gene-environment interactions international society for nurses in genetics may 2007 jan dorman, phd...
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Gene-Environment Interactions
International Society for Nurses in GeneticsMay 2007Jan Dorman, PhDUniversity of PittsburghPittsburgh, PA, USA
Objectives
Identify gene-environment interactions
Determine if the interaction follows an additive or multiplicative model
Assess the importance of the interaction for clinical practice
Apply ACMG guidelines for genetic testing for Factor V Leiden mutations and follow-up
Evidence of Gene-Environment Interactions
Familial aggregation of disease– Greater prevalence of disease in 1st
degree relatives vs. spouses– Higher disease concordance among
MZ vs. DZ twins– Earlier age at onset among familial
vs. non-familial cases– Stronger phenotypic correlations
between parents and biologic vs. adopted children
Evidence of Gene-Environment Interactions
International studies– Geographic variation in rates of
disease– Temporal trends worldwide– Higher disease incidence among
immigrants vs. source population• Age differences in risk depending on age
at migration
Example: Multiple Sclerosis Incidence is higher in countries far
from the equator
– High risk countries• US, Canada, Northern Europe
– Low risk countries• Southern Europe, SE Asia, Africa
Incidence of MS per 100,000 / yr Among Immigrants to Israel
Age at Source Population Migration European Asian/African
< 15 yrs 0.76 0.65
15-29 yrs 3.54 0.40
30-34 yrs 1.35 0.26
Gordis, 1996
Gene-Environment Interactions Often tested in case control studies
Require careful definitions of– Disorder (phenotype)– Environmental risk factors– High-risk genotypes (genetic susceptibility)
Stratify cases and controls– Susceptible
• With / without exposure– Not susceptible
• With / without exposure
Gene-Environment Interactions Occur when the risk of disease in
exposed and susceptible individuals differs from that expected based on their individual effects– Expected effects can be additive or
multiplicative
Positive interaction – Synergistic
Negative interaction– Antagonistic
Strata Cases(Affected)
Controls(Unaffected)
Susceptible & Exposed (S+E+)
a b
Susceptible & Not Exposed (S+E-)
c d
Not Susceptible & Exposed (S-E+)
e f
Not Susceptible & Not Exposed (S-
E-)
g h
Gene-Environment Interactions
Gene-Environment Interactions
Strata Cases Controls
S+E+ a b
S+E- c d
S-E+ e f
S-E- g h
Odds Ratio (OR)
ah / bg
ch / dg
eh / fg
1
Example of Additive Effects
S+E+ 21 7S+E- 15 5S-E+ 9 3S-E- 3 1
66
66
StrataStrata RiskRisk RatioRatioDifference Difference AbsoluteAbsolute OddsOdds
Example of Additive Effects
OR Interaction = ORS+E+ - (ORS+E- + ORS-E+ - 1)
If OR Interaction = 0, additive effects
Example: OR Interaction =7 – (5 + 3 – 1) OR Interaction = 0
Effects are additive, which is expected
Example of Multiplicative Effects
S+E+ 45 15S+E- 15 5S-E+ 9 3S-E- 3 1
33
33
StrataStrata RiskRisk Difference Difference AbsoluteAbsolute
RatioRatio Odds Odds
Example of Multiplicative Effects
OR Interaction = ORS+E+ / ORS+E- X ORS-E+
If OR Interaction = 1, multiplicative effects
Example: OR Interaction = 15 / 5 x 3 OR Interaction = 1
Effects are multiplicative, which is expected
Advantages of 2 x 4 Table
Data displayed clearly and completely
OR for joint effects are readily generated and directly comparable– Based on same reference group
Can easily evaluate additive or multiplicative effects and identify interactions
Highlights sample size issues
Limitations of 2 x 4 Table
Only 2 risk factors are considered
Are not evaluating dose-response effects in exposure or susceptibility
Can only examine additive or multiplicative effects– Most gene-environment interactions
are more complicated
Evaluating Gene-Environment Interactions – Clinical Example Vandenbroucke JP, Koster T, Briet
E, et al. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344:1453-1547
Venous Thrombosis
Most frequent cardiovascular event in young women
Generally manifests as thrombosis of deep leg veins or pulmonary embolism
Incidence in women age 20-49 yrs is ~ 2 /10,000 persons/yr
Case fatality rate is ~ 1% to 2%
Oral Contraceptive Pills (OCP) and Venous Thrombosis (VT) Association between OCP and VT has
been known since early 1960s
Led to development of OCP with lower estrogen content– Incidence of VT is ~12 to 34 / 10,000 in OCP
users
Risk of VTis highest during the 1st year of exposure
Factor V Leiden Mutations R506Q mutation – amino acid substitution
Geographic variation in mutation prevalence– Frequency of the mutation in Caucasians
is~2% to 10%– Rare in African and Asians
Prevalence among individuals with VT– 14% to 21% have the mutation
Relative risk of VT among carriers– 3- to 7-fold higher than non-carriers
What is risk of venous thrombosis among women who use OCP and carry the mutation?
Is there a gene-environment interaction?
If so, what are the clinical implications?
OCP, Factor V Leiden Mutations and Venous Thrombosis
OCP, Factor V Leiden Mutations and Venous ThrombosisStrata Cases Control
sS+E+ 25 2
S+E- 10 4
S-E+ 84 63
S-E- 36 100
OR (95% CI)
34.7 (7.8, 310.0)
6.9 (1,8, 31.8)
3.7 (1.2, 6.3)
Reference
Total 155 169Lancet 1994;344:1453
Additive Effect?
