Table 1.
Summary of Lessons Learned From G×E Research Activity.
| Lessons | Interaction and Phenotype |
|---|---|
| 1. G×E in metabolism genotypes/phenotypes are usually related to absorption, distribution, metabolism, and excretion (ADME) characteristics of targeted exposures. These are an obvious place to explore biological pathways and candidate genes. | Phenylketonuria and glucose-6-phosphate deficiency: single metabolism genes × diet/pharmacological agents |
| CYP2D6/PON1/ALDH2 with pesticide exposure for Parkinson disease | |
| NAT2 and smoking for bladder cancer | |
| ALDH2*2 and alcohol intake for esophageal cancer | |
| AS3MT and arsenic for skin lesions | |
| Genes relevant to pharmacogenomics | |
| 2. G×E discoveries can lead to environmental interventions to prevent diseases (especially in cases where presence of both are required for outcome). | Phenylketonuria and glucose-6-phosphate deficiency: single metabolism genes × diet/pharmacological agents |
| CYP2C9/VKORC1 and warfarin for anticoagulation response | |
| Nicotine-metabolism genes and therapy for smoking cessation | |
| Aspirin/NSAIDs use and MGST1/IL16 for colorectal cancer | |
| 3. Temporal considerations (birth cohorts, timing of exposure, etc.) may influence G×E findings and need to be considered. | PON1 and pesticide exposure for Parkinson's disease |
| FTO and physical activity for BMI | |
| 4. Quality of exposure assessment affects detection of G×E. | PON1 and pesticide exposure for Parkinson disease |
| FTO and physical activity for BMI | |
| NOS2 and traffic pollution for respiratory symptoms | |
| 5. Scale studied can affect the detection of interactions. | NAT2 and smoking for bladder cancer |
| 6. Large population sizes are typically needed for G×E discovery. | NAT2 and smoking for bladder cancer |
| FTO and physical activity for BMI (Caucasian populations) | |
| Aspirin/NSAIDs use and MGST1/IL16 for colorectal cancer | |
| 7. Variability in exposure distribution increases the power to detect G×E and the importance of investigating ethnically and geographically diverse populations. | ALDH2*2 and alcohol intake for esophageal cancer |
| FTO and physical activity for BMI | |
| AS3MT and arsenic for skin lesions | |
| NOS2 and traffic pollution for respiratory symptoms | |
| Carbamazepine × HLA-B*1502 for Stevens-Johnson syndrome | |
| 8. No single G×E method is universally the most powerful. The appropriate G×E method depends on underlying assumptions, correlations between risk factors, and the true G×E model. | ALDH2*2 and alcohol for esophageal squamous-cell carcinoma |
| See Gauderman et al. (1) | |
| 9. Studying highly exposed populations/cohorts can provide high-quality exposure assessment. | FTO and physical activity for BMI |
| 10q24.32 × arsenic and arsenical lesions | |
| 10. Model systems and functional approaches may provide G×E insights. | Genetics of lead susceptibility (Drosophila model) |
| FTO and physical activity for BMI (human tissue samples/mouse models) | |
| ALDH2 and pesticides for Parkinson disease (ex vivo model system) | |
| NOS2 and traffic pollution for respiratory symptoms (biomarker study) |
Abbreviations: ALDH2, aldehyde dehydrogenase 2 gene; AS3MT, arsenite methyltransferase gene; BMI, body mass index; CYP, cytochrome P-450 family; FTO, fat mass– and obesity-associated gene; G×E, gene-environment interaction; HLA-B, human leukocyte antigen-B; IL16, interleukin 16 gene; MGST1, microsomal glutathione s-transferase 1 gene; NAT2, N-acetyltransferase 2 gene; NOS2, nitric oxide synthase 2 gene; NSAID, nonsteroidal antiinflammatory drug; PON1, paraoxonase 1 gene; VKORC1, vitamin K epoxide reductase complex subunit 1 gene.