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GENE-ENVIRONMENT INTERACTION

GENE-ENVIRONMENT INTERACTION. Herman Autrup Dept Environmental Medicine Institute of Public Health University of Aarhus. GENE –ENVIRONMENT INTERACTIONS MECHANISM. Influence gene expression Interacts with gene – adducts coding sites – mutation transcription site – expression

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GENE-ENVIRONMENT INTERACTION

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  1. GENE-ENVIRONMENT INTERACTION Herman Autrup Dept Environmental Medicine Institute of Public Health University of Aarhus

  2. GENE –ENVIRONMENT INTERACTIONS MECHANISM Influence gene expression Interacts with gene – adducts coding sites – mutation transcription site – expression Gene product modifies effect of environmental risk factor

  3. Several Mechanistic Possibilities GENE-ENVIRONMENT- INTERACTION Disease Genotype Risk Factor Genotype enhances risk factor expression

  4. Several Mechanistic Possibilities GENE-ENVIRONMENT- INTERACTION Disease Genotype Risk Factor Both genotype and risk factor affect disease

  5. Several Mechanistic Possibilities GENE-ENVIRONMENT- INTERACTION Disease Genotype Risk Factor Risk factor alters gene/disease association

  6. Several Mechanistic Possibilities GENE-ENVIRONMENT- INTERACTION Disease Genotype Risk Factor Genotype alters risk factor/disease association

  7. Influence gene expression

  8. Cell membrane Cytoplasm Nuclear membrane ATP Ah ADP + Pi Ah Arnt Ah Nuclei Arnt Arnt Ah Ah XRE XRE XRE XRE XRE CYP1A1 Steroid Hormones vævsspecifikke transcription faktorer Negative regulatoriske Phosphorylation elementer

  9. METAL TOXICITY - TRANSCRIPTOMES Andrew, Env Health Persp 111: 825-838, 2003

  10. Interacts with genes - adducts

  11. BULKY CARCINOGEN - DNA ADDUCT DNA component 32P-label resolve nucleotides DNA: Lymphocytes Procedure: P32 postlabelling Enrichment: P1 nuclease Quantification: phosphor image

  12. 14 12 10 8 6 4 2 0 10 1 0.1 DNA adducts / 108 nucl.) DNA adducts / 108 nucl. 0.1 1 10 100 0 20 40 60 80 carc. PAH (ng/m3) carc. PAH (ng/m3) No correlation with inhaled PAH or other ambient air pollution parameters CARCINOGEN-DNA ADDUCTS AND EXPOSURE Thailand police: No correlation between total PAH and bulky DNA adduct levels Medical students, DK: No correlation between PM2.5 and bulky-carcinogen adduct levels Meta-analysis (Peluso et al, 2001): Significant association between PAH (and BP) and bulky-adducts in industrial workers.

  13. CARCINOGEN-DNA ADDUCTS AND CANCER RISK Conclusion: Carcinogen-DNA adducts appears to be a risk indicator for cancer, especially in smokers

  14. Effect modification

  15. CANDIDATE GENES • Low Penetrance: Phase I • CYP1A1 PAH’s cigarette smoke • CYP1A2 HAA’s cooked meat • CYP2E1 Nitrosamines processed meat • NAT1 HAA’s cooked meat • NAT2 HAA’s cooked meat

  16. CANDIDATE GENES • Low Penetrance: Phase II • NAT1, NAT2 Arylamines cigarette smoke • GST PAH’s cigarette smoke HAA’s cooked meat

  17. CANDIDATE GENES • Some Problems • Expressed in target tissue? • Inducible? • Polymorphisms functional? • Dual role (NAT)

  18. GST and GASTRIC CANCER – Meta analysis GSTM1 Deletion 1.24 + ever smoking 2.39 GSTT1 Deletion 1.08 + ever smoking 2.37 GSTM1 and T1 deletions 2.08 Boccia et al, Cancer Letter, 2005

  19. GSTM1 and NEVER SMOKERS Passive smokers Total group Plus 1.00 Null 1.03 Null + null passive 0.52 + 1-19 h-years 0.77 + 20+ 2.32 Wenzloft et al, Carcinogenesis 2005

  20. GSTM1 and ALCOHOL INTERACTION Esophegeal Gastric Alcohol 1.52 1.73 GSTM1 Del 2.17 1.02 GSTM1 + and low alcohol = 1 GSTM1 Del 3.76 1.34 high and GSTM1+ 4.003.48 high and Del 2.98 1.58

  21. BIOTRANSFORMATION BENZENE NQO

  22. BENZENE TOXICITY Benzene Benzene oxide Risk Lack of NQO1 (2.6) High CYP2E1 (2.5) Combined (7.8) Phenol Hydroquinone 1,4-Benzoquinone

  23. Significant difference BENZENE : S-PHENYLMERCAPTURIC ACID (PMA) AND MUCONIC ACID (TMA) Low activity genotype = 100 Sources of benzene. Ambient air, cigarette smoking, grilling (charcoal) Population: Non-smoking medical students, Copenhagen, DK (ambient air benzene 2.53 ug/m3) TMA PMA Sørensen et al., 2003

  24. BULKY-ADDUCTS – EFFECT OF GSTM1 GSTM1*1/*1 = 100 Lymphocytes Tissues Placenta Breast Lung * * * * * * * Statistically significant Occupational studies

