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of genetic susceptibility factors for human longevity – A SNP study

Friederike Flachsbarta, Andre Frankea, Rabea Kleindorpa, Amke Caliebeb, Hélène Blanchéc, Stefan Schreibera,1, Almut Nebela,∗,1

a Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, Germany b Institute of Medical Informatics and Statistics, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, c Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH), Paris, France



Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25–32%. Experimental model organisms point to the existence of core survival and anti-ageing path- ways that have been conserved throughout evolution. It has been shown that mutations in single genes involvedinthesepathwayscaneitherdelayoracceleratetheageingprocessandthatmanyofthesegenes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynony- mous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotypeinaGermansamplecomprisingabout400centenariansandanequalnumberofyoungercon- trol subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity researchconductedto-date.Thethreetop-rankingmarkers,whicharelocatedinthegenesDUSP6,NALP1 and PERP, revealed p-values≤0.01 in the allelic case–control comparisons. Although the association sig- nals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.

human adult life span [1–4]. A twin study has revealed that genetic influences on survival are minimal before the age of 60 but increase thereafter [5]. It is still debated to what extent a long and healthy lifeisbasedontheabsenceofharmfulgeneticvariantsthatresultin age-related disorders [6] and/or on the presence of polymorphisms with beneficial effects in so-called “longevity-enabling genes” [7].

1. Introduction

Longevityinhumansisconsideredamultifactorialtraittowhich both genetic and environmental factors are likely to contribute. Epidemiological studies have shown that the modulation of age- ing processes is inherited in long-lived families, and genetic factors havebeenestimatedtoaccountforabout25–32%ofthevariationin

There is mounting evidence from experimental model organ- isms (S. cerevisiae, C. elegans, D. melanogaster, M. musculus) for the existence of core survival/anti-ageing pathways [8–10]. They influ- ence the ageing process by increasing the capacity of an organism to cope with the accumulation of stress-induced molecular dam- age [11] and thus represent key candidates for attaining longevity [12]. On the other hand, disruptions in these pathways lead to age- related failure of cellular maintenance and function, reduced stress tolerance, diseases and ultimately death [13]. Mutations in sin- gle genes involved in the pathways can either delay or accelerate the ageing process in diverse model organisms [14–16]. Many of the survival genes and pathways are evolutionarily conserved and also present in H. sapiens, thus providing a rationale to search for corresponding human loci. However, longevity candidate studies in humans are very often hampered by difficulties to adequately replicate results in independent population samples [17]. The most

Abbreviations: A2M,alpha-2-macroglobulin;APOE,apolipoproteinE;BMBF,Ger- man Federal Ministry of Science and Education; CCA, case–control analyses at the allele level; CCG, case–control analyses at the genotype level; CI, confidence inter- val; DFG, Deutsche Forschungsgemeinschaft; DUSP6, dual specificity phosphatase 6; EXO1, exonuclease 1; FOXO3A, forkhead box O3A; GEHA, GEnetics of Healthy Aging;IIS,insulin-likegrowthfactor-Isignaling;IR,insulinreceptor;NALP1,NACHT leucine-rich-repeat protein 1; NGFN, National Genome Research Network; nsSNPs, nonsynonymous single nucleotide polymorphisms; OR, odds ratio; P , p-value CCA obtained from an allele-based case–control comparison, using a (cid:2)2-test with 1 degree of freedom; PERP, p53 apoptosis effector related to PMP22.

∗ Corresponding author at: Institute of Clinical Molecular Biology, Christian- Albrechts-University Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany. Tel.: +49 431 597 1373; fax: +49 431 597 2196.

consistent association findings so far have been reported for the apolipoprotein E (APOE) [6,17] and the forkhead box O3A (FOXO3A) genes [18–21]. Interestingly, FOXO3A is the human orthologue of daf-16 in the nematode C. elegans. This transcription factor is a key regulator of the insulin receptor (IR)/insulin-like growth factor-I signaling (IIS) pathway, which is known to mediate life span exten- sion in various laboratory species [22–28].