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

Soerensen & Serena Dato & Qihua Tan & Thinggaard & Rabea Kleindorp & Beekman & H. Eka D. Suchiman & Jacobsen & Matt M

ue & Tinna Stevnsner A. Bohr & Anton J. M. de Craen & G. J. Westendorp & Stefan Schreiber & Eline Slagboom & Almut Nebel & W. Vaupel & Kaare Christensen & Christiansen

Received: 31 August 2011 /Accepted: 15 December 2011 # American Aging Association 2012

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

Abstract In this study, we investigated 102 single- nucleotide polymorphisms (SNPs) covering the com- mon genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE;

Electronic supplementary material The online version of this article (doi:10.1007/s11357-011-9373-7) contains supplementary material, which is available to authorized users.

S. Dato

M. Soerensen (*) S. Dato Q. Tan M. Thinggaard : : : R. Jacobsen M. M

ue J. W. Vaupel K. Christensen L. Christiansen The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej

B,

Odense C, Denmark e-mail: msoerensen@health.sdu.dk

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

M. Soerensen Q. Tan K. Christensen L. Christiansen Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark

M. Soerensen Q. Tan K. Christensen L. Christiansen Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29,

M. Beekman H. E. D. Suchiman P. E. Slagboom Netherlands Consortium for Healthy Ageing, Leiden University Medical Center,

RC Leiden, the Netherlands

frequency (MAF) of rs769449 (APOE) was cantly decreased in the oldest-old, while the MAF rs9923854 (CETP) was significantly enriched. effects were supported when investigating – oldest-old (ages 95 110) and 1,104 middle-aged mans. rs769449 was in modest linkage (R20 0.55) with rs429358 of the APOE-ε 4 and adjusting for rs429358 eliminated the of rs769449, indicating that the association reflects the well-known effect of rs429358. based analysis confirmed the effects of variation APOE and CETP and furthermore pointed to as a longevity gene. In a longitudinal study 11 years of follow-up on survival in the Danes, only one SNP, rs2069827 (IL6), was significantly associated with survival from age 92 0 corrected 0.064). This advantageous effect of the nor allele was supported when investigating a 0 longitudinal cohort (N 563) of oldest-old (age Since rs2069827 was located in a putative tion factor binding site, quantitative RNA studies were conducted. However, no difference in expression was observed between rs2069827 groups. In conclusion, we here support and expand evidence suggesting that genetic variation in CETP, and IL6, and possible HSPA14, is associated human longevity.

Introduction

Approximately 25% of the variation in human lifespan is thought to be caused by genetic variation (Herskind et al. 1996), a contribution considered to be minimal before age 60 years and most profound after age 85 years (Hjelmborg et al. 2006). Candidate genes for longevity encode proteins engaged in different biological processes including lipoprotein metabolism and inflammatory processes (Christensen et al. 2006).

the common genetic variation within candidate genes previously reported to contain lifespan associated poly- morphisms. Furthermore, we expand the study to include the genetic variation of genes belonging to the same functional groups. Of the 16 genes included in this study, only SIRT1 and 3 have previously been investigated by a tagging single-nucleotide polymorphism (SNP) ap- proach in a candidate association study (Flachsbart et al. 2006; Kuningas et al. 2007; Lescai et al. 2009).

We investigate the apolipoprotein E, C3, and A4 genes (APOE, APOC3, and APOA4), all of which are involved in lipoprotein metabolism, believed to pose an effect on longevity (Christensen et al. 2006). The APOE ε 4 haplotype is by far the most validated ge- netic variation and has repeatedly been associated with human longevity (e.g., Asada et al. 1996; Bathum et al. 2006; Deelen et al. 2011; Gerdes et al. 2000; McKay et al. 2011; Nebel et al. 2011; Schachter et al. 1994), whereas one study has found association of rs2542052 in APOC3 with longevity (Atzmon et al. 2006). The APOE polymorphism was recently reviewed in (Seripa et al. 2011). Also involved in lipoprotein metabolism is the cholesteryl ester transfer protein (cetp) for which rs5882 in CETP has been reported as a longevity SNP (Barzilai et al. 2003).

T. Stevnsner V. A. Bohr The Danish Aging Research Center, Department of Molecular Biology, Aarhus University, C. F. Moellers Allé

,

Aarhus C, Denmark

V. A. Bohr

Genes encoding proteins engaged in immune regu- latory processes are also key candidates for longevity (reviewed in Jylhava and Hurme 2010). Frequently discussed is the cytokine interleukin 6 (IL6) and its receptor alpha (IL6R); in IL6, a variable number of − tandem repeat (VNTR) and a 174C/G polymorphism (rs1800795) have been described as associated with longevity (Capurso et al. 2007; Christiansen et al.

A. J. M. de Craen R. G. J. Westendorp Department of Gerontology and Geriatrics, Leiden University Medical Center, C

-R, PO Box

,

RC Leiden, the

J. W. Vaupel

Max Planck Institute for Demographic Research, Konrad-Zuse-Str.

,

Rostock, Germany