title: 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.
abstract: 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.
authors.affiliation: The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, JB Winsloews Vej 9B, 5000 Odense C, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.forename: Serena
authors.initials: S
authors.lastname: Dato
authors.forename: Qihua
authors.initials: Q
authors.lastname: Tan
authors.forename: Mikael
authors.initials: M
authors.lastname: Thinggaard
authors.forename: Rabea
authors.initials: R
authors.lastname: Kleindorp
authors.forename: Marian
authors.initials: M
authors.lastname: Beekman
authors.forename: Rune
authors.initials: R
authors.lastname: Jacobsen
authors.forename: H Eka D
authors.initials: HE
authors.lastname: Suchiman
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.forename: James W
authors.initials: JW
authors.lastname: Vaupel
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000378:metabolism; D016022:Case-Control Studies; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D000975:Antioxidants; D007328:Insulin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I