1 / 71

Genetic Epidemiology of Cancer and its Risk Factors

Genetic Epidemiology of Cancer and its Risk Factors. Hermine Maes Cancer Control March 2006. Scandinavian Twin Registries Lichtenstein et al. 2000 NEJM 343:78-85. Swedish Twin Registry Born 1886-1925: N=10,503p Ncancer=4490 Born 1926-1958: N=12,883p Ncancer=1157

leyna
Télécharger la présentation

Genetic Epidemiology of Cancer and its Risk Factors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Genetic Epidemiology of Cancer and itsRisk Factors Hermine Maes Cancer Control March 2006

  2. Scandinavian Twin RegistriesLichtenstein et al. 2000 NEJM 343:78-85 • Swedish Twin Registry • Born 1886-1925: N=10,503p Ncancer=4490 • Born 1926-1958: N=12,883p Ncancer=1157 • Swedish Mortality Registry/ Swedish Cancer Registry • Danish Twin Registry • Born 1870-1930: N=8461p Ncancer=3572 • Central register of Deaths/ Danish Cancer Registry • Finnish Twins • Born 1880-1958: N=12,941p Ncancer=1584 • Central Population Register/ Finnish Cancer Registry

  3. Types of cancer and concordance by sex/zygosity in 44,788 pairs of twins from Sweden, Denmark and FinlandLichtenstein et al. 2000 NEJM 343:78-85

  4. Genetic Epidemiology of Cancers Lichtenstein et al. 2000 NEJM 343:78-85

  5. Genetic Epidemiology of CancersLichtenstein et al. 2000 NEJM 343:78-85

  6. Correlations Mammography densityBoyd et al. 2002 NEJM 347:886-894

  7. Heritability Mammography densityBoyd et al. 2002 NEJM 347:886-894

  8. Familial Risk for CancerSwedish Family-Cancer Database

  9. Standardized incidence ratioHemminki et al. 2001 Br J Cancer 84:388-391

  10. Population Attributable FractionHemminki & Czene 2002 CEBP 11:1638-1644

  11. Risk Factors for Cancer • Obesity • Exercise / Physical Activity • Smoking • Alcohol / Drug Use

  12. Obesity

  13. Cancer Mortality due to BMI -menCalle et al. 2003 NEJM 348:1625-1638

  14. Cancer Mortality due to BMI -womenCalle et al. 2003 NEJM 348:1625-1638

  15. Population Attributable FractionCalle et al. 2003 NEJM 348:1625-1638

  16. Cancer-attributable deaths EUBanegas et al. 2003 Eur J Clin Nutr 57:201-208

  17. All-cause deaths to excess weightBanegas et al. 2003 Eur J Clin Nutr 57:201-208

  18. Reviews on Genetics of Obesity • Price, 1987; Bouchard & Pérusse, 1988; Stunkard, 1991; Meyer and Stunkard, 1993; Sorensen and Stunkard, 1994; Meyer and Stunkard, 1994; Bouchard and Pérusse, 1994; Sorensen, 1995, Meyer, 1995; Maes et al. 1997; …. • focus:particular type of study: adoption, twin or family • main conclusion:genetic factors play a significant role in variation of body fatness • debate: how much is explained by genetic factors? • heritability: h2 • twin (.50-.90) > • family (.20-.80) > • adoption (.20-.60) studies • measure: body mass index (BMI) weight (kg)/height2 (m)

  19. Twin correlations for BMI

  20. Sibling & PO correlations for BMI

  21. Non-biological correlations BMI

  22. Correlations between RelativesMaes et al. 1997 Behav Genet 27:325-351 • Weighted mean correlation pooled across studies: • .74 MZ twins .32 DZ twins • .24 siblings .19 parents and offspring (PO) • .12 spouses .06 adoptive relatives • Expectations based on correlations: • 1-rMZ: specific environmental factors • rMZ > rDZ: additive genetic factors • rDZ > 1/2rMZ: shared environmental factors • rDZ < 1/2rMZ: dominance genetic factors • rDZ > rSib: twin effects • rSib > rPO: age x gene interaction, dominance • rPO > rSib: cultural transmission • rSpouse > 0: assortment • rAdoptSib/PO > 0: shared environmental factors

  23. Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  24. Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  25. Longitudinal Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  26. Family & Adoption Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

  27. Integrated Approach • all collateral two-generational relationships identified in kinships of twins (first and second degree relatives) • > estimate sex-dependent contributions of genes and environment to complex traits in presence of assortative mating • > resolve genetic and cultural transmission, and both special MZ and special DZ twin environment effects • Stealth Eaves, 1999; ET-model Maes, 2006

  28. Virginia 30,000 • Structure of the Virginia 30,000 Sample • pedigrees: twins + parents, siblings, spouses, children • > 80 sex-specific two-generation relationships • Ascertainment of the Virginia 30,000 Sample • questionnaires on 14,763 twins, ascertained from 2 sources: • N=5287 families <Virginia Twin Registry • N=9476 twins <American Association of Retired Persons • BMI • log transformed, corrected for the linear and quadratic effects of age, sex, twin status, source of ascertainment (Virginia vs. AARP), and interactions between these terms

  29. ET Model Results • proportions of variance for most parsimonious model • additive genes: 35% males 39% females • genetic effects of assortative mating: 2% • dominance: 31% males 26% females > broad heritabilities of .66 males .65 females • special twin environment: 7-8% • unique environmental: remaining 27% • special MZ twin environment, non-scalar sex limitation, cultural transmission, non-parental shared environment not significant • confidence intervals: quite narrow < large sample sizes • < relative simplicity of model which accounts for covariation in 88 different familial relationships with only 10 parameters

  30. Summary • convergent results for wide variety of relationship • studies with smaller sample sizes: greater variability in estimates of correlation between relatives • > substantial role for genetic factors in the etiology of individual differences in BMI • why higher heritability estimates in twin vs family studies: • separate special twin environment for MZs &DZs • significance of dominance variance • twins controlled for age effects • maternal effect (intrauterine effects on growth of fetus with lasting differences) • special MZ twin environment • epistatic effects from interaction of genes at two or more loci

  31. GenomeEUtwin ProjectSchousbou et al. 2003 Twin Res 6:409-421

  32. Genetic Epidemiology of BMISchousbou et al. 2003 Twin Res 6:409-421

  33. Human Obesity Gene MapPerusse et al. 2004 Obes Res 13:381-490

  34. Heritability of change in weight/fatBouchard & Tremblay 1997 J Nutr 127:943S-947S

  35. Heritability of fat mass and BMIFaith et al. 1999 Pediatrics 104:61-67

  36. Heritability of eating patternsvan den Bree et al. 1999, Am J Clin Nutr 70:456-465

  37. Heritability of food intakeHeitmann et al. 1999 Am J Clin Nutr 69:597-602

More Related