  25. OH HO highly inducible by PAHs in CYP1A1*2 carriers HO OH mEH DNA O HO CYP1A1/ CYP1B1 mEH CYP1A1 HO HO O HO OH OH OH GSTM/ GSTP GSTM/ GSTP SG HO HO GS HO OH 2,00 all subjects high ETS exposure 1,75 0.002 GSTM1 null 1,50 0.009 GSTP1 ile/val & val/val mEH exon 4 0.025 1,25 0.011 0.026 DNA adducts 1,00 0,75 0,50 0,25 inducible individuals (23.7%) non-inducible individuals (76.3%) 0,00 CYP1A1*2+/+ CYP1A1*2 +/- & -/- GENE-GENE INTERACTION Study population: Greek technical school students, non-smokers

  26. INTERACTION OF GSTM1 AND GSTP1 PAH-adducts – WBC OR GSTM1*2/*2 1.25 GSTP*2/ 1.44 GSTM1*2/*2 & GSTP*2 2.20 GSTM1 no effect in current smokers Strongest effect in former smokers Perera et al., Carcinogenesis, 2002

  27. GENOTYPES AFFECTING BULKY-DNA ADDUCT LEVEL Gene CYP1A1 GSTM1 GSTT1 GSTP1 MPO NQO1 EH NAT2 Genotype *2/*2 *2/*2 *2/*2 *2/*2 *1/*1 *1/*1 Tyr113Tyr Slow Effect No effect No effect Combinations

  28. COMBINED EFFECT OF BIOMARKERS ON LUNG CANCER RISK Adduct level GSTM1 OR Low present 1.0 Low null 2.3 High present 6.9 High null 16.2 Tang et al., Carcinogenesis 1998

  29. GEN-AIR - OBJECTIVES • Risk factors in smoking-related cancers in non-smokers • ambient air • environmental tobacco smoke • susceptibility genes • Bulky carcinogen-DNA adducts as risk indicator • Gene-environment interactions

  30. MOLECULAR EPIDEMIOLOGY Definition: Application of molecular markers of exposure and susceptibility in epidemiological studies

  31. GEN-AIR - OBJECTIVES • Risk factors in smoking-related cancers in non-smokers • ambient air • environmental tobacco smoke • susceptibility genes • Bulky carcinogen-DNA adducts as risk indicator • Gene-environment interactions

  32. GEN-AIR STUDY 271 lung cancer cases Risk factors: Passive smoking Ambient air pollution-residence Genetic polymorphism: 26 genes, 39 polymorphisms Bulky carcinogen-DNA adduct: risk indicator

  33. STATISTICAL ANALYSIS Cox´s proportional hazard models Adjusted: Gender, age, smoking habits, time of recruitment, country, school year, energy intake, fruit & vegetable, physical activity, educational level

  34. AMBIENT AIR POLLUTION • Residence – road • Estimated exposure – Residence and monitoring stations

  35. LUNG CANCER RISK - RESIDENCE AOR No major road 1.0 Moderately busy road 1.52 Busy road 1.22 Slightly higher risk for people living along roads with medium and high traffic

  36. ETS EXPOSURE IN INFANCY • Parental smoking HR • Daily • Ex-smokers 1.65 • Never smokers 2.04 • Daily – many hours • Ex-smokers 2.98 • Never smokers 3.63 Increased risk for lung cancer in people who has been exposed to ETS

  37. SUSCEPTIBILITY GENES Xenobiotica metabolism: NAT1, NAT2, GSTM1, GSTM3, GSTT1, GSTP1, CYP1A1, CYP1B1, MPO, NQO1 DNA repair: ERCC1, ERCC3, ERCC5, OGT Others: MnSOD, BBRC1, RAD51, TP53 Total: 29 genes, 36 polymorphisms

  38. SUSCEPTIBILITY GENES Metabolism genes OR CYP1A1*2/*2 3.0 (0.5 - 18.1) CYP1B1*2/*2 1.2 (0.5 - 2.6) GSTM1*2/*2 1.1 (0.7 - 1.9) GSTP1*2/*2 1.8 (1.8 - 3.9) NQO1* 8.0 (1.7 - 37.2) No major role of these genes on lung cancer risk in low exposure situations

  39. RISK GENOTYPES RISK ALLELE : The genotypes associated with an increased risk of cancer in previous studies

  40. GENE-ENVIRONMENT INTERACTION Ambient air AOR Less than 3 polymorphism 3+ polymorphic alleles No major road 1.0 1.0 Type A/B 1.40 2.19

  41. GENE-ENVIRONMENT INTERACTION Environmental tobacco smoke AOR 3+ polymorphic alleles Less than 3 polymorphism NO 2.97 1 YES 3.96 1.43 In case of ETS exposure increased risk with increasing number of at risk genotypes (trend P < 0.01)

  42. CARCINOGEN DNA ADDUCTS • Involved in initiation of cancer – mutation • Related to exposure • Indicator of cancer risk – integrating exposure and genetic susceptibility

  43. BULKY ADDUCT AS RISK INDICATOR Detectable vs non-detectable AOR All subjects 1.82 Never smokers 2.26 Ex-smokers 2.24 Persons with detectable adduct level have an increased risk of developing cancer

  44. ADDUCTS AND LUNG CANCER Only people with detectable adducts All subject below 1.93 above 1.51 Never smokers below 1.78 above 4.04 Ex-smokers below 3.91 above 1.20 Never-smokers with an above median adduct level have an increased risk of lung cancer

  45. N= 0 1 2 3 4 5 DNA ADDUCTS AND SUSCEPTIBILITY Adduct level increases with number of risk alleles

  46. GENETIC POLYMORPHISM IN XENOBIOTICA METABOLIZING ENZYMES Cytochrome P450: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2E1, CYP3A4, Glutathione S-Transferase: GSTM1, GSTT1, GSTP1, GSTA1 Others: NQO1, MPO, mEH

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