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.

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