The combination of the ACE DD genotype and at least one PAI-1 4G allele was initially associated with an increased risk of myocardial infarction (OR 1.50), but this interaction failed internal and external validation.
Case-Control (n=686)
Do interactions among ACE, PAI-1, and t-PA gene polymorphisms increase the risk of myocardial infarction in U.S. male physicians?
Significant gene-gene interactions detected by data-driven methods require rigorous internal and external validation to avoid reporting type 1 errors.
Odds Ratio: 1.5 (95% CI 1.04–2.17)
p-value: p=0.02
BACKGROUND: To examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation. RESULTS: The overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance. CONCLUSIONS: The significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings.
Coffey et al. (Fri,) conducted a case-control in Myocardial infarction (n=686). ACE I/D and PAI-1 4G/5G gene polymorphisms interaction vs. Other genotype combinations was evaluated on Risk of myocardial infarction for ACE DD genotype vs ACE DI/II among those with at least one PAI-1 4G allele (OR 1.50, 95% CI 1.04-2.17, p=0.02). The combination of the ACE DD genotype and at least one PAI-1 4G allele was initially associated with an increased risk of myocardial infarction (OR 1.50), but this interaction failed internal and external validation.