Methodological problems in genetic association studies of longevity--the apolipoprotein E gene as an example.

BACKGROUND

Cross-sectional genetic association studies are now widely employed to look for genes which confer longevity. Such studies are based on two assumptions; (a) initial relative allele frequencies in the different age cohorts are similar, and (b) the risk of mortality conferred by genotypes does not depend on year of birth.

METHODS

We explored the validity of these assumptions and reviewed 15 cross-sectional studies of common apolipoprotein E (APOE) polymorphisms and longevity.

RESULTS

Higher relative epsilon2 frequencies, and lower relative epsilon4 allele frequencies were observed in elderly versus younger populations. If assumptions (a) and (b) were correct the estimates for epsilon2 and epsilon4 alleles respectively versus epsilon3 alleles would be 1.34 (95% CI: 1.19, 1.35) and 0.54 (95% CI: 0.46, 0.63) in elderly versus younger individuals. However, there was an association between relative epsilon4 allele frequency in controls and APOE epsilon4 effect (beta = -0.45, 95% CI: -0.89, 0.00). In relation to assumption (a) there is substantial variation in relative APOE allele frequencies (4-21%), with considerable heterogeneity evident within geographically proximate populations, population admixture is likely to have resulted in changes in allele frequency over time, and assumption (b) APOE related causes of death are context specific and have changed considerably over the last 30 years.

CONCLUSION

The validity of case-control type studies of the genetic basis of longevity based on the above assumptions is questionable, especially when considerable differences exist in allele frequency by population and when the genes in question interact with environmental factors, which vary by time and place.