Utility of the predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men aged 65 to 84 years is dependent on context defined by Apo E genotype and area of residence

A common assumption underlying most genetic studies is that individuals wit h different genotypes respond similarly to exposure to internal (epigenetic and background genotype effects) and external (ecological) environments. H ere we evaluate whether this assumption is true in individuals with differe nt genotypes of the gene coding for the apolipoprotein E (Apo E) molecule, an important determinant of the metabolic fate of plasma lipids and lipopro teins. We addressed whether the utility of known risk factors of coronary h eart disease (CHD) in the prediction of CHD death in a 5-year follow-up is the same for the two most common Apo E genotypes, epsilon 3/3 and epsilon 4 /3, in two cohorts of elderly Finnish men (age at baseline: 65-84 years), o ne in Eastern and the other in Southwestern Finland. The CHD mortality rate was higher in the epsilon 4/3 than in the epsilon 3/3 genotype in both coh orts (11.1 versus 7.8%, Pr = 0.281 in the Eastern cohort and 19.6 versus 8. 2%, Pr = 0.002 in the Southwestern cohort). In the Eastern cohort, serum hi gh density lipoprotein (HDL) cholesterol level was identified as a strong p redictor of CHD death in the epsilon 3/3 genotype (beta = - 2.155, Pr = 0.0 19). In the Southwestern cohort, age (beta = 0.139, Pr = 0.006), body mass index (BMI) (beta = 0.149, Pr = 0.016), and serum total cholesterol level ( beta = 0.453, Pr = 0.051) were identified as strong predictors in the epsil on 3/3 genotype, as were smoking (beta = 0.236, Pr = 0.008) and BMI (beta = - 0.124, Pr = 0.057) in the epsilon 4/3 genotype. The latter observation i ndicates that in Southwestern Finland the probability of CHD death decrease s with increasing BMI in elderly men with the epsilon 4/3 genotype, while i n their counterparts with the epsilon 3/3 genotype the risk increases with increasing BMI. This difference was statistically significant (Pr = 0.002). These observations clearly argue against the assumption that individuals w ith different genotype respond similarly to exposures to internal and/or ex ternal environments. These observations are consistent with a complex patho biology of CHD involving biochemical and physiological agents that are unde r the influence of interactions between genetic and environmental factors. Information about these interactions is necessary for developing a more pre cise risk assessment and ultimately to improve public health and clinical s trategies to prevent this devastating disease both at the individual and po pulation levels.