Lecture 10 GEI Presentation PDF

How Genes and the Environment Work Together to Affect Health Lecture: 10 Exploring Gene-Environment Interactions (GEIs) By Dr. Hadil Alahdal  Introduction to the Field of GEI Advantages and Challenges in GEI Analysis Lecture Integration of Multi-omics Data ou...

How Genes and the Environment Work Together to Affect Health Lecture: 10 Exploring Gene-Environment Interactions (GEIs) By Dr. Hadil Alahdal  Introduction to the Field of GEI Advantages and Challenges in GEI Analysis Lecture Integration of Multi-omics Data outline Clinical Applications of GEI Research Social Impacts of GEI Research GEI within the Precision Environmental Health (PEH) Framework  Introduction Key Focus: Exploring the complex interplay of genetic and environmental factors in disease development. Key Concepts: Importance of GEIs in disease etiology. Overview of development-stage impacts of GEI. What are Gene-Environment Interactions (GEIs)? GEIs happen when your environment (like what you eat or breathe) interacts with your genes, affecting your risk of disease. Example: Exposure to pollution can increase asthma risk, but genetics determine how much?. Gene-environment Interactions (GEI) Overview Definition: A GEI Examples: occurs when BRCA-1 mutation and environmental asbestos exposure (mesothelioma). exposure impacts DRD4 gene and disease risk based parenting style on individual (ADHD). genetic makeup.  Gene-Environment Interactions (GEIs) primarily study: A) How genetics and environment independently influence health B) The interaction between genetic factors and environmental exposures in affecting health C) The impact of lifestyle factors alone on health outcomes D) Disease processes that are only genetically determined Answer: B) The interaction between genetic factors and environmental exposures in affecting health  GEIs have different effects at various life stages, such as during prenatal Developmental development or early Stages Matter: childhood, which significantly influence gene regulation and disease risk. How the Environment Affects Genes Precision Environmental Health (PEH): PEH uses genetic and environmental data to predict disease and customize healthcare. It focuses on integrating omics data (genomics, epigenomics, etc.) with environmental exposures to improve personalized health strategies. Example: How pollution, stress, and diet interact with your genes to affect health. Why GEIs Are Important Importance of GEIs: GEI research helps us understand disease mechanisms, improve disease prediction, and develop better prevention strategies. It also has implications for drug efficacy, safety, and public health interventions. For example:Some people who smoke may never get lung cancer due to their genes, while others have a higher risk.  GEIs can help researchers understand: A) Single-gene causes of disease B) How only environmental factors contribute to disease C) Disease mechanisms by analyzing the combined effects of genes and environment D) The role of ancestry alone in health outcomes Answer: C) Disease mechanisms by analyzing the combined effects of genes and environment  Behavioral and systemic consequences also involves … Environmental exposures affect health and illness not just at the cellular level but also via behavioral and systemic consequences. Toxic exposures can affect cellular function, while lifestyle factors can modify phenotypes by affecting brain networks or hormone levels. A diverse range of environmental factors affect biological systems from the cellular to organism level and interact with genetics in intricate ways. Exposure measurement Exposome Definition: Encompasses all lifetime environmental exposures, including external (e.g., pollution, social factors) and internal factors (e.g., microbiome, oxidative stress).  Measurement Techniques: 1- Mass Spectrometry (MS): High-throughput, untargeted MS can detect pollutants, food additives, and internal metabolites. However, it produces complex data that require advanced analysis tools.  Measurement Techniques: 2- Sensors and machine learning to 3- Wearable devices that track better understand GEIs. pollution exposure and your body’s response.  Measurement Techniques: 4- Questionnaires: Collect data on lifestyle, exposures, and social health factors. Disadvantage: Standardization issues, recall bias, and cultural differences. To improve accuracy, questionnaires are increasingly combined with biomonitoring and sensor data.  Challenges with Standardizing the Exposome: 1-High Disease Risk from Environmental Exposures: Environmental factors contribute to 70%-90% of disease risk, but accurately measuring this impact is difficult. 2-Measurement Challenges: The exposome lacks standardized measurement methods and comprehensive data-sharing systems. Due to these limitations, the influence of environmental factors on disease is likely underestimated. 3-Overlapping Risk Estimates: Disease risk estimates from genetic and environmental studies often add up to more than 100%, highlighting the need to account for Gene-Environment Interactions (GEIs). 4-Complexity of GEIs in Disease: The interplay of genetics and the environment adds complexity to understanding disease causation, making accurate estimation of GEI contributions an open question in research.  