62 results on '"Flachsbart, F."'
Search Results
2. Clinical Problem-Solving: Multiple Pulmonary Emboli
- Author
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Mendelowitz, Paul C., Flachsbart, F., and Thibault, George E.
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- 1995
3. Clinical Problem-Solving: Recurrent Pulmonary Emboli
- Author
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Greenfield, Lazar J., Flachsbart, F., Pauker, Stephen G., and Kopelman, Richard I.
- Published
- 1995
4. Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus
- Author
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Jüptner, M, primary, Flachsbart, F, additional, Caliebe, A, additional, Lieb, W, additional, Schreiber, S, additional, Zeuner, R, additional, Franke, A, additional, and Schröder, J O, additional
- Published
- 2017
- Full Text
- View/download PDF
5. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study
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Beekman, M., Blanche, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., Flachsbart, F., Christiansen, L., Craen, A.J.M. de, Kirkwood, T.B.L., Rea, I.M., Poulain, M., Robine, J.M., Valensin, S., Stazi, M.A., Passarino, G., Deiana, L., Gonos, E.S., Paternoster, L., Sorensen, T.I.A., Tan, Q.H., Helmer, Q., Akker, E.B. van den, Deelen, J., Martella, F., Cordell, H.J., Ayers, K.L., Vaupel, J.W., Tornwall, O., Johnson, T.E., Schreiber, S., Lathrop, M., Skytthe, A., Westendorp, R.G.J., Christensen, K., Gampe, J., Nebel, A., Houwing-Duistermaat, J.J., Slagboom, P.E., Franceschi, C., GEHA Consortium, Leiden University Medical Center (LUMC), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), National Institute for Health and Welfare [Helsinki], Tampere School of Public Health, Institute of Gerontology [Kiev], Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Christian-Albrechts University of Kiel, University of Southern Denmark (SDU), Netherlands Consortium for Healthy Ageing, Newcastle University [Newcastle], The Queen’s University of Belfast, Université Catholique de Louvain = Catholic University of Louvain (UCL), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), University of Bologna, Istituto Superiore di Sanita [Rome], Università della Calabria [Arcavacata di Rende] (Unical), Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Theoretical and Physical Chemistry Institute NHRF, National Hellenic Research Foundation, University of Bristol [Bristol], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Odense University Hospital (OUH), Institute for Ageing and Health, Newcastle University, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, University of Colorado [Boulder], Leiden University Medical Centre [Leyde, Pays-Bas], Leiden University, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute for Ageing and Health, École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Sassari, Danish Aging Research Center, Institute of Public Health, and Institute for Behavioral Genetics
- Subjects
Aging ,Genetic Linkage ,APOE gene ,Genome-wide association study ,Association analysis ,Human familial longevity ,[SHS]Humanities and Social Sciences ,0302 clinical medicine ,Mitochondrial Precursor Protein Import Complex Proteins ,Cluster Analysis ,Nonagenarian sibling pairs ,media_common ,Aged, 80 and over ,Genetics ,0303 health sciences ,Longevity ,Chromosome Mapping ,Middle Aged ,Europe ,genome-wide linkage analysis ,association analysis ,nonagenarian sibling pairs ,apoe gene ,human familial longevity ,congenital, hereditary, and neonatal diseases and abnormalities ,media_common.quotation_subject ,Locus (genetics) ,Biology ,Article ,03 medical and health sciences ,Apolipoproteins E ,SDG 3 - Good Health and Well-being ,Genetic linkage ,Humans ,Allele ,Alleles ,Aged ,030304 developmental biology ,Genetic association ,Chromosomes, Human, Pair 14 ,Apolipoprotein C-I ,Genome, Human ,Siblings ,Membrane Transport Proteins ,Cell Biology ,Heritability ,Apoe gene ,Genetic Loci ,Human genome ,Lod Score ,Chromosomes, Human, Pair 19 ,Genome-wide linkage analysis ,030217 neurology & neurosurgery ,Chromosomes, Human, Pair 17 ,Genome-Wide Association Study - Abstract
Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10 -8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10 -5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
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- 2013
6. Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus.
- Author
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Jüptner, M., Flachsbart, F., Caliebe, A., Lieb, W., Schreiber, S., Zeuner, R., Franke, A., and Schröder, J. O.
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SYSTEMIC lupus erythematosus , *DNA copy number variations , *HLA histocompatibility antigens , *POLYMERASE chain reaction , *RHEUMATOLOGY , *DISEASE risk factors - Abstract
Objectives: Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods: We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupusassociated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results: Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR)=5.329; p=7.7×10-3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR=3.699; p=6.8×10-3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p=4.9×10-6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR=4.044; p=0.040 and OR=5.798; p=0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p=0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR=2.231; p=1.33×10-5). Conclusions: Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLADRB1*0301 without a proven pathophysiological mechanism. [ABSTRACT FROM AUTHOR]
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- 2018
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7. Genetic Variation in the CYP2C Monooxygenase Enzyme Subfamily Shows No Association With Longevity in a German Population
- Author
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Flachsbart, F., primary, Ufer, M., additional, Kleindorp, R., additional, Nikolaus, S., additional, Schreiber, S., additional, and Nebel, A., additional
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- 2011
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8. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity
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FLACHSBART, F, primary, CROUCHER, P, additional, NIKOLAUS, S, additional, HAMPE, J, additional, CORDES, C, additional, SCHREIBER, S, additional, and NEBEL, A, additional
- Published
- 2006
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9. Anticoagulation as prevention of “infection” — Recurrent pulmonary embolism
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Flachsbart, F., primary
- Published
- 1994
- Full Text
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10. A functional haplotype in the 3'untranslated region of TNFRSF1B is associated with tuberculosis in two African populations.
