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.

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

England

2017-06-02T19:01:49Z

2017-06-02T19:01:49Z

2012-05

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.

https://www.ncbi.nlm.nih.gov/pubmed/22406557

S0531-5565(12)00041-1

1873-6815

https://hdl.handle.net/10161/14774

eng

Elsevier BV

Exp Gerontol

10.1016/j.exger.2012.02.010

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

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.

Journal article

https://www.ncbi.nlm.nih.gov/pubmed/22406557

379

387

5

Center for Population Health & Aging

Duke

Duke Population Research Institute

Sanford School of Public Policy

Published

47