Coronary Heart Disease as a Paradigm of Gene-Environment Interaction: Genetic Mechanisms, Environmental Regulation, and Clinical Translation
Coronary heart disease (CHD) arises from a dynamic interplay between genetic and environmental factors. Modern genomics and epidemiological studies confirm that 40–60% of CHD risk is attributable to genetic variation, with the remainder linked to lifestyle, environmental exposures, and epigenetic regulation. Below is a systematic analysis of polygenic genetic foundations, environmental regulation pathways, gene-environment interactions, and clinical translation strategies.
I. Genetic Basis: Polygenic Risk Networks and Functional Mechanisms
1. Clinical Application of Polygenic Risk Scores (PRS)
- Genome-wide association studies (GWAS) have identified over 250 CHD-associated loci spanning lipid metabolism (PCSK9, LDLR, APOB), inflammation (IL6R, CCR2), and vascular function (VEGF-A) pathways.
- PRS models incorporating millions of SNPs achieve an AUC of 0.8 for CHD prediction, outperforming traditional risk factors (e.g., LDL-C, blood pressure). Multi-ancestry PRS demonstrates superior predictive power in Mexican populations, highlighting genetic heterogeneity.
2. Rare Variants and Monogenic Contributions
- Monogenic familial hypercholesterolemia (e.g., LDLR mutations) increases CHD risk by 3–5-fold. Rare SYNE1 variants (e.g., rs36215567) associate with early-onset CHD, potentially disrupting nuclear membrane-cytoskeleton interactions.
3. Systems Biology of Gene Regulatory Networks
- Systems biology reveals 28 independent regulatory networks contributing to CHD heritability, including novel risk genes (e.g., ADTRP, ApoE family) beyond GWAS findings. These networks drive plaque formation via lipid metabolism reprogramming, endothelial inflammation, and immune dysregulation.
II. Environmental Regulation: Modifiable Risk Factor Pathways
1. Lifestyle Impacts
- Smoking and Oxidative Stress: Smoking induces DNA methylation changes (e.g., LOX-1 promoter hypomethylation), enhancing oxidized LDL uptake and foam cell formation.
- Diet and Epigenetics: High-fat diets upregulate SREBP-1c, increasing hepatic lipid synthesis, while Mediterranean diets suppress systemic inflammation via NF-κB inhibition.
2. Metabolic Disease Synergy
- Diabetes and obesity activate the PPARγ-LXRA axis via insulin resistance, impairing macrophage cholesterol efflux and accelerating atherosclerosis.
3. Transgenerational Environmental Effects
- Prenatal malnutrition or toxin exposure (e.g., PM2.5) may increase offspring CHD susceptibility through placental epigenetic modifications (e.g., ACE gene DNA methylation).
III. Molecular Evidence of Gene-Environment Interactions
1. Risk Amplification
- Individuals with high PRS and unhealthy lifestyles (smoking, sedentary behavior) face 6.7x higher CHD risk than low-PRS healthy counterparts. For example, PCSK9 loss-of-function mutations partially counteract pro-atherogenic effects of high-fat diets.
2. Epigenetically Mediated Mechanisms
- Environmental stressors (e.g., hypoxia) activate VEGF-A epigenetic regulation via HIF-1α signaling, promoting intraplaque angiogenesis and hemorrhage risk.
- Smoking interacts with the IL6R locus to enhance IL-6 pathway activity, increasing plaque instability by 40%.
3. Mendelian Randomization Validation
- Mendelian randomization confirms a linear relationship between genetically determined LDL-C levels and CHD risk (54% risk reduction per 1 mmol/L LDL-C decrease), amplified by lifestyle interventions.
IV. Clinical Translation and Precision Medicine Strategies
1. Risk Stratification and Personalized Prevention
- Integrating PRS with traditional risk scores (e.g., Framingham) improves high-risk cohort identification, especially for early-onset CHD families.
- High-PRS individuals benefit from intensive lipid-lowering (PCSK9 inhibitors) and anti-inflammatory therapies (IL-6 antagonists), reducing cardiovascular events by 30%.
2. Gene Editing and Targeted Therapies
- CRISPR-Cas9 editing of PCSK9 (VERVE-101) achieves 55% LDL-C reduction with durable effects exceeding 1 year.
- Base editing (e.g., VERVE-201) silences ANGPTL3, ameliorating triglyceride metabolism disorders.
3. Precision Environmental Interventions
- Genetic risk-tailored lifestyle plans: High-PRS individuals require stricter LDL-C targets (<1.4 mmol/L) and exercise regimens (≥300 minutes weekly).
V. Challenges and Future Directions
1. Genetic Heterogeneity and Population Specificity
- East Asian populations harbor unique susceptibility loci (e.g., QTRT1), necessitating ancestry-specific PRS models.
2. Quantifying Environmental Exposures
- Wearable devices enable real-time monitoring of air pollution and dietary patterns, facilitating dynamic gene-environment risk models.
3. Multi-Omics and Systems Medicine
- Integrating single-cell sequencing and spatial transcriptomics elucidates spatiotemporal gene-environment dynamics in plaque microenvironments.
Conclusion
CHD exemplifies the interplay of polygenic inheritance and environmental exposure. Genetic risk networks establish a “framework” of susceptibility, dynamically modified by environmental factors through epigenetics and metabolic reprogramming. Future advancements in multi-omics integration, gene editing therapies, and precision environmental interventions promise to transform CHD management from risk prediction to root-cause eradication.
Data sourced from public references. Contact: chuanchuan810@gmail.com.
