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.

Authors: Soerensen M; Dato S; Tan Q; Thinggaard M; Kleindorp R; Beekman M; Jacobsen R; Suchiman HE; de Craen AJ; Westendorp RG; Schreiber S; Stevnsner T; Bohr VA; Slagboom PE; Nebel A; Vaupel JW; Christensen K; McGue M; Christiansen L

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: Aged; Aged, 80 and over; Antioxidants/metabolism; Case-Control Studies; DNA Damage/*physiology; DNA Repair/physiology; Female; Human Growth Hormone/*genetics; Humans; Insulin/*genetics; Insulin-Like Growth Factor I/*genetics; Longevity/*genetics/physiology; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; Polymorphism, Single Nucleotide; Signal Transduction/genetics/physiology
Journal: Experimental gerontology
Volume: 47
Issue: 5
Pages: 379-87
Date: March 13, 2012
PMID: 22406557
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Notes:

Alleles in candidate pathways (GH/IGF1 signaling, DNA damage signaling and repair and pro/antioxidants) were investigated for association with longevity in 1089 oldest-old (age 92-93) and 736 middle-aged Danes.

Six SNPs (in TNXRD1, XDH, GHRL, MLH1, H2AFX, XRCC5) were associated with mortality in late life after correction for multiple hypothesis testing. No replications were observed in German and Dutch populations.



Categories: Single-Nucleotide Polymorphism
Citation:

Soerensen M, Dato S, Tan Q, Thinggaard M, Kleindorp R, Beekman M, Jacobsen R, Suchiman HE, de Craen AJ, Westendorp RG, 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 47: 379-87.


Lifespan Factors:
  • KL klotho
  • GHSR growth hormone secretagogue receptor
  • RAD52 RAD52 homolog (S. cerevisiae)
  • WRN Werner syndrome, RecQ helicase-like
  • RAD23B RAD23 homolog B (S. cerevisiae)
  • POLB polymerase (DNA directed), beta
  • NTLH1 nescient helix loop helix 1
  • GSR glutathione reductase
  • INS insulin
  • GHRHR growth hormone releasing hormone receptor
  • IGF2R insulin-like growth factor 2 receptor
  • NTHL1 nth endonuclease III-like 1 (E. coli)
  • MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
  • XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining)
  • XDH xanthine dehydrogenase

  • Longevity Variant Associations (p-value):
  • rs1002149 (0.0335)
  • rs1207362 (0.0001)
  • rs2267723 (0.0001)
  • rs3842755 (0.0001)
  • rs572169 (0.0045)
  • rs9456497 (0.005)
  • rs11571461 (0.0001)
  • rs13251813 (0.0002)
  • rs1805329 (0.0309)
  • rs2953983 (0.0225)
  • rs3211994 (0.0056)
  • rs1002149 (0.0335)
  • rs3842755 (0.0001)
  • rs1207362 (0.0001)
  • rs2267723 (0.0001)
  • rs572169 (0.0045)
  • rs9456497 (0.005)
  • rs11571461 (0.0001)
  • rs13251813 (0.0002)
  • rs1805329 (0.0225)
  • rs2953983 (0.0309)
  • rs3211994 (0.0056)
  • rs10047589 (0.043)
  • rs207444 (0.046)
  • rs26802 (0.032)
  • rs13320360 (0.0036)
  • rs2509049 (0.017)
  • rs705649 (0.029)

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