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



Twenty-five-year population-based cohort study.



Kungsholmen cohort, Stockholm, Sweden.



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



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.



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.



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.
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Debora
D
Rizzuto
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.|Alzheimer Disease Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Lina
L
Keller
Unit of Nutritional Epidemiology and Unit of Biostatistics, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Nicola
N
Orsini
Alzheimer Disease Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.|Department of Geriatric Medicine Karolinska, Karolinska University Hospital, Stockholm, Sweden.
Caroline
C
Graff
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.|Stockholm Gerontology Research Center, Stockholm, Sweden.
Lars
L
Bäckman
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.
Rino
R
Bellocco
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Hui-Xin
HX
Wang
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.|Department of Geriatric Medicine Karolinska, Karolinska University Hospital, Stockholm, Sweden.|Stockholm Gerontology Research Center, Stockholm, Sweden.
Laura
L
Fratiglioni
D000368:Aged; D000483:Alleles; D053302:Apolipoprotein C-I / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D005260:Female; D006801:Humans; D007339:Insulysin / Q000235:genetics; D008019:Life Style; D008136:Longevity / Q000235:genetics*; D008297:Male; D012307:Risk Factors; D012309:Risk-Taking; D013548:Sweden
C505803:APOC1 protein, human; C000612345:ApoE protein, human; D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; D058544:Class Ib Phosphatidylinositol 3-Kinase; D007339:Insulysin
genes; lifestyle behaviors; mortality; population-based cohort study; survival