Effect of the Interplay Between Genetic and Behavioral Risks on Survival After Age 75.

OBJECTIVES

To explore the association between genes that may be related to human mortality, taking into account the possible contribution of morbidity, and investigate whether lifestyle behaviors may attenuate genetic risk.

DESIGN

Twenty-five-year population-based cohort study.

SETTING

Kungsholmen cohort, Stockholm, Sweden.

PARTICIPANTS

Individuals aged 75 and older (N = 1,229).

MEASUREMENTS

The associations between single-nucleotide variations in 14 genes (previously associated with mortality or to diseases linked to mortality), relevant lifestyle risk behaviors (smoking; mental, physical, or social inactivity; moderate or poor social network), and mortality were estimated using Cox regression.

RESULTS

People with allelic variation in four genes related to cardiovascular diseases and metabolism were more likely to die: apolipoprotein (APO)C1 GG and AG carriers, APOE ɛ4 carriers, insulin-degrading enzyme (IDE) TC carriers, and phosphatidylinositol 3-kinase (PI3KCB) GG carriers. Individuals with multiple adverse alleles had 62% higher mortality rate than those with none. In contrast, people with no risk behaviors (low-risk profile) had 65% lower mortality rate than people with all examined risk behaviors (high-risk profile). Combining the genetic and environmental factors, it was found that, independent of genetic profile, individuals with a low-risk profile had up to 64% lower mortality rate than those with a moderate high- or high-risk profile and at least one genetic risk factor.

CONCLUSION

This study supports and expands evidence that genetic variations in APOE, IDE, and PI3KCB are associated with lower mortality rate, although lifestyle behaviors can modulate their effects.