Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing 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)), 5 GH/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 study with 11. years of follow-up on survival in the oldest-old Danes we found 2 pro/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 correction for multiple testing.When examining the 11 SNPs from the case-control study in the 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 also in late life survival. In addition, rs207444 (. XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in the case-control data, hence, suggesting an effect also in survival from middle age to old age.No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (. RAD52) did show a supportive non-significant tendency (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 the longitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N. =. 563).In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.
Bibliographical noteFunding Information:
This study was supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R. N (by EU funds from the European Regional Development Fund), the National Institute on Aging ( P01 AG08761 ), a Dutch grant from the Netherlands Consortium for Healthy Aging (Grant 050-060-810 ) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) , the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 , the Novo Nordisk Foundation , the Aase and Ejnar Danielsen Foundation , the Augustinus Foundation , the Brødrene Hartmann Foundation , the King Christian the 10th Foundation and the Einer Willumsens Mindelegat Foundation . The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sørensen and Lene Elnegaard are thanked for excellent technical work.
- Association study
- Candidate study
- Case-control data
- Human longevity
- Longitudinal data