Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes: cross sectional and longitudinal studies.

Here we explore association with human longevity of common genetic variation inthree major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genescomposing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP (rs1002149 (GSR)), 5GH/IGF-1/INS SNPs (rs1207362 (KL), rs2267723 (GHRHR), rs3842755 (INS), rs572169(GHSR), rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 (RAD23B), rs2953983 (POLB), rs3211994 (NTLH1)) to be associated with longevity after correction for multiple testing. In a longitudinal studywith 11 years of follow-up on survival in the oldest-old Danes we found 2pro/antioxidant SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP(rs26802 (GHRL)) and 3 DNA repair SNPs (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late life after correctionfor multiple testing. When examining the 11 SNPs from the case-control study inthe longitudinal data, rs3842755 (INS), rs13251813 (WRN) and rs3211994 (NTHL1)demonstrated the same directions of effect (p<0.05), while rs9456497 (IGF2R) and rs1157146 (RAD52) showed non-significant tendencies, indicative of effects alsoin late life survival. In addition, rs207444 (XDH) presented the same directionof effect when inspecting the 6 SNPs from the longitudinal study in thecase-control data, hence, suggesting an effect also in survival from middle ageto old age. No formal replications were observed when investigating the 11 SNPsfrom the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significanttendency (OR=1.162, 95% CI=0.927-1.457). The same was true for rs10047589(TNXRD1) (HR=0.758, 95%CI=0.543-1.058) when examining the 6 SNPs from thelongitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563).In conclusion, the present candidate gene based association study, the largest todate applying a pathway approach, not only points to potential new longevityloci, but also underlines the difficulties of replicating association findings inindependent study populations and thus the difficulties in identifying universal longevity polymorphisms.