Gene-Environment Interactions

Nazarbayev UniversityJuly 2012

Jan Dorman, PhDUniversity of PittsburghPittsburgh, PA, USAjsd@pitt.edu

Evidence of Gene-Environment Interactions

Familial aggregation of disease– Greater prevalence of disease in 1st

degree relatives vs. general population– Earlier age at onset among familial vs.

non-familial cases– Stronger phenotypic correlations

between parents and biologic vs. adopted children

– Higher disease concordance among MZ vs. DZ twins

Evidence of Gene-Environment Interactions

International studies– Geographic variation in rates of

disease– Temporal trends worldwide– Higher disease incidence among

immigrants vs. source population• 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– Trait (phenotype)– Environmental risk factors (exposure)– High-risk genotypes (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

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 VT is 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 Effects?

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 Effects?

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

Absolute Risk

What is absolute risk for S+E+?– Several ways to estimate– Population incidence = 2/10,000 PY

• 2 cases/10,000 PY = 155 cases / X PY• X ~ 740,000 PY• Distribute across strata

– Absolute risk per strata• # cases / PY

Person Years & Risk per Strata

Strata Number of Cases

Prevalence

Controls

Person Years

Risk/10,000/ yr

S+E+ 25 1.1% 8,800 28.5

S+E- 10 2.4% 17,760 5.7

S-E+ 84 37.3% 276,020 3.0

S-E- 36 59.2% 438,082 0.8

Total 155 100.0% 740,000 2.1

Risk of VT per 10,000/year

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

Genetic Testing for Factor V Leiden

ACMG Recommendations– Age <50, any VT– Recurrent VT– VT with positive family history– VT in a women on OP– Relatives of individuals with VT <50

yrs– MI in women who smoke <50 yrs

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– Mean age 41-60 yrs; 92% Caucasian; 46%

female; 37% had income >$70,000

Assessed knowledge, satisfaction, information needs, resources, & health perception– Quantitative and qualitative methods

J Thromb Haemost 2003; 1:2335

Individuals with Factor V Leiden Mutation

Knowledge– 39% did not recall giving consent – 10% did not know they were tested– 13% did not know that they carried the

mutations– 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 genetic counseling:– Genetic and environmental risk

factors– Disclosure– Meaning of test results– Other risks/benefits– Follow-up

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 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.