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

Mette Soerensen; Serena Dato; Qihua Tan; Mikael Thinggaard; Rabea Kleindorp; Marian Beekman; Rune Jacobsen; Eka H.D. Suchiman; Anton J.M. de Craen; Rudi G.J. Westendorp; Stefan Schreiber; Tinna Stevnsner; Vilhelm A. Bohr; P. Eline Slagboom; Almut Nebel; James W. Vaupel; Kaare Christensen; Matt McGue; Lene Christiansen

doi:10.1016/j.exger.2012.02.010

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

Mette Soerensen, Serena Dato, Qihua Tan, Mikael Thinggaard, Rabea Kleindorp, Marian Beekman, Rune Jacobsen, Eka H.D. Suchiman, Anton J.M. de Craen, Rudi G.J. Westendorp, Stefan Schreiber, Tinna Stevnsner, Vilhelm A. Bohr, P. Eline Slagboom, Almut Nebel, James W. Vaupel, Kaare Christensen, Matt McGue, Lene Christiansen

Psychology (Twin Cities)

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

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.

Original language	English (US)
Pages (from-to)	379-387
Number of pages	9
Journal	Experimental Gerontology
Volume	47
Issue number	5
DOIs	https://doi.org/10.1016/j.exger.2012.02.010
State	Published - May 2012

Bibliographical note

Funding Information:
This study was supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R. N (by EU funds from the European Regional Development Fund), the National Institute on Aging ( P01 AG08761 ), a Dutch grant from the Netherlands Consortium for Healthy Aging (Grant 050-060-810 ) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) , the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 , the Novo Nordisk Foundation , the Aase and Ejnar Danielsen Foundation , the Augustinus Foundation , the Brødrene Hartmann Foundation , the King Christian the 10th Foundation and the Einer Willumsens Mindelegat Foundation . The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sørensen and Lene Elnegaard are thanked for excellent technical work.

Keywords

Association study
Candidate study
Case-control data
Human longevity
Longitudinal data

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Soerensen, M., Dato, S., Tan, Q., Thinggaard, M., Kleindorp, R., Beekman, M., Jacobsen, R., Suchiman, E. H. D., de Craen, A. J. M., Westendorp, R. G. J., Schreiber, S., Stevnsner, T., Bohr, V. A., Slagboom, P. E., Nebel, A., Vaupel, J. W., Christensen, K., McGue, M., & Christiansen, L. (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. Experimental Gerontology, 47(5), 379-387. https://doi.org/10.1016/j.exger.2012.02.010

Soerensen, M, Dato, S, Tan, Q, Thinggaard, M, Kleindorp, R, Beekman, M, Jacobsen, R, Suchiman, EHD, de Craen, AJM, Westendorp, RGJ, Schreiber, S, Stevnsner, T, Bohr, VA, Slagboom, PE, Nebel, A, Vaupel, JW, Christensen, K, McGue, M & Christiansen, L 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', Experimental Gerontology, vol. 47, no. 5, pp. 379-387. https://doi.org/10.1016/j.exger.2012.02.010

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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.",

keywords = "Association study, Candidate study, Case-control data, Human longevity, Longitudinal data",

author = "Mette Soerensen and Serena Dato and Qihua Tan and Mikael Thinggaard and Rabea Kleindorp and Marian Beekman and Rune Jacobsen and Suchiman, {Eka H.D.} and {de Craen}, {Anton J.M.} and Westendorp, {Rudi G.J.} and Stefan Schreiber and Tinna Stevnsner and Bohr, {Vilhelm A.} and Slagboom, {P. Eline} and Almut Nebel and Vaupel, {James W.} and Kaare Christensen and Matt McGue and Lene Christiansen",

note = "Funding Information: This study was supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R. N (by EU funds from the European Regional Development Fund), the National Institute on Aging ( P01 AG08761 ), a Dutch grant from the Netherlands Consortium for Healthy Aging (Grant 050-060-810 ) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) , the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 , the Novo Nordisk Foundation , the Aase and Ejnar Danielsen Foundation , the Augustinus Foundation , the Br{\o}drene Hartmann Foundation , the King Christian the 10th Foundation and the Einer Willumsens Mindelegat Foundation . The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff S{\o}rensen and Lene Elnegaard are thanked for excellent technical work. ",

year = "2012",

month = may,

doi = "10.1016/j.exger.2012.02.010",

language = "English (US)",

volume = "47",

pages = "379--387",

journal = "Experimental Gerontology",

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TY - JOUR

T1 - Human longevity and variation in GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidant pathway genes

T2 - Cross sectional and longitudinal studies

AU - Soerensen, Mette

AU - Dato, Serena

AU - Tan, Qihua

AU - Thinggaard, Mikael

AU - Kleindorp, Rabea

AU - Beekman, Marian

AU - Jacobsen, Rune

AU - Suchiman, Eka H.D.

AU - de Craen, Anton J.M.

AU - Westendorp, Rudi G.J.

AU - Schreiber, Stefan

AU - Stevnsner, Tinna

AU - Bohr, Vilhelm A.

AU - Slagboom, P. Eline

AU - Nebel, Almut

AU - Vaupel, James W.

AU - Christensen, Kaare

AU - McGue, Matt

AU - Christiansen, Lene

N1 - Funding Information: This study was supported by the Max-Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R. N (by EU funds from the European Regional Development Fund), the National Institute on Aging ( P01 AG08761 ), a Dutch grant from the Netherlands Consortium for Healthy Aging (Grant 050-060-810 ) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) , the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement n° 259679 , the Novo Nordisk Foundation , the Aase and Ejnar Danielsen Foundation , the Augustinus Foundation , the Brødrene Hartmann Foundation , the King Christian the 10th Foundation and the Einer Willumsens Mindelegat Foundation . The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sørensen and Lene Elnegaard are thanked for excellent technical work.

PY - 2012/5

Y1 - 2012/5

N2 - 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.

AB - 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.

KW - Association study

KW - Candidate study

KW - Case-control data

KW - Human longevity

KW - Longitudinal data

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SN - 0531-5565

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JO - Experimental Gerontology

JF - Experimental Gerontology

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ER -

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

Bibliographical note

Keywords

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