Gene by environment interaction in human longevity as observed in Danish birth cohorts from 1905 to 1915

The frequencies of variants of major candidate genes (APOE and FOXO3A) have been shown to vary in long-lived individuals of different Danish birth cohorts, e.g. with significantly decreased frequencies in the recent birth cohorts for the e4e4 genotype and also for the minor allele of rs7762395 of FOXO3A gene. We collected genotype and survival information on two birth cohorts, 1905 (1424 subjects) and 1915 (1105 subjects), aged over 95 years at intake. Since genotype frequency in a population cannot be expected to change over a very short period of 10 years (1905 to 1915), we assume that the reported change in genotype frequencies could reflect cohort-specific genetic risk on mortality resulted from gene-environment interaction. Based on the same observations and recently updated mortality information in the two birth cohorts, we conduct a survival analysis introducing cohort- and sex-specific population survivals from population statistics and specifying and estimating genotype-specific relative risks in cohort 1905 and change in relative risk from 1905 to 1915, with consideration of unobserved frailty. We estimated a trend of risk reduction for APOE4 allele carriers (-0.119, 95% CI: -0.355 to 0.119) while the risk for APOE2 allele carriers remained constant (-0.007, 95% CI: -0.200 to 0.206), in nonagenarians and centenarians. The risk of death for carriying the rs479744 minor allele of FAXO3A showed a trend of increase (0.106, 95% CI: -0.049 to 0.292) while that for rs7762395 was unchanged (-0.038, 95% CI: -0.204 to 0.156). Our novel analysis provided evidence to the varying risks of major candidate genes on mortality at advanced ages due to interaction with the changing environment.