Exposome Heritability Disease Environmental Factors Contribution Estimate Air pollution (e.g., PM2.5), contributing to Cardiovascular Disease atherosclerosis, Over 80% 40%-60% (CVD) hypertension, myocardial infarction Dietary patterns, obesity, physical inactivity, chemical Type 2 Diabetes (T2D) 70%-90% 25%-75% exposure (e.g., phthalates, bisphenol A) Air pollutants (e.g., NO2, O3), indoor allergens (e.g., Asthma and Respiratory dust mites, mold), tobacco 60%-70% 35%-95% Diseases smoke, occupational exposures Tobacco smoking, dietary factors, alcohol Variable (low to high, Cancer 70%-90% consumption, sun exposure, depending on type) environmental pollutants Neurodegenerative Physical inactivity, diet, air 25%-80%, depending Diseases (e.g., Alzheimer’s pollution, occupational Up to 60% on familial or Disease) exposures sporadic cases  GEI Analysis Advantages: Incorporates both genetic and environmental factors influencing complex traits. Enhances understanding of disease mechanisms and individual heterogeneity. Addresses "missing heritability" (heritability not explained by genetics alone). Established Associations: Replicated GEIs include: Air pollution and cardiovascular disease Alcohol and liver disease Smoking and lung cancer Diet and obesity Pesticide exposure and Parkinson’s disease  GEI Analysis Advantages: Improved Prediction: GEI analyses explain significantly more phenotypic variance than genome-only models. Utilize the exposome framework to capture additive and non-additive effects. Increased Statistical Power: Accounting for environmental exposures boosts the power of health phenotype studies. Enhanced Polygenic Scores (PGS): Integrating the exposome improves PGS predictive power across diverse populations, especially with varying genetic ancestry and socioeconomic status.  A major benefit of GEI analysis over genome-only models is that it: A) Only considers genetic factors B) Ignores environmental factors C) Includes environmental exposures that impact health D) Simplifies the study of complex traits by excluding environmental factors Answer: C) Includes environmental exposures that impact health  Which of the following is an established association identified by GEI studies? A) Physical exercise and lung cancer B) Smoking and liver disease C) Air pollution and cardiovascular disease D) Diet and genetic makeup only Answer: C) Air pollution and cardiovascular disease  How to get there? Family Studies: Help distinguish between genetic and environmental risks. Explain population heterogeneity. Genetic Markers: Provide objective measures of ancestry, improving study design. Help adjust for population stratification to reduce selection bias.  Environmental Effect Identification: Enhances detection Genetic effects may of environmental only be evident effects in when stratified by subgroups. exposure levels.  Selection Context: Depends on the study context and existing knowledge. Classes of Environmentally Responsive Genes: Cytochrome P450 Enzymes (CYPs): Metabolize drugs and detoxify xenobiotics. DNA Repair Genes: Correct damage from UV light and chemicals. Candidate Metabolic Genes: Transform substances for easier excretion. Genes in Antioxidant Genes: Combat oxidative stress from pollutants. GEI studies Heat Shock Proteins (HSPs): Protect against environmental stressors by ensuring proper protein folding. Xenobiotic Receptors: Regulate metabolism and excretion of foreign compounds. Inflammatory Response Genes: Mediate reactions to environmental agents. Transporter Genes: Facilitate movement of substances across cell membranes, including efflux pumps for exporting toxins.  Gene Classes Highly Responsive to Environmental Factors Gene Class Function Cytochrome P450 Enzymes (CYPs) Metabolize drugs and detoxify xenobiotics. Correct damage caused by agents like UV light and DNA Repair Genes chemicals. Metabolic Genes Transform substances for easier excretion. Antioxidant Genes Combat oxidative stress from pollutants. Protect against environmental stressors by ensuring proper Heat Shock Proteins (HSPs) protein folding. Xenobiotic Receptors Regulate metabolism and excretion of foreign compounds. Inflammatory Response Genes Mediate reactions to environmental agents. Facilitate the movement of substances across cell Transporter Genes membranes, including exporting toxins via efflux pumps.  Epidemiology contributes to GEI studies by: A) Collecting standardized data on disease outcomes and exposures B) Ignoring environmental influences on disease C) Reducing the role of genetics in disease studies D) Limiting study populations to genetically similar individuals Answer: A) Collecting standardized data on disease outcomes and exposures  Definition: Study of non-sequence modifications to DNA and chromatin that affect gene accessibility and regulation. Gene-Environment Interactions (GEIs) Epigenetics connects genetic makeup and environmental exposures, contributing to disease development. Environmental factors can alter epigenetic markers, affecting cell communication and growth. Epigenetics Key Epigenetic Modifications DNA CpG Methylation: First and easiest Overview epigenetic signature to assess. Other modifications (e.g., heterochromatic histone modifications) are limited by technological costs and challenges. Epigenome-Wide Association Studies (EWASs) Important for understanding GEI mechanisms. High-density BeadChips are making EWAS more accessible, although costs still hinder large population studies.  