Strata OR
S+E+ 34.7
S+E- 6.9
S-E+ 3.7
S-E- Ref
OR Interaction =
34.7 – (6.9 + 3.7 - 1) = 25.1
Multiplicative Effect?
OR Interaction =
34.7 / 6.9 x 3.7 = 1.4
Strata OR
S+E+ 34.7
S+E- 6.9
S-E+ 3.7
S-E- Ref
Prevalence of Mutation in Controls
Strata Prevalence
S+E+ 1.2%
S+E- 2.4%
S-E+ 37.3%
S-E- 59.2%
Used incidence of 2.1/10,000/yr to determine the number of person years that would be required for 155 new (incident) cases to develop.
Used prevalence rates of mutation in controls to estimate the distribution of person years for each strata
Absolute Risk (Incidence) of VT
Strata Risk/10,000/ yr
Risk/10,000/ yr*
S+E+ 28.5 27.8
S+E- 5.7 5.2
S-E+ 3.0 3.0
S-E- 0.8 0.8
* From formula presented in last lecture, R= 2/10.000/yr
Risk of VT per 10,000/year
0
5
10
15
20
25
30
S+E+ S+E- S- E+ S- E-
Bar represents background risk
Attributable Risk (AR) and Attributable Fraction (AF)
Strata
AR per 10,000/yr
AF
S+E+ 27.7 97%
S+E- 4.4 86%
S-E+ 2.2 73%
S-E- Baseline Baseline
Genetic Testing for Factor V Leiden Debate about the need to test for
Factor V Leiden mutations before prescribing OCP– Mutation is prevalent (~2% to 10%)– May prevent death in carriers– Testing is readily available
May be appropriate for women with a positive family history– Offer genetic testing prior to
prescribing OCP
Genetic Testing for Factor V Leiden
Arguments against genetic testing– Carriers will not receive OCP– Small number of deaths prevented– Results have implications for relatives– Possible insurance discrimination– Psychological distress/anxiety– False positive/negative results– Requires genetic counseling
Genetic Testing for Factor V Leiden
ACMG Recommendations– Age <50, any VT– VT in unusual sites– Recurrent VT– VT with positive family history– VT in a pregnant woman– VT in a women on OP– Relatives of individuals with VT <50 yrs– MI in women who smoke <50 yrs
Screening Questions Developed by Nurse Practitioners 1. Why do you want to be on HRT?2. Have you had a blood clot?3. Any family history of blood clots?4. Any family history of stroke?5. Lifestyle with prolonged immobility?6. Breast, ovarian or cervical cancer?7. Cancers in sister, mother, grandmother?8. Any family history of CHD?If yes to #2-5, may be candidate for testing
Park et al, 2003
Individuals with Factor V Leiden Mutation
Study of 110 mutation positive individuals identified in a North Carolina, US lab between 9/95 and 10/01
Assessed knowledge; information needs, resources, satisfaction; health perception and anxiety; genetic testing issues– Quantitative and qualitative methods
J Thromb Haemost 2003; 1:2335
Individuals with Factor V Leiden Mutation
Knowledge– 39% did not recall giving consent – 13% did not know that they carried the
mutation (excluded)– 94% knew mutation increased risk for
clots– 30% did not know to exercise/not smoke– 79% overestimated their risk of VT– 50% did not understand its inheritance
Individuals with Factor V Leiden Mutations
Satisfaction– 64% said they received little information– Varied according to seeing a hematologist
• 40% satisfied if with hematologist • 19% satisfied if not with hematologist
– 68% had many more questions– Confidence in providers knowledge
• 65% for males• 33% for females
Individuals with Factor V Leiden Mutations Information Needs
– Most needed more information– 50% used internet as primary source
Health Perception– 28% spent much time trying to
understand health implications– 51% made positive lifestyle changes– 43% reported increased worry– 85% were glad to know carrier status
Implications for Future
Patients interested in genetic testing for any condition need:– More information about genetic and
environmental risk factors– Genetic counseling
• Disclosure• Testing in children• Insurance discrimination• Other risks/benefits• Meaning of test results• Follow-up
Implications for Future
Nurses are key– Genetic epidemiology literature
(estimates of OR and incidence rates) are useful resources for estimating risk associated with genetic and environmental risk factors
References
American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. Genet Med 2001; 3:139-148.
Bank I, Scavenius MPRB, Buller H, et al. Social aspects of genetic testing for factor V leiden mutation in healthy individuals and their importance for daily practice. Thrombosis Research 2004; 113: 7-12.
References
Botto LD, Khoury MJ. Commentary: facing the challenge of gene-environment interaction: the 2 x 4 table. Am J Epidemiol 2001; 153:1016-1020
Burton PR, Tobin MD, Hopper JL. Key concepts in genetic epidemiology. Lancet 2005; 366:941-951.
References
Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 2001; 358:1356-1360.
Gordis L. Epidemiology. WB Saunders Co., Phildelphia, 1996.
Hellmann EA, Leslie ND, Moll S. Knowledge and educational needs of individuals with the factor V Leiden mutation. J Thromb Haemost 2003; 1:2335-2339.
References Horne MK and McCloskey DJ. Factor V
Leiden as a common genetic risk factor for venous thromboembolism. J Nursing Scholarsh 2006; 38: 19-25.
Park BD, Lookinland S, Beckstrand RL, et al. Factor V Leiden and Venous Thromboembolism: risk Associated with Hormone Replacement Therapy. J Am Acad Nurse Pract 2004; 15:458-466.
References
Vandenbroucke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344:1453-1547.
Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, et al. Factor V Leiden: should we screen oral contraceptive users and pregnant women? BMJ 1996; 313:1127-1130.