Gene-Environment Interactions in Health

Gene-Environment Interactions (GEIs)

• GEIs occur when environmental factors (diet, air, etc.) interact with genes, modifying disease risk.
• GEIs are crucial for understanding disease etiology, not just genetic factors alone.
• Development stages significantly influence gene regulation, impacting disease risk.

Lecture Outline

• Introduction to GEI
• Advantages and challenges in GEI analysis
• Integration of multi-omics data
• Clinical applications of GEI research
• Social impacts of GEI research
• GEI within the Precision Environmental Health (PEH) framework

GEI Definition

• A GEI occurs when environmental exposures affect disease risk, based on an individual's genetic makeup.

GEI Examples

• BRCA-1 mutation and asbestos exposure (mesothelioma)
• DRD4 gene and parenting style (ADHD)

Precision Environmental Health (PEH)

• PEH uses genetic and environmental data to predict disease and customize healthcare through integrating omics (genomic, epigenomic, etc.) data with environmental exposures.

Measurement Techniques

• Mass Spectrometry (MS): High-throughput untargeted MS detects pollutants, food additives, and metabolites, creating complex data needing advanced analysis.
• Sensors and machine learning: used to further understand GEIs.
• Wearable devices: track pollution exposures and body responses.
• Questionnaires: collect data on lifestyle, exposures, and social factors. Questionnaires frequently combine with biomonitoring and sensor data to increase accuracy.

Challenges in Standardizing the Exposome

• Environmental factors are a major contributor to disease risk (70-90%).
• The exposome lacks standardized measurement methods and comprehensive data-sharing systems.
• Overlapping risk estimates from genetic and environmental studies often exceed 100%.
• The interplay of genes and environment adds complexity to disease causation estimation.

Exposome Definition

• The exposome encompasses all lifetime environmental exposures, including external factors (e.g., pollution, social factors) and internal factors (e.g., microbiome, oxidative stress).

GEI Analysis Advantages

• Incorporates both genetic and environmental factors, significantly enhancing understanding of disease mechanisms, individual heterogeneity, and "missing heritability".
• Accounts for environmental exposures and increases the power of health phenotype studies.
• Improves prediction, and enhances polygenic scores (PGS) by utilizing the exposome framework.

GEI Analysis: Importance

• GEI analysis' advantage over simpler (genome-only) models lies in its ability to incorporate environmental exposures impacting health, which better illuminates disease mechanisms.

Replication of GEI Associations

• Replicated GEI associations, such as air pollution and cardiovascular disease, alcohol and liver disease, smoking and lung cancer, diet, and obesity and pesticide exposure and Parkinson's disease, are well-established.

GEI Analysis: How it improves predictions

• GEI analysis greatly improves the accuracy in predicting disease risks compared to approaches that only consider genetic factors.

How PEH helps reduce health disparities

• Personalized Environmental Health (PEH) combines individual and community environmental data with biological data improving public health and addressing health disparities.
• GEI analysis helps identify genetic vulnerabilities to pollution, allowing for targeted interventions in vulnerable populations, especially as climate change intensifies.

How to improve GEI studies

• Family studies provide insight to differentiate between environmental and genetic risks.
• Genetic markers offer objective measures of ancestry that improve the design of studies to adjust for population stratification for better results.

Epigenetics Overview

• Epigenetics studies non-sequence modifications to DNA, like CpG methylation, that affect gene accessibility and its roles in the interaction of environmental factors with genetic makeups.
• Environmental exposures can alter epigenetic markers.
• DNA CpG methylation is the simplest epigenetic marker.

Candidate Genes in GEI Studies

• Genes like Cytochrome P450 enzymes (CYPs) metabolize drugs and xenobiotics.
• DNA Repair Genes correct UV damage and environmental damage.
• Metabolic Genes transform substances for excretion.
• Antioxidant Genes combat oxidative stress resulting from pollutants.
• Heat Shock Proteins (HSPs) protect against environmental stressors by ensuring proper protein folding.
• Xenobiotic Receptors regulate environmental compound metabolism and excretion.
• Inflammatory Response Genes mediate reactions to environmental agents.
• Transporter Genes facilitate the movement of substances across cell membranes and export toxins.

Returning GEI Results

• Returning GEI study results to participants is ethically important, but can raise challenges.
• Participants want to know their genetic risks and exposures, even for ambiguous findings, necessitating a transparent and trustworthy reporting mechanism.
• Patient concerns about exposures and genetic susceptibilities, especially high exposure cases, shape how findings are communicated.
• Researchers should support patients with actionable health steps for reducing environmental exposures.

Data Privacy

• Collecting environmental exposure data (especially geospatial and sensor-based) requires more robust policies & protections compared to genetic data.
• Data like geospatial data requires encryption and informed consent for collection, storage, and sharing, which needs specific safeguards to prevent re-identification.

Conclusion

• Understanding GEIs helps predict disease risks more accurately.
• Future research focuses on more accurate ways to measure environmental exposures, and studying more diverse populations.