GeneEnvironment Interactions

1
Gene-Environment Interactions

• International Society for Nurses in Genetics
• May 2007
• Jan Dorman, PhD
• University of Pittsburgh
• Pittsburgh, PA, USA

2
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

3
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

4
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

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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

6
Incidence of MS per 100,000 / yr Among Immigrants
to Israel
Gordis, 1996
7
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

8
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

9
Gene-Environment Interactions
10
Gene-Environment Interactions
Odds Ratio (OR) ah / bg ch / dg eh /
fg 1
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Example of Additive Effects

• SE 21 7
• SE- 15 5
• S-E 9 3
• S-E- 3 1

Absolute
Odds
Strata
Risk
Ratio
Difference
6
6
12
Example of Additive Effects

• OR Interaction ORSE - (ORSE- 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

13
Example of Multiplicative Effects

• SE 45 15
• SE- 15 5
• S-E 9 3
• S-E- 3 1

Absolute
Odds
Strata
Risk
Difference
Ratio
3
3
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Example of Multiplicative Effects

• OR Interaction ORSE / ORSE- 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

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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

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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

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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 3441453-1547

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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

19
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

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Factor V Leiden Mutations

• R506Q mutation amino acid substitution
• Geographic variation in mutation prevalence
• Frequency of the mutation in Caucasians is2 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

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OCP, Factor V Leiden Mutations and Venous
Thrombosis

• 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?

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OCP, Factor V Leiden Mutations and Venous
Thrombosis
OR (95 CI) 34.7 (7.8, 310.0) 6.9 (1,8,
31.8) 3.7 (1.2, 6.3) Reference
Total 155 169
Lancet 19943441453
23
Additive Effect?
Strata OR SE 34.7 SE- 6.9
S-E 3.7 S-E- Ref
OR Interaction
34.7 (6.9 3.7 - 1) 25.1
24
Multiplicative Effect?
Strata OR SE 34.7 SE- 6.9
S-E 3.7 S-E- Ref
OR Interaction
34.7 / 6.9 x 3.7 1.4
25
Prevalence of Mutation in Controls
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
26
Absolute Risk (Incidence) of VT
From formula presented in last lecture, R
2/10.000/yr
27
Risk of VT per 10,000/year
Bar represents background risk
28
Attributable Risk (AR) and Attributable Fraction
(AF)
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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

30
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

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Genetic Testing for Factor V Leiden

• ACMG Recommendations
• Age lt50, 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 lt50 yrs
• MI in women who smoke lt50 yrs

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Screening Questions Developed by Nurse
Practitioners

• Why do you want to be on HRT?
• Have you had a blood clot?
• Any family history of blood clots?
• Any family history of stroke?
• Lifestyle with prolonged immobility?
• Breast, ovarian or cervical cancer?
• Cancers in sister, mother, grandmother?
• Any family history of CHD?
• If yes to 2-5, may be candidate for testing

Park et al, 2003
33
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 12335
34
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

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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

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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

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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

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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

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References

• American College of Medical Genetics Consensus
  Statement on Factor V Leiden Mutation Testing.
  Genet Med 2001 3139-148.
• 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.

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References

• Botto LD, Khoury MJ. Commentary facing the
  challenge of gene-environment interaction the 2
  x 4 table. Am J Epidemiol 2001 1531016-1020
• Burton PR, Tobin MD, Hopper JL. Key concepts in
  genetic epidemiology. Lancet 2005 366941-951.

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References

• Clayton D, McKeigue PM. Epidemiological methods
  for studying genes and environmental factors in
  complex diseases. Lancet 2001 3581356-1360.
• 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
  12335-2339.

42
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 15458-466.

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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 3441453-1547.
• Vandenbroucke JP, van der Meer FJM, Helmerhorst
  FM, et al. Factor V Leiden should we screen
  oral contraceptive users and pregnant women? BMJ
  1996 3131127-1130.