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IJE Advance Access published online on August 19, 2004
International Journal of Epidemiology, doi:10.1093/ije/dyh214
© 2004 by International Epidemiological Association
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Accepted March 30, 2004

Original paper

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

Sarah J. Lewis 1* Eric J. Brunner 1

1 International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, London, UK

* To whom correspondence should be addressed. E-mail: s.j.lewis{at}bristol.ac.uk.


  Abstract

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 {varepsilon}2 frequencies, and lower relative {varepsilon}4 allele frequencies were observed in elderly versus younger populations. If assumptions (a) and (b) were correct the estimates for {varepsilon}2 and {varepsilon}4 alleles respectively versus {varepsilon}3 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 {varepsilon}4 allele frequency in controls and APOE {varepsilon}4 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.

Keywords: Longevity, ageing, genetic association, gene, APOE, methodology.
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