Genetics 101 All Diseases Result from Gene-Environment Interaction Genetic variation Environmental risk factors Human Disease 3 billion base pairs, Potentially modifiable millions of mutations & hence public health variants, Non- Modifiable interest Genetic Diseases: (Mendelian disorders-PKU Example, 5000+ conditions, 5%-10% of human disease “Complex” Diseases (heart disease, cancer, diabetes, environmental & infectious agents – 90%-95% of human disease ) Genetics 101 Interactions Getting More Complex What Genomes? What Genome? Environmental Genetic variation Inherited (germ) risk factors Acquired (somatic) Human What Environments? (e.g. cancer) Disease Infection Symbiotic (microbiome) Chemicals Vectors Physical agents Diet Behavioral Social Genetics 101 Interaction Getting Even More Complex Epigenetics!! What Genome? Environmental Genetic variation Inherited risk factors Acquired Human What Environments? (e.g. cancer) Disease Infection Symbiotic (microbiome) Chemicals Vectors Physical agents Epigenetic and post-genomic Diet Potentially modifiable modification hence public health Behavioral interest Social “Epigenetics” in the Scientific Literature A Tale of Two Mice (Agouti gene & Epigenetics) Identical twins: In yellow mouse, Agouti gene is unmethylated and turned on all the time, while in the brown mouse, the gene is completely methylated and shut down Effect of BPA exposure Effect of Folic acid http://www.pbs.org/wgbh/nova/body/epigenetic-mice.html Two Biological Codes Genetic code: sequence of DNA (nucleotide sequences) that tells a cell how to build one protein. Set for life. Epigenetic code: chemical modifications in the structure of the chromosomes that influence which genes can be expressed and in which tissues. Potentially altered in response to environments (especially early environments). From C. Kuzawa EPIGENETICS 3 Types of Epigenetic alterations –transcriptional, translational, or post-translational levels without change in DNA sequence Methylation of DNA Modifications of RNA-mediated histones modifications DNMT1 P U • RNA-directed DNA methylation DNMT3a Me • RNA-interference mediated chromatin DNMT3b remodeling • RNAi, siRNA, miRNA … -3.0 0 3.0 SAM SAH Control Treated A A - acetylation Me - methylation Genomic Imprinting P - phosphorylation U - ubiquitination Epigenetics, Environment and Development ART, Assisted Reproductive Technology CVS, Cerebrovascular System. Foley et al. Am J Epid 169:389. Maternal Transgenerational Epigenetic Inheritance Also applies to fathers! Drake & Liu (2009), Trends Endocrinology Metab 21(4) Developmental Origins of Adult Health Barker, DP (1997) Nutrition: 13(9) 807-13 Stress hormones or Fetal Stress or nutrient restriction Undernutrition Developmental response Inflammation Insulin resistance Visceral fat Hypertension Cardiovascular Disease From C. Kuzawa Early Environments Can Influence Development & Adult Health • Developmental biology is sensitive to prenatal and early postnatal conditions. • Parental psychosocial and nutritional stressors lead to durable biological changes in offspring that elevate future risk for cardiovascular and other common diseases. • Allows environmental experiences of one generation to have lingering impacts on adult health disparities in future generations. • Epigenetics is a biological mechanism mediating such effects – From C. Kuzawa Exposures Genetic Epigenetic Inherited Acquired Inherited Acquired genetic DNA damage/ epigenetic epigenetic make-up mutation make-up changes Adverse Effects P. Schulte Using Epigenetics in Public Health Methylation Epidemiology studies have measured both methylation of specific genes and global methylation (e.g. benzene, pollutants, lead, arsenic) Both hypo and hypermethylation results found Perhaps most intriguing are studies that explore associations between social or behavioral factors and epigenetic regulation (e.g. economic deprivation, work stress, and inflammation) To date, studies that incorporate epigenetic measurements have rarely validated biological effects of epigenetic changes via RNA or protein expression Impact of perinatal exposures on long term outcomes (BPA) Using Epigenetics in Public Health Histones: a few studies have investigated the influence of environmental exposures on global levels of specific histone modifications. These studies require availability of intact protein fractions, and quantification is currently not cost-effective for large studies For example, higher inhalational exposure to iron, arsenic, and nickel, as quantified by personal air monitors Cancer: Epigenetic Disease Remains the most actively studied field. A heterogeneous set of diseases, displaying both genetic and epigenetic etiologies. In general the epigenome is widely hypomethylated compared to normal tissue- inactivated tumor suppression genes (some exceptions) Animal and cell line models of specific pathways serve as critical tools Need integration of laboratory and epidemiological approaches Methodologic Issues How to make sense out of epigenetic data . Pattern and level may vary across tissues and cells . Impact of confounders . Selecting appropriate statistical models . Can DNA from specimen banks be used? . Need to link epigenetic changes and apical endpoints P. Schulte Methodologic Issues No Consensus How to Model Methylation Appropriate statistical model will depend on the scientific question of interest and knowledge about biological pathways Since methylation CpG sites often exist in clusters and may show correlated methylation changes, analytical methods for summarizing correlated are needed Since most epigenetic data summarizes methylation at individual CpG sites as proportions specific models for proportional data will be required Disentangling genetic and epigenetic effects could be a challenge. P. Schulte Summary Public health in the genomics era We are paying more attention to how we can use pathogen and human to improve health & prevent disease Genetics and epigenetics 101 Epigenetics as a link between genes & environment and possible biological mediator for health disparities Using epigenetics in public health Numerous opportunities and challenges, stay tuned In the meantime, increasing number of genomic applications can be used to save lives today.
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