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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.

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Date
2012-05
Authors
Soerensen, Mette
Dato, Serena
Tan, Qihua
Thinggaard, Mikael
Kleindorp, Rabea
Beekman, Marian
Jacobsen, Rune
Suchiman, H Eka D
de Craen, Anton JM
Westendorp, Rudi GJ
Schreiber, Stefan
Stevnsner, Tinna
Bohr, Vilhelm A
Slagboom, P Eline
Nebel, Almut
Vaupel, James W
Christensen, Kaare
McGue, Matt
Christiansen, Lene
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(19 total)
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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 article
Subject
Aged
Aged, 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
Permalink
https://hdl.handle.net/10161/14774
Published Version (Please cite this version)
10.1016/j.exger.2012.02.010
Publication 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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Scholars@Duke

Vaupel

James Walton Vaupel

Research Professor Emeritus in the Sanford School of Public Policy
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
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