Genetic-Environmental Interaction: Implications for Osteoporosis Prevention Strategies

1. Genetic-Environmental Interaction:Implications for Osteoporosis Prevention Strategies

2. How many Australians have osteoporosis? Current Increased BMD by 10% x1000 x1000

3. Annual incidence of fractures in Australia? All fractures Hip fractures x1000 x1000 Year Year

4. Can we predict, reduce, prevent, eliminate osteoporosis and fractures?

5. Aetiology • Mendelian • Chromosomal aetiology • Multifactorial aetiology with high heritability • Multifactorial aetiology with low heritability • Infectious aetiology • Environmental aetiology

6. Determinants of BMD Genetics Environment Lumbar spine 0.778 0.222 Femoral neck 0.764 0.236 Total body 0.786 0.214

7. Can we use environmental factors to predict fracture? Can we use genetic factors to predict fracture?

8. Criteria • Validity and available of tests • Public health impact • Magnitude of association between risk factor and fracture • Interaction between known environmental factors and genes • Availability of safe and efficacious treatment • Confidentiality, ethics

9. Risk Factors for Hip Fx in Females Risk factor Relative Risk Prevalence AR Osteoporosis 1 (Y/N) 7.9 (3.9 - 16.1) 0.26 0.65 Body sway (75th pct) 3.6 (1.8 - 7.0) 0.25 0.48 Previous falls (Y/N) 3.5 (1.8 - 6.9) 0.31 0.44 Any of the three factors 22.9 (3.1 - 34.7) 0.60 0.93 1: Defined by FNBMD

10. Distribution of BMD & incidence of fractures

11. Familial Relative Risk of Fracture Intraclass correlation RR of BMD r=0.8 r=0.9 _________________________________________________ 5 1.14 1.16 6 1.17 1.20 7 1.21 1.24 8 1.24 1.28 _________________________________________________

12. Strategies for Prevention of Osteoporosis • Population-based strategy • High risk strategy • Genetic-environmental based strategy ?

13. Some Epidemiological Concepts Population Attributable Risk (PAF) • proportion by which the incidence rate of disease in the population would be reduced if the risk factors were eliminated Positive Predictive Value (PPV) • Risk of disease among individuals with the presence of a risk factor

14. General Formulation of a Screening Model Parameters • Lifetime risk of fracture (d) • Prevalence of risk factor (e) • Relative risk of risk factor (R) Sensitivity, Specificity and PPV Sensitivity = R / [(1 + e(R-1)] Specificity = [(1-e)/(1-d)] [1 - Rd/(1 + e(R-1))] PPV = Rd / (1 + e(R-1))

15. Effectiveness Strategy Fx Reduction Sens Spec PPV _______________________________________________________________ Population-based 1 20% 0.625 0.467 0.714 High risk 2 9% 0.952 0.275 0.476 _______________________________________________________________ Assumptions: Lifetime risk = 0.4; RR = 5 1 Shift the whole distribution by 10% increase 2 Selecting only osteoporotic subjects and increase BMD by 10%

16. What about an genetic-environmental approach ?

17. What is Gene-Environment Interaction? • Effects of high risk genotypes vary depending on environmental exposure or restricted to exposed subjects • Effects of environmental risk factor vary depending on susceptible genotypes

18. . . . more emphasis has been placed on the concept of "effect" rather than on "interaction". There is no reason to believe that VDR gene would act in isolation from other genetic and environmental factors

19. Some Misunderstanding A single, simple observation of differential effect between genotypes of a genetic marker across different environmental milieu is not sufficient evidence for genetic-environmental interaction A statistical interaction is not necessary the same with a GxE interaction

20. Detection of GxE Interaction? • Twin modelling • Regression analysis • Sibling interaction analysis

21. Heritability of Bone Density Age rMZ rDZ H2 LSBMD Slemenda et al 44 0.85 0.330.97 Pocock et al 47 0.92 0.36 0.92 Nguyen et al 50 0.74 0.43 0.78 Spector et al 60 0.68 0.29 0.78 Flicker et al 69 0.70 0.33 0.74

22. Formulation of G x E Models: Parameters • Lifetime risk of fracture (d) • Prevalence of risk factor (e) • Relative risk of risk factor (R) • Prevalence of genotype (g) Formulation Genotype Risk Prevalence RR Absence Absence (1-g)(1-e) 1 Absence Presence (1-g)e Re Presence Absence (1-e)g Rg Presence Presence ge Rge

23. Models of Interaction • Model I: Re = Rg = 1 • Model II: Re > 1, Rg = 1 • Model III: Rg > 1, Re = 1 • Model IV: Re > 1, Rg > 1

24. Effects of GxE on PPV and PAF g No GxE Model 1 Model 2 Model 3 Multiplicative _____________________________________________________________________________________ 0.1 0.22 1.00 (0.23) 0.75 (0.12) 0.56 (0.15) 0.82 (0.14) 0.15 0.23 0.89 (0.23) 0.56 (0.12) 0.27 (0.09) 0.72 (0.18) 0.20 0.23 0.69 (0.23) 0.46 (0.12) 0.15 (0.04) 0.64 (0.21) 0.30 0.23 0.50 (0.23) 0.37 (0.13) 0.06 (0.02) 0.52 (0.23) 0.40 0.23 0.40 (0.23) 0.32 (0.13) 0.03 (0.01) 0.44 (0.25) d=0.15, R = 2, e = 0.30

25. Summary • For a RR=2 or 3, low PPV and PAF • Introduction of GxE increases PPV, but decreases PAF • High prevalence of susceptible genotype increases PAF, but decreases PPV

26. Future Directions • Description of osteoporosis/fx in population:gene frequencies, prevalence of risk factors • Determinants of osteo/fx in population: risk factors, genetic markers, population genetics. • Determination of osteo/fx in families: familial aggregation, heritability studies, segregation studies • Gene environmental studies

27. Future Directions • Natural history of osteporosis • Intervention: clinical trials, genetic differences in response to treatments • Prevention: screening, counselling, carrier detection • Impact of osteoporosis: mortality, morbidity, QoL