The Independent and Joint Effects of the Genotypes of FOXO1A and FOXO3A on Long-term Survival From Middle Age to Age 100+

TheanalysesconcerningFOXO1ApresentedinTable1 of the present study employing Formula (1) of the FAD methodandinpreviousrelevantstudiesfollowingthecon- ventionalgeneticandstatisticalapproach(6)arebasedon comparingthefrequenciesofcarryingtheminoralleleof theSNPsofFOXO1A(regardlessofwhethercarryingthe minoralleleoftheSNPsofFOXO3A)betweencentenari- ansandyoungercontrols.Soaretheanalysesconcerning FOXO3ApresentedinTable1andinthepreviousstudies (2–7).Althoughtheyareusefulinexploringthegeneralim- pactsofonegenotypeonlongevityregardlessofcarryingor not-carrying the other relevant genotype, these analyses cannotrevealtheindependent,joint,andinteractiveeffects ofthegenotypesofFOXO3AandFOXO1A,whichinflu- encesurvivalinoppositedirections.

In men, the patterns of the independent effects FOXO1A and FOXO3A are substantially different thoseofwomen.Ascomparedwithmenwhoarenoncarri- FOXO1Ainmenareallnonsignificant(seethepanelsfor theminoralleleofoneofthetwoSNPsofFOXO1Aand FOXO3Aareallhighlysignificant(p = thegeneraleffects.

ApplyingourextendedFADmethodexpressedinFor- survival(RS ij/00 allelesofoneofthethreeSNPsofFOXO3A,withtherefer- the independent effects (RS  and RS ), joint 10/00 01/00 (RS 11/00 withinthethreeSNPsofFOXO3Ageneandthecombina-

Dual presence of the minor allele of one of the three SNPsofFOXO3Aandtheminoralleleofoneofthetwo SNPsofFOXO1Amayincreasethechanceofsurvivalfrom middleagetoage100+by12%–19% inwomenandby 14%–30% in men, as compared with those who neither carrytheminoralleleofthecorrespondingSNPofFOXO3A nor carry the minor allele of the corresponding SNP of FOXO1A,butalloftheestimatesassociatedwiththedual

statisticallysignificant(seetheitalicandboldvaluesinTa- ofFOXO3AandthenegativeeffectsofFOXO1Asubstan- tially compensate each other, whereas the impacts FOXO3Aaresomewhatstronger.

from.618to.643).Toavoidtheproblemsofmulticollinearity, weshouldnotincludemorethanoneSNPofFOXO1Aand morethanoneSNPofFOXO3Aineachregressionmodel. Instead,inModelsI,II,III,andIV,whichdonotinclude anyG×GandG×Einteractions,weincludeoneofthetwo SNPsofFOXO1AoroneofthethreeSNPsofFOXO3Aone byone.Inotherwords,eachofthesefourmodelshasfive submodels and each submodel includes one SNP only. ModelsI,II,III,andIValsosequentiallyintroducethepo- tentially confounding variables step by step. Model I in- cludes demographic and basic socioeconomic status: gender,singleyearofage,residence(urbanvsrural),edu- cationalattainmentandeconomicindependence.ModelII furtherincludesfamilyandsocialsupportvariables(suchas marital status, living arrangement, proximity to children, whetherhadfamilymembersascaregiver,andleisureac- tivitiesscore)andtheresiliencescore.ModelIIIaddshealth practice including regular exercise, smoking in recent 5 years,andheavyalcoholuse.ModelIVfurtherincludesthe deficitsindex(DI),asummaryindicatorofcumulativedefi- citsofdifferenthealthdimensionsofdailyactivities,physi- calperformance,cognitivefunction,depressivesymptoms, self-ratedhealth,chronicdisease,etc.,atoldages(seeAp- pendix3).ModelsV,VI,andVIIincludetheG×Ginterac- tions between 1A-209 and one of the three SNPs of FOXO3A,andModelsVIII,IX,andXincludetheG×G interactionsbetween1A-213andoneofthethreeSNPsof FOXO3A.ModelsV,VI,VII,VIII,IX,andXalsoinclude allpossibleG×EinteractionstermsamongtheSNPsand the social and behavior confounders in the Cox hazards models;weonlypresentthesignificantG×Eestimatesin Table4.

The Effects of Interaction Between FOXO1A and FOXO3A on Survival From Middle Age to Age 100+

Theabsolutevaluesofthecorrelationcoefficientsbe- <.01 and another half .01–.05). Moreover, FOXO1A on chromosome 13, FOXO3A on chromosome 6), theyarephysicallyindependentintermsoflinkagedis- equilibrium. Consequently, the assumption of indepen- CI are estimated by the bootstrap simulation the FOXO3A are not statistically significant (data shown).

The Effects of SNPs of FOXO1A and FOXO3A and Their G × G and G × E Interactions on Survival at Very Advanced Ages, Based on Longitudinal Cohort Data From the Long-Lived Cases

Four interesting findings appeared from the survivalfrommiddleagetoage100+discoveredinourcase previous studies (2–7) remain statistically significant veryadvancedages92–110.Asshownbytheestimatesof onlyveryslightlychangedtheestimatesofpreviouslyin- andtheconfounders.AftertheDIisaddedto likelihoodatveryadvancedages,werenolongersignifi- throughaffectinghealthstatus.However,thepositiveef-

discussedinprevious subsectionsareallbasedoncross- sectionaldatafromlong-livedcasesandmiddle-agedcon- trols and the FAD approach. In this subsection, we presentthemultivariatesurvivalanalysisbasedonlongitu- 92–110, adjusted for 15 potentially confounding andhowweestimatedthese15potentiallyconfoundingfac- FOXO3Agenesarenotcorrelatedwitheachother.How- each other (with correlation coefficients ranging

Table4. Relativehazardsofthegenotypes,theG×G(gene–gene),andthesignificantG×E(gene–environment)interactionsonsurvival likelihoodatveryadvancedages