title: Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis.
abstract: DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondrial DNA processes. The study population was 1089 long-lived and 736 middle-aged Danes. A self-contained set-based test of all SNPs displayed association with longevity (P-value=9.9 × 10(-5)), supporting that the overall pathway could affect longevity. Investigation of the nine sub-processes using the competitive gene-set analysis by Wang et al indicated that BER, HRR and RECQ associated stronger with longevity than the respective remaining genes of the pathway (P-values=0.004-0.048). For HRR and RECQ, only one gene contributed to the significance, whereas for BER several genes contributed. These associations did, however, generally not pass correction for multiple testing. Still, these findings indicate that, of the entire pathway, variation in BER might influence longevity the most. These modest sized P-values were not replicated in a German sample. This might, though, be due to differences in genotyping procedures and investigated SNPs, potentially inducing differences in the coverage of gene regions. Specifically, five genes were not covered at all in the German data. Therefore, investigations in additional study populations are needed before final conclusion can be drawn.
authors: Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors: Birgit
authors: B
authors: Debrabant
authors: 1] Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark [2] Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Mette
authors: M
authors: Soerensen
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors: Friederike
authors: F
authors: Flachsbart
authors: Department of Biology, Ecology and Earth Science, University of Calabria, Rende, Italy.
authors: Serena
authors: S
authors: Dato
authors: 1] Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark [2] Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Jonas
authors: J
authors: Mengel-From
authors: Department of Molecular Biology and Genetics, The Danish Aging Research Center, Aarhus University, Aarhus, Denmark.
authors: Tinna
authors: T
authors: Stevnsner
authors: 1] Department of Molecular Biology and Genetics, The Danish Aging Research Center, Aarhus University, Aarhus, Denmark [2] Laboratory of Molecular Gerontology, National Institute on Aging, National Institute of Health, Baltimore, MD, USA.
authors: Vilhelm A
authors: VA
authors: Bohr
authors: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Torben A
authors: TA
authors: Kruse
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors: Stefan
authors: S
authors: Schreiber
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors: Almut
authors: A
authors: Nebel
authors: 1] Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark [2] Department of Clinical Genetics, Odense University Hospital, Odense, Denmark [3] Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors: Kaare
authors: K
authors: Christensen
authors: 1] Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark [2] Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Qihua
authors: Q
authors: Tan
authors: 1] Epidemiology, Biostatistics and Biodemography, The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark [2] Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Lene
authors: L
authors: Christiansen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D045643:DNA Repair Enzymes