- Author
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Möller M, Flachsbart F, Till A, Thye T, Horstmann RD, Meyer CG, Osei I, van Helden PD, Hoal EG, Schreiber S, Nebel A, Franke A, Möller, Marlo, Flachsbart, Friederike, Till, Andreas, Thye, Thorsten, Horstmann, Rolf D, Meyer, Christian G, Osei, Ivy, and van Helden, Paul D
- Abstract
Rationale: Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. The pleiotropic cytokine tumor necrosis factor-alpha is essential to control tuberculosis infection, and various tumor necrosis factor family members and their respective receptors may contribute to tuberculosis risk.Objectives: To investigate four functionally relevant polymorphisms in the tumor necrosis factor receptor 2-encoding gene, tumor necrosis factor receptor superfamily member 1B, for association with tuberculosis susceptibility.Methods: Genotyping of four polymorphisms was performed in independent populations from South Africa (429 cases and 482 control subjects) and Ghana (640 cases and 1,158 control subjects), and the association of the variants with tuberculosis was tested using two case-control association studies.Measurements and Main Results: Single-point and haplotype analysis in South Africans revealed an association in the 3'untranslated region of the investigated gene. The T allele of rs3397 alone and/or the 3' untranslated region haplotype GTT may confer protection against tuberculosis insofar as both allele and haplotype frequencies were significantly lower in case subjects than in controls. The GTT genotype had previously been shown to increase the decay of tumor necrosis factor receptor 2 messenger ribonucleic acid, and messenger ribonucleic acid destabilization may represent a key molecular mechanism for disease susceptibility. Interestingly, the association signal appeared to be restricted to women. The genetic finding was validated in female participants from Ghana. The combined P value in the haplotype analysis was P = 0.00011.Conclusions: Our finding emphasizes the importance of tumor necrosis factor/tumor necrosis factor receptor-mediated immune responses in the pathogenesis of tuberculosis. [ABSTRACT FROM AUTHOR]- Published
- 2010
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11. Clinical Problem-Solving: Multiple Pulmonary Emboli.
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Flachsbart, F.
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LETTERS to the editor , *PULMONARY embolism - Abstract
A letter to the editor is presented in response to an article on recurrent pulmonary embolism in a previous issue.
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- 1995
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12. Clinical Problem-Solving: Recurrent Pulmonary Emboli.
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Flachsbart, F.
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LETTERS to the editor , *PULMONARY embolism - Abstract
A letter to the editor is presented in response to the article "Some Familiar Trade-Offs," by S.G. Pauker and R.I. Kopelman.
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- 1995
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13. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age
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Doris Lechner, Miriam Capri, Stefan Böhringer, Stefan Schreiber, Gonneke Willemsen, Paolo Garagnani, Irene Maeve Rea, Andres Metspalu, Palmi V. Jonsson, Thomas B. L. Kirkwood, Lene Christiansen, Fernando Rivadeneira, Giuseppina Rose, J. Wouter Jukema, Serena Dato, Owen A. Ross, Almut Nebel, Cornelia M. van Duijn, Gary Saunders, Bernard Jeune, David J. Stott, Jeanine J. Houwing-Duistermaat, A. Murphy, Anton J. M. de Craen, Friederike Flachsbart, Karen Andersen-Ranberg, Albert Hofman, Ian Ford, Ellen A. Nohr, Giuseppe Passarino, Krista Fischer, Elisa Cevenini, Carmen Martin-Ruiz, Jutta Gampe, Iris Postmus, Christopher P. Nelson, Stefano Salvioli, Alberto Montesanto, Mark Lathrop, Marianne Nygaard, Marie E. Breen, Jennifer Harrow, Hae-Won Uh, Erik B. van den Akker, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexander Viktorin, Bastiaan T. Heijmans, Susan E. McNerlan, Quinta Helmer, Naveed Sattar, Claudio Franceschi, Eco J. C. de Geus, E. Mihailov, Jouke-Jan Hottenga, Qihua Tan, Kari Stefansson, Yoichiro Kamatani, Paolina Crocco, Henning Tiemeier, Stella Trompet, Patrik K. E. Magnusson, Marian Beekman, Riin Tamm, Amke Caliebe, Maris Alver, Femke-Anouska Heinsen, Pilar Galan, Daníel F. Guðbjartsson, Joris Deelen, Linda Broer, Ruud van der Breggen, Kristin L. Ayers, Anna M. Bennet, Dorret I. Boomsma, P. Eline Slagboom, Kaare Christensen, Diana van Heemst, Joanna Collerton, Karen Davies, Rudi G. J. Westendorp, Hélène Blanché, Lavinia Paternoster, Nilesh J. Samani, Hreinn Stefansson, Simon P. Mooijaart, Heather J. Cