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

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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 (R 2 = 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.

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Acknowledgments

This study was financially 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), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Brødrene Hartmann Foundation, the King Christian the 10th foundation, the Einer Willumsens Mindelegat Foundation, and by a Dutch grant from the Netherlands Consortium for Healthy Ageing (grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). 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.

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Authors and Affiliations

  1. The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000, Odense C, Denmark

    Mette Soerensen, Serena Dato, Qihua Tan, Mikael Thinggaard, Rune Jacobsen, Matt McGue, James W. Vaupel, Kaare Christensen & Lene Christiansen

  2. Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Mette Soerensen, Qihua Tan, Kaare Christensen & Lene Christiansen

  3. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Mette Soerensen, Qihua Tan, Kaare Christensen & Lene Christiansen

  4. Department of Cell Biology, University of Calabria, Ponte Pietro Bucci cubo 4C, 87036, Rende, Cosenza, Italy

    Serena Dato

  5. Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein and Christian-Albrechts-University, Schittenhelmstrasse 12, 24105, Kiel, Germany

    Rabea Kleindorp, Stefan Schreiber & Almut Nebel

  6. Department of Molecular Epidemiology, Leiden University Medical Center, S5-P, PO Box 9600, 2300 RC, Leiden, the Netherlands

    Marian Beekman, H. Eka D. Suchiman & P. Eline Slagboom

  7. Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands

    Marian Beekman, H. Eka D. Suchiman & P. Eline Slagboom

  8. Department of Psychology, University of Minnesota, N218 Elliott Hall 75 East River Road, Minneapolis, MN, USA

    Matt McGue

  9. The Danish Aging Research Center, Department of Molecular Biology, Aarhus University, C. F. Moellers Allé 3, 8000, Aarhus C, Denmark

    Tinna Stevnsner & Vilhelm A. Bohr

  10. Laboratory of Molecular Gerontology, National Institute on Aging, National Institute of Health, 5600 Nathan Shock Drive, Baltimore, MD, USA

    Vilhelm A. Bohr

  11. Department of Gerontology and Geriatrics, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC, Leiden, the Netherlands

    Anton J. M. de Craen & Rudi G. J. Westendorp

  12. Max Planck Institute for Demographic Research, Konrad-Zuse-Str. 1, 18057, Rostock, Germany

    James W. Vaupel

Authors
  1. Mette Soerensen
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  2. Serena Dato
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  3. Qihua Tan
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  4. Mikael Thinggaard
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Corresponding author

Correspondence to Mette Soerensen.

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Soerensen, M., Dato, S., Tan, Q. et al. Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. AGE 35, 487–500 (2013). https://doi.org/10.1007/s11357-011-9373-7

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  • DOI: https://doi.org/10.1007/s11357-011-9373-7

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