European Journal of Human Genetics (2009) 17, 1515-1519 & 2009 Macmillan Publishers Limited. All rights reserved. 1018-4813/09 $32.00.

Human longevity and 11p15.5: a study in 1321 centenarians

Francesco Lescai*,1,2,3, Helene Blanche4, Almut Nebel5, Marian Beekman6, Mourad Sahbatou5, Friederike Flachsbart6, Eline Slagboom6, Stefan Schreiber7,8, Sandro Sorbi1, Giuseppe Passarino and Claudio Franceschi.

1 C.I.G. Centro Interdipartimentale L.Galvani per Studi Integrati di Bioinformatica, Biofisica e Biocomplessita`, Alma Mater Studiorum Universita` di Bologna, Bologna, Italy; 
2 Dipartimento di Patologia Sperimentale, Alma Mater Studiorum Universita` di Bologna, Bologna, Italy; 
3 ITB Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Milano, Italy; 
4 Fondation Jean Dausset-CEPH Biological Resource Centre, Paris, France; 
5 Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; 
6 LUMC Leiden University Medical Centre Molecular Epidemiology, Leiden, The Netherlands; 
7 Dipartimento di Scienze Neurologiche e Psichiatriche Universita` di Firenze, Firenze, Italy; 
8 Dipartimento di Biologia Cellulare, Universita` della Calabria, Cosenza, Italy; 
9 INRCA Istituto Nazionale Ricovero e Cura Anziani, Ancona, Italy.

Introduction

In the search for determinants of longevity, we investigated the chromosomal region, 11p15.5, in four European samples collected from southern Italy (n92 centenarians, age range 100-108 years old, mean 101.9; and n97 controls aged 20-60 years old, mean 41.44), northern-central Italy (n307 centenarians, age range 99-109 years old, mean ; and n controls aged years old, mean ), Germany (n centenarians, age range years old, mean ; and controls aged years old, mean ) and France (n centenarians, age range years old, mean ; and controls aged years old, mean ). We analyzed a total of centenarians (males and females) and younger subjects (males and females), who shared ethnicity and geographical origin with the centenarians.

Methods

We scanned the area in four European sample groups for a total of 1321 centenarians and younger subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 SNPs. The obtained genotypes were tested for Hardy-Weinberg equilibrium. The genotyping results were analyzed using three different approaches: single-point analysis, sliding window multi-point regression analysis corrected with permutations and permutation analysis of the haplotype statistics.

Results

No significant results (P<0.05) have been found on the earlier associated loci (i.e., TH, IGF2, INS and HRAS1), and this study could not confirm the earlier findings on each of those genes. A meta-analysis carried out on the SIRT3 SNP data; a total number of 2461 samples were included but no positive association was found except for one SNP having a significant effect (rs939915). The same approach has been applied to the other 229 markers, and six SNPs have been found significant for the frequent genotype (rs4073591, DEAF1-rs4073590, KRTAP5-6-rs11040489, rs4930001, TSPAN32-rs800140 and rs16928120). This experience, although unable to confirm the earlier findings of the literature, highlights all the common difficulties of such studies in human longevity. Despite the rather negative findings presented here, the results derived from unprecedented studies involving such a large number of centenarians should be disseminated, thus contributing to set up adequate strategies to disentangle complex and likely heterogeneous phenotypes.

Conclusion

The 11p15.5 chromosomal region (2.8 Mb) is of particular interest as it encloses five genes (HRAS1, SIRT3, INS and IGF2), the variability of which was found to be associated with life extension by association studies. Mostly important, the above genes are homologous of genes that modulate lifespan in model organisms. We scanned the area in four European sample groups for a total of 132the 11p15.5 region, for six SNPs at the frequent genotype level and allelic level. The q-values are also listed. The results suggest that DEAF1 and TSPAN32 may be associated with longevity, but further analysis is needed to confirm these findings. The study also highlights the challenges of studying complex traits like longevity and the importance of considering population heterogeneity. A total of 239 SNPs were analyzed using a meta-analysis approach on 1600 samples from different populations. False discovery rate analysis was applied to filter the results, and six SNPs were found to be significant. However, further analysis is needed to confirm these findings.The significant P-values for only 11p15.5 are provided together with their associated q-value contributions. Longevity, more than any other complex trait, may result from a lifelong interaction (more than 100 years) between genetic and environmental factors. Moreover, epigenetics and stochasticity could also contribute to longevity, but such topics are still largely unexplored in humans. Despite the rather negative findings presented here, we believe that results from unprecedented studies involving such a large number of centenarians should be disseminated, thus contributing to setting up adequate strategies to disentangle complex and likely heterogeneous phenotypes. As the number of males among centenarians is very low, it is difficult to set up gender-matched samples. The choice is then to have samples representative of the overall population. Although earlier findings clearly indicate gender-specific associations, stratification by gender in these centenarian populations leads to unacceptable power in the analysis.