Here we explore association with human longevity of common genetic variation inthree major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genescomposing 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)), 5GH/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 studywith 11 years of follow-up on survival in the oldest-old Danes we found 2pro/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 correctionfor multiple testing. When examining the 11 SNPs from the case-control study inthe 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 alsoin late life survival. In addition, rs207444 (XDH) presented the same directionof effect when inspecting the 6 SNPs from the longitudinal study in thecase-control data, hence, suggesting an effect also in survival from middle ageto old age. No formal replications were observed when investigating the 11 SNPsfrom the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significanttendency (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 thelongitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563).In conclusion, the present candidate gene based association study, the largest todate applying a pathway approach, not only points to potential new longevityloci, but also underlines the difficulties of replicating association findings inindependent study populations and thus the difficulties in identifying universal longevity polymorphisms.

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.

DATO, Serena;
2012-01-01

Abstract

Here we explore association with human longevity of common genetic variation inthree major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genescomposing 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)), 5GH/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 studywith 11 years of follow-up on survival in the oldest-old Danes we found 2pro/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 correctionfor multiple testing. When examining the 11 SNPs from the case-control study inthe 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 alsoin late life survival. In addition, rs207444 (XDH) presented the same directionof effect when inspecting the 6 SNPs from the longitudinal study in thecase-control data, hence, suggesting an effect also in survival from middle ageto old age. No formal replications were observed when investigating the 11 SNPsfrom the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans, although rs11571461 (RAD52) did show a supportive non-significanttendency (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 thelongitudinal study in a Dutch longitudinal cohort of oldest-old (age 85+, N=563).In conclusion, the present candidate gene based association study, the largest todate applying a pathway approach, not only points to potential new longevityloci, but also underlines the difficulties of replicating association findings inindependent study populations and thus the difficulties in identifying universal longevity polymorphisms.
2012
Human longevity; Association study; Candidate study
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/148210
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