Fictional Scenario To Test Your Knowledge of
Gene-Environment Interaction: Rheumatoid Arthritis,
Herbal Supplements and Fictitious Rheumatoid Arthritis Gene

Answers and Bibliography

Question 1

Based on this study, what is the magnitude of the overall association between C677T and rheumatoid arthritis? between ImmuneBlast and rheumatoid arthritis? Show calculations in terms of relative risks and population attributable fractions.

Answer 1

Construct Two by Two tables for genotype and exposure as follows

Odds Ratio (OR) = 6 (estimates relative risk)
Population Attributable Fraction = (Miettinen formula)=(Frequency of gene variant among cases) * ([OR-1]/OR)=0.8 * 5/6 = 0.66

Odds Ratio= 4
Population Attributable Fraction 0.8 * ¾=0.60

Question 2

Is there evidence of gene-environment interaction in this case-control study? Compute the effects of the exposure alone, the genotype alone and the combination.  Show calculations in terms of relative risks and population attributable fractions.

Answer 2

Construct a Two by Four table as follows:

Based on the above data. It looks like the combined effect of the genotype and exposure is more than multiplicative (10.5 > 1.0 + 1.5 –1), strongly suggesting evidence of gene-environment interaction. Furthermore, it does look like the genotype alone or the exposure alone don't really increase the risk significantly and that most if not all their main effects are due to their interaction (type I interaction). IN fact, it looks like the combination of gene variant and the exposure may account for about 63% cases in this population.

Question 3

Discuss the etiologic inference of the authors in terms of causal criteria including comment on study design and analysis.

Answer 3

The following findings enhance biological plausibility for causal association

• Strong relative risks and also high attributable fraction
• Biologic plausibility (yes, strong because of the biology and finding interactions)
• Needs replication in other studies (especially population-based)

Study design: Cases highly selected may not reflect general population of cases and controls may not be comparable to cases (possible selection bias).  Because of frequency-matching, we may also need matched analysis (not done here).  No adjustment for potential confounding variables (diet, lifestyle, etc.)

Question 4

If the authors did not have a control group, what kind of inference on gene-environment interaction could they obtain from a case only analysis? Is this a valid result? Discuss pros and cons of this approach compared to a standard case-control analysis.

Answer 4

Case-only analysis

• This is an index of interaction on a multiplicative scale and suggests that the combined effects of exposure and genotype is more than multiplicative.
• This is a valid result only if we assume independence between genotype and exposure in the population. We can test this by repeating same analysis among controls.

Control-only analysis

This indicates that there is no association between exposure and genotype in the general population which make results of case-only analysis valid.

Case only analysis: 
Pros: quick and efficient, improves statistical power
Cons:
- needs independence assumption and cannot estimate separate effects of exposures and genotype, only the existence of their interaction.
- Also can only test for interaction on a multiplicative scale
- Good screening tool

Question 5

Can you comment on the recommendations of the authors to test the general population for the RA gene before taking ImmuneBlast?

Answer 5

Obviously before issuing such recommendations, these data need to be validated in other well designed population-based studies.

Even then, the bottom line will be: should we test people before taking ImmuneBlast or ask everyone not to take ImmuneBlast regardless of their genotype? Either way, we can prevent ImmuneBlast associated RA in the population. It looks like 40% of the population (controls) have the susceptible genotype to this exposure. Given that herbal preparation are over the counter food additives, their safety and effectiveness have not gone through the usual rigorous studies required by the Food and Drug Administration (FDA). One may not favor a genotypic-based intervention but across the board caution (if not banning) of ImmuneBlast by the FDA. Obviously, more studies are needed before such a policy is arrived at.