AGE

, Volume 35, Issue 2, pp 487–500

Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

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

DOI: 10.1007/s11357-011-9373-7

Cite this article as:
Soerensen, M., Dato, S., Tan, Q. et al. AGE (2013) 35: 487. doi:10.1007/s11357-011-9373-7

Abstract

In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case–control study of 1,089 oldest-old (ages 92–93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95–110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R2 = 0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

Keywords

Human longevityCandidate gene association studyCase–control dataLongitudinal data

Supplementary material

11357_2011_9373_MOESM1_ESM.pdf (65 kb)
ESM 1(PDF 64 kb)
11357_2011_9373_MOESM2_ESM.pdf (127 kb)
ESM 2(PDF 127 KB)
11357_2011_9373_MOESM3_ESM.pdf (56 kb)
ESM 3(PDF 56 kb)
11357_2011_9373_MOESM4_ESM.pdf (63 kb)
ESM 4(PDF 63 kb)
11357_2011_9373_MOESM5_ESM.pdf (107 kb)
ESM 5(PDF 107 kb)

Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Mette Soerensen
    • 1
    • 2
    • 3
  • Serena Dato
    • 1
    • 4
  • Qihua Tan
    • 1
    • 2
    • 3
  • Mikael Thinggaard
    • 1
  • Rabea Kleindorp
    • 5
  • Marian Beekman
    • 6
    • 7
  • H. Eka D. Suchiman
    • 6
    • 7
  • Rune Jacobsen
    • 1
  • Matt McGue
    • 1
    • 8
  • Tinna Stevnsner
    • 9
  • Vilhelm A. Bohr
    • 9
    • 10
  • Anton J. M. de Craen
    • 11
  • Rudi G. J. Westendorp
    • 11
  • Stefan Schreiber
    • 5
  • P. Eline Slagboom
    • 6
    • 7
  • Almut Nebel
    • 5
  • James W. Vaupel
    • 1
    • 12
  • Kaare Christensen
    • 1
    • 2
    • 3
  • Lene Christiansen
    • 1
    • 2
    • 3
  1. 1.The Danish Aging Research Center, Epidemiology, Institute of Public HealthUniversity of Southern DenmarkOdense CDenmark
  2. 2.Department of Clinical GeneticsOdense University HospitalOdense CDenmark
  3. 3.Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdense CDenmark
  4. 4.Department of Cell BiologyUniversity of CalabriaRendeItaly
  5. 5.Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein and Christian-Albrechts-UniversityKielGermany
  6. 6.Department of Molecular EpidemiologyLeiden University Medical CenterLeidenthe Netherlands
  7. 7.Netherlands Consortium for Healthy AgeingLeiden University Medical CenterLeidenthe Netherlands
  8. 8.Department of PsychologyUniversity of MinnesotaMinneapolisUSA
  9. 9.The Danish Aging Research Center, Department of Molecular BiologyAarhus UniversityAarhus CDenmark
  10. 10.Laboratory of Molecular Gerontology, National Institute on AgingNational Institute of HealthBaltimoreUSA
  11. 11.Department of Gerontology and GeriatricsLeiden University Medical CenterLeidenthe Netherlands
  12. 12.Max Planck Institute for Demographic ResearchRostockGermany