Genetic-Environmental Interaction:

Implications for Osteoporosis Prevention Strategies

How many Australians have osteoporosis?

0

200

400

600

800

1000

1200

1400

1600

1996 2001 2011 2021 2031 2041

564.5698

889.6

1142.81338.2

86.8101.9

127

214.4

250

512

164.3

Males

Females

0

100

200

300

400

500

600

700

800

900

1996 2001 2011 2021 2031 2041

299372.5

464.8

611.1

733.4

39.546.2

57.4

97.4

113.7

267.7

74.6

Males

Females

Current Increased BMD by 10%

x1000 x1000

Annual incidence of fractures in Australia?

0

50

100

150

200

250

300

350

1996 2001 2011 2021 2031 2041

82.05 91.23114.1

142.17187.28

225.3534.83

41.37

87.46

102.9

52.4

66.28

Males

Females

0

20

40

60

80

100

120

1996 2001 2011 2021 2031 2041

23.72 26.94 33.2 40.5356.24

70.79.32

11.49

18

25.2

30.8

14.46

Males

Females

All fractures Hip fractures

x1000 x1000

Year Year

Can we

predict,

reduce,

prevent,

eliminate

osteoporosis and fractures?

Aetiology

• Mendelian• Chromosomal aetiology• Multifactorial aetiology with high heritability• Multifactorial aetiology with low heritability• Infectious aetiology• Environmental aetiology

Determinants of BMD

Genetics Environment

Lumbar spine 0.778 0.222

Femoral neck 0.764 0.236

Total body 0.786 0.214

Can we use environmental factors to predict fracture?

Can we use genetic factors to predict fracture?

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

Risk Factors for Hip Fx in Females

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

Risk factor Relative Risk Prevalence AR

1: Defined by FNBMD

0

5

10

15

20

25

30

35

<=0.6 .66- .76- .86- .96-

Femoral neck BMD

Percent

0

10

20

30

40

50

60

70

80Incidence of fx per 1000 pyrs

Prevalence

Incidence

Distribution of BMD & incidence of fractures

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_________________________________________________

Strategies for Prevention of Osteoporosis

• Population-based strategy

• High risk strategy

• Genetic-environmental based strategy ?

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

Some Epidemiological Concepts

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 PPVSensitivity = R / [(1 + e(R-1)]

Specificity = [(1-e)/(1-d)] [1 - Rd/(1 + e(R-1))]

PPV = Rd / (1 + e(R-1))

Effectiveness

_______________________________________________________________

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 = 51 Shift the whole distribution by 10% increase2 Selecting only osteoporotic subjects and increase BMD by 10%

Strategy Fx Reduction Sens Spec PPV

What about an genetic-environmental approach ?

• 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

What is Gene-Environment Interaction?

. . . 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

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

Some Misunderstanding

• Twin modelling

• Regression analysis

• Sibling interaction analysis

Detection of GxE Interaction?

Heritability of Bone Density

Age rMZ rDZ H2

LSBMD

Slemenda et al 44 0.85 0.33 0.97Pocock et al 47 0.92 0.36 0.92Nguyen et al 50 0.74 0.43 0.78Spector et al 60 0.68 0.29 0.78Flicker et al 69 0.70 0.33 0.74

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)

FormulationGenotype 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

• Model I: Re = Rg = 1

• Model II: Re > 1, Rg = 1

• Model III: Rg > 1, Re = 1

• Model IV: Re > 1, Rg > 1

Models of Interaction

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

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

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

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