genetic-environmental interaction: implications for osteoporosis prevention strategies
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Genetic-Environmental Interaction: Implications for Osteoporosis Prevention Strategies. How many Australians have osteoporosis?. Current. Increased BMD by 10%. x1000. x1000. Annual incidence of fractures in Australia?. All fractures. Hip fractures. x1000. x1000. Year. Year. Can we - PowerPoint PPT PresentationTRANSCRIPT
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