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.
Type
Journal articleSubject
AgedAged, 80 and over
Antioxidants
Case-Control Studies
DNA Damage
DNA Repair
Female
Human Growth Hormone
Humans
Insulin
Insulin-Like Growth Factor I
Longevity
Longitudinal Studies
Male
Middle Aged
Oxidation-Reduction
Polymorphism, Single Nucleotide
Signal Transduction
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https://hdl.handle.net/10161/14774Published Version (Please cite this version)
10.1016/j.exger.2012.02.010Publication Info
Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea;
Beekman, Marian; ... Christiansen, Lene (2012). 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.
Exp Gerontol, 47(5). pp. 379-387. 10.1016/j.exger.2012.02.010. Retrieved from https://hdl.handle.net/10161/14774.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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James Walton Vaupel
Research Professor Emeritus in the Sanford School of Public Policy
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