Which epigenetic modification is the easiest to assess and commonly used in GEI research? A) DNA CpG Methylation B) RNA sequencing C) Protein folding changes D) Cell differentiation markers Answer: A) DNA CpG Methylation  Exemplars of GEI Translation in Personalized and Preventive Health (PEH): GEI Research in Pharmacogenomics and Disease Prevention in PEH: Healthcare: Personalized Medicine: By identifying interactions Warfarin dosing: Guided by VKORC1 and BAP1 gene mutations: between genetic variations CYP2C9 variations to balance efficacy Linked to increased cancer and environmental and bleeding risk. risk (e.g., mesothelioma) in exposures, such as: HLA-B∗57:01 testing: Used before those exposed to asbestos, CYP2D6 and pesticides prescribing abacavir (HIV treatment) to enabling targeted screening (Parkinson’s disease) prevent hypersensitivity. and prevention. NAT2 and smoking TPMT gene variants: Guide dose (bladder cancer) adjustments for thiopurine drugs (e.g., ALDH2∗2 and alcohol azathioprine) to reduce toxicity. (esophageal cancer) CYP2D6 variants: Influence AS3MT and arsenic (skin antidepressant choice and dosage. lesions) BRCA1/2 mutations and HER2: Enable personalized cancer therapy with drugs like PARP inhibitors and trastuzumab.  Genetic Susceptibility/Exposure Health Impact/Application 1 Personalized air-quality alerts Genetic susceptibilities to respiratory conditions and air quality Manage respiratory symptoms and prevent exacerbation by reducing exposure to pollutants. Lead exposure and genetic susceptibility Genetic variations and lead exposure Implement interventions to reduce the risk of cognitive and developmental delays in susceptible children. BAP1 and asbestos exposure BAP1 mutations and asbestos exposure Use targeted surveillance and early detection strategies for improved outcomes in individuals at high risk for asbestos-related diseases.  Genetic Susceptibility/Exposure Health Impact/Application 2 UV exposure and skin cancer risk MC1R gene variants and UV radiation Conduct skin cancer screening and provide personalized sun-protection advice to reduce melanoma risk. Personalized nutrition plans Genetic variations and nutrient intake Tailor dietary modifications to manage chronic conditions and reduce the risk of diet-related diseases like type 2 diabetes and cardiovascular disease. Pesticide exposure and Parkinson’s disease Genetic susceptibilities and pesticide exposure Implement protective measures and monitoring to manage and potentially prevent Parkinson’s disease in susceptible individuals.  Social and Societal Considerations in GEI Research: Environmental Justice: Personalized Environmental Health (PEH) combines individual and community environmental data with biological data to improve public health and address health disparities. GEI Analysis helps identify genetic vulnerabilities to pollutants, allowing targeted interventions for vulnerable populations, particularly as climate change impacts intensify. PEH focuses on unequal pollutant exposure in low-income and marginalized communities, addressing gaps in genetic studies that predominantly include populations of European descent. Health Disparities and Epigenetics: Exposure Impacts on gene expression differ across individuals and groups, affecting disease risk. Research considers effects of racism and discrimination on intergenerational epigenetics, aiming to identify populations at risk for lasting epigenetic changes due to toxic exposures and stress, and to develop interventions to protect current and future generations.  How might PEH help reduce health disparities related to environmental exposures in marginalized communities?  Return of Results in GEI Research: Ethical Considerations: Returning GEI study findings to participants raises ethical, legal, and social concerns, as participants often wish to know about their exposures and genetic risks—even those with uncertain implications. Routine Report-Back: Sharing findings respects participants' rights and builds transparency, reciprocity, and trust with communities. Community-Guided Report-Back: Participant concerns should shape how findings are communicated, especially for high exposures or genetic susceptibilities to environmental risks. Researchers can guide participants to resources for actionable health steps and reducing exposures. Supportive Resources: Effective report-back requires community engagement, guidelines, educational resources, training, and tool development for clear communication of results. Findings can also inform clinical decisions and policy development to address health risks associated with GEI.  Data Privacy in GEI Research: Data Privacy Concerns: Collecting environmental exposure data, especially geospatial and sensor- based data, lacks robust policies and protections compared to genetic data. Geospatial Data in PEH: Safeguards like encryption, access controls, and informed consent are essential for collecting, storing, and sharing geospatial data. Risks of Re-identification: Impact on Public Trust:  Why is it important to return GEI results to participants, and what challenges might arise in doing so? What measures would you recommend to protect the privacy of individuals’ environmental exposure data in GEI research?  Conclusion Looking Ahead: Future Main Idea: research will focus on Understanding GEIs can more accurate ways to help us predict disease measure environmental risks more accurately and exposure and study create better treatments. diverse populations.  References https://www.cell.com/cell- genomics/fulltext/S2666-979X(24)00175-7