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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

Soerensen a,b, Serena Dato a,c, Qihua Tan a,b, Mikael Thinggaard a, Rabea Kleindorp d, Beekman e,f, Rune Jacobsen a, H. Eka D. Suchiman e,f, Anton J.M. de Craen g, Rudi G.J. Schreiber d, Tinna Stevnsner h, Vilhelm A. Bohr h,i, P. Eline Slagboom e,f, Almut Nebel ⁎ W. Vaupel a,j, Kaare Christensen a,b, Matt McGue a,k, Lene Christiansen a,b,

a The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark b Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark c Department of Cell Biology, University of Calabria, Ponte Pietro Bucci cubo 4C, 87036 Rende (Cs), Italy d Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Schittenhelmstrasse 12, 24105 Kiel, Germany e Department of Molecular Epidemiology, Leiden University Medical Center, S5-P, PO Box 9600, 2300 RC Leiden, The Netherlands f Netherlands Consortium for Healthy Aging, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands g Department of Gerontology and Geriatrics, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, The Netherlands h The Danish Aging Research Center, Department of Molecular Biology and Genetics, Aarhus University, C. F. Moellers Allé 3, 8000 Aarhus C, Denmark i Laboratory of Molecular Gerontology, National Institute on Aging, National Institute of Health, 5600 Nathan Shock Drive, 21224-6825 Baltimore, Maryland, USA j Max Planck Institute for Demographic Research, Konrad-Zuse-Str. 1, 18057 Rostock, Germany k



Here we explore association with human longevity of common genetic variation in three major pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by ing 1273 tagging SNPs in 148 genes composing these pathways. rs9456497 (IGF2R)) and 5 DNA repair SNPs (rs11571461 (RAD52), rs13251813 (WRN), rs1805329 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 SNPs (rs10047589 (TNXRD1), rs207444 (XDH)), 1 GH/IGF-1/INS SNP (rs26802 (GHRL)) and 3 DNA repair (rs13320360 (MLH1), rs2509049 (H2AFX) and rs705649 (XRCC5)) to be associated with mortality in late after correction for multiple testing. When examining the 11 SNPs from the case–control study in the longitudinal data, rs3842755 (INS), (WRN) and rs3211994 (NTHL1) demonstrated the same directions of effect (pb0.05), while rs9456497 rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study 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 old (age 95–110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive significant tendency (OR=1.162, 95% CI=0.927–1.457). The same was true for rs10047589 cohort of oldest-old (age 85+, N=563). Inconclusion,thepresentcandidategenebasedassociationstudy,thelargesttodateapplyinga not only points topotentialnewlongevity loci, but alsounderlines thedifficulties ofreplicating in independent study populations and thus the difficulties in identifying universal longevity polymorphisms.

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

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 (pb0.05), while rs9456497 (IGF2R) andrs1157146(RAD52)showednon-significanttendencies,indicativeofeffectsalsoinlatelifesurvival.Inaddition, rs207444 (XDH) presented the same direction of effect when inspecting the 6 SNPs from the longitudinal study in

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)whenexaminingthe6SNPsfromthelongitudinalstudyinaDutchlongitudinal cohort of oldest-old (age 85+, N=563).

Inconclusion,thepresentcandidategenebasedassociationstudy,thelargesttodateapplyinga pathwayapproach, not only points topotentialnewlongevity loci, but alsounderlines thedifficulties ofreplicating associationfindings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms. © 2012 Elsevier Inc. All rights reserved.

1. Introduction

⁎ Corresponding author at: Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense C, Denmark. Tel.: +45 65503378; fax: +45 65503682.

Genetic factors contribute approximately 25% to variation in human life span (Herskind et al., 1996), an effect thought to be

0531-5565/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2012.02.010