title: Immunochip analysis identifies association of the RAD50/IL13 region with human longevity.
abstract: Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip  = 7.01 × 10(-9) ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip  < 5 × 10(-4) for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl  = 5.42 × 10(-7) (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Flachsbart
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Liljana
authors.initials: L
authors.lastname: Gentschew
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Femke-Anouska
authors.initials: FA
authors.lastname: Heinsen
authors.affiliation: Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
authors.forename: Amke
authors.initials: A
authors.lastname: Caliebe
authors.affiliation: Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern, Denmark, Odense, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.affiliation: Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern, Denmark, Odense, Denmark.|Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Nygaard
authors.affiliation: Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern, Denmark, Odense, Denmark.|Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Fondation Jean Dausset-Centre du Polymorphisme Humain (CEPH), Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.affiliation: Fondation Jean Dausset-Centre du Polymorphisme Humain (CEPH), Paris, France.|Centre National de Génotypage CNG-IG-CEA, Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Centre National de Génotypage CNG-IG-CEA, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Derbois
authors.affiliation: Université Sorbonne Paris Cité-UREN, Unité de Recherche en Epidémiologie Nutritionnelle; U557 Inserm; U1125 Inra; Cnam; Université Paris 13, CRNH IdF, Bobigny, France.
authors.forename: Pilar
authors.initials: P
authors.lastname: Galan
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Büning
authors.affiliation: Department of Medicine II - Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.affiliation: Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.|Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Epidemiology and Popgen Biobank, Kiel University, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.|Clinic for Internal Medicine I, University Hospital of Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
mesh_terms: D017766:Acid Anhydride Hydrolases; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics*; D008136:Longevity / Q000235:genetics* / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D004268:DNA-Binding Proteins; C578095:IL13 protein, human; D018793:Interleukin-13; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes
keywords: 5q31.1; IL13; Immunochip; RAD50; genetic association; human longevity