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Gene Environment Interactions Henrik E. Poulsen

Gene Environment Interactions Henrik E. Poulsen. One genetic constitution provides Advantage in one environment - Disadvantage in another environment. Embryonic Development. 20K genes – 100K proteins. Simple organisms One gene - one protein.

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Gene Environment Interactions Henrik E. Poulsen

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  1. Gene Environment Interactions Henrik E. Poulsen

  2. One genetic constitution provides Advantage in one environment - Disadvantage in another environment

  3. Embryonic Development.

  4. 20K genes – 100K proteins Simple organisms One gene - one protein

  5. Generale Project (Framework 5, coordinator JT Salonen) Genetic and chemical biomarkers for arterisclerosis development (events and IMT progression) Foam Cell NO. O2-. H2O2 OH. Vit C Vit E SOD Gpox urate bill. ? -T -T* Ox AA* DNA LDL Protein AA Cancer Arteriosclerosis Cataract

  6. Dave Flavell PhD, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories

  7. Paul Lichtenstein et al. NEJM Volume 343:78-85, 2000 Conclusions Inherited genetic factors make a minor contributionto susceptibility to most types of neoplasms. This finding indicatesthat the environment has the principal role in causing sporadiccancer. The relatively large effect of heritability in cancerat a few sites (such as prostate and colorectal cancer) suggestsmajor gaps in our knowledge of the genetics of cancer

  8. Lung Cancer: Lung cancer in non-smokers is rare ( 0-10%) 20 % of hard-core smokers develop lung cancer The lung cancer gene ?

  9. A major lung cancer susceptibility locus maps to chromosome 6q23-25.Bailey-Wilson JE, et al. Am J Hum Genet. 2004 Sep;75(3):460-74. Epub 2004 Jul 21 • National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

  10. 26,108lung cancer cases screenedat GELCC sites, 13.7%had at least onefirst-degree relative with lungcancer. Following the initialfamily history screening process,we collected, from 3,541probands and/or their familyrepresentatives, data regarding additionalpersons affected with anycancers in the extendedfamily, vital status ofaffected individuals, availability ofarchival tissue, and willingnessof family members toparticipate in the study.Full pedigree development andbiospecimen collection were performedon 771 families withthree or more first-degreerelatives affected with lungcancer. Cancers were verifiedby medical records, pathologyreports, cancer registry records,or death certificates for69% of individuals affectedwith LT, and byreports of multiple familymembers for the other31% of family membersaffected with LT

  11. Methylenetetrahydrofolate reductase gene polymorphisms and response to fluorouracil-based treatment in advanced colorectal cancer patients Etienne, Marie-Christine et al. Pharmacogenetics Dec 2004, 14(12): 785-92 MTHFR 1298A>C polymorphism MTHFR 677C>T polymorphism 12.3% mut/mut 18.4% mut/mut

  12. What does a single gene change lead to? One change in a single function ? Multiple changes in multiple functions ?

  13. C 8oxodG  :No tumor (PNAS 96:13300,1999; 97:4156, 2000; Carcinogenesis 23:2005, 2002) OGG1 KO hMTH 8oxodG  :Tumor (Cancer Res. 63:902,2003) 8oxodG NO Tumor OGG1 KO OGG1 KO 8oxodG  : No Tumor (Cancer Res. 63:902,2003) hMYH hMYH NO Tumor OGG1 KO 8oxodG  : NoTumor (Cancer Res. 63:902,2003) hMTH Repair of 8-oxodG: Tumor effects in KO mice dGTP T G A •OH •OH 8-oxodGTP Goxo Goxo C A hMTH OGG1 8-oxodGMP hMYH Goxo G A C Goxo C hMYH OGG1 Goxo Goxo OGG1 A/C C + G T C A

  14. Nested case-control study (1091 Caucasian lung cancer patients and 1240 controls) (OR) of XRCC1 Arg399Gln polymorphism 1.3 [ (CI), 1.0 –1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For non-smokers, OR 2.4 (95% CI, 1.2–5.0), heavy smokers OR 0.5 (95% CI, 0.3–1.0). Cancer Epidemiology, Biomarkers & Prevention 12, 359–365, 2003

  15. This lecture also ran in a zig-zag pattern, just like the real world. Hope you are confused, but on a higher level

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