Gene Environment Interactions Henrik E. Poulsen

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

Embryonic Development.

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

Generale Project (Framework 5, coordinator JT Salonen) Genetic and chemical biomarkers for arterisclerosis development (events and IMT progression)  -T  -T* Ox A AA* Foam Cell NO. O 2 -. H 2 O 2 OH. Vit C Vit E SOD Gpox urate bill. ? DNA LDL Protein Cancer Arteriosclerosis Cataract

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

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

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

A major lung cancer susceptibility locus maps to chromosome 6q Bailey-Wilson JE, et al. Am J Hum Genet Sep;75(3): 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.

26,108 lung cancer cases screened at GELCC sites, 13.7% had at least one first-degree relative with lung cancer. Following the initial family history screening process, we collected, from 3,541 probands and/or their family representatives, data regarding additional persons affected with any cancers in the extended family, vital status of affected individuals, availability of archival tissue, and willingness of family members to participate in the study. Full pedigree development and biospecimen collection were performed on 771 families with three or more first- degree relatives affected with lung cancer. Cancers were verified by medical records, pathology reports, cancer registry records, or death certificates for 69% of individuals affected with LT, and by reports of multiple family members for the other 31% of family members affected with LT

MTHFR 1298A>C polymorphism MTHFR 677C>T polymorphism 12.3% mut/mut 18.4% mut/mut 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):

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

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

Nested case-control study (1091 Caucasian lung cancer patients and 1240 controls) (OR) of XRCC1 Arg399Gln polymorphism1.3 [ (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

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