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 Blanche´4 , Almut Nebel5 , Marian Beekman6 , 4 5 6 5 Mourad Sahbatou , Friederike Flachsbart , Eline Slagboom , Stefan Schreiber 7 8 1,2,9 Sandro Sorbi , Giuseppe Passarino and Claudio Franceschi

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

– Centro Interdipartimentale ‘L.Galvani’ per Studi Integrati di Bioinformatica, Biofisica e Biocomplessita` Mater Studiorum Universita` di Bologna, Bologna, Italy; 2Dipartimento di Patologia Sperimentale, Alma Mater Universita` di Bologna, Bologna, Italy; 3ITB – Istituto di Tecnologie Biomediche, Consiglio Nazionale delle

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 Mostly important, the above genes are homologous of genes that modulate lifespan in model We scanned the area in four European sample groups for a total of 1321 centenarians and 1140 subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 SNPs.

TH, 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 1321 centenarians and younger subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 No significant results (Po0.05) have been found on the earlier associated loci (ie, 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.

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.

Introduction

In the search for determinants of longevity, we investigated the chromosomal region, 11p.15.5, in four European samples collected from southern Italy (n¼92 centenarians, age range 100–108 years old, mean 101.9; and n¼97 controls aged 20–60 years old, mean 41.44), northern-central Italy (n¼307 centenarians, age range

–

years old, mean

; and n¼

controls aged

–

years old, mean

), Germany (n¼

cente- narians, age range

–

years old, mean

; and

controls aged

–

years old, mean

) and France (n¼

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.

99–109 years old, mean 101.0; and n¼352 controls aged 17–60 years old, mean 41.2), Germany (n¼376 cente- narians, age range 100–110 years old, mean 104.41; and 376 controls aged 60–75 years old, mean 67.52) and France (n¼546 centenarians, age range 99–106 years old, mean 103.1; and 315 controls aged 18–70 years old, mean 51.2). We analyzed a total of 1321 centenarians (232 males and 1089 females) and 1140 younger subjects (530 males and 610 females), who shared ethnicity and geographical origin with the centenarians.

to be suitable for analysis using SNPlex technology (Applied Biosystems, Foster City, CA, USA). The obtained genotypes were tested for Hardy–Weinberg equilibrium and the three populations (Central Italy, South Italy and Germany) were subjected to AMOVA,9 which suggested not to pool the three population data. The genotyping results were analyzed using three different approaches: single- point analysis, sliding window multi-point regression analysis corrected with permutations10 and permutation analysis of the haplotype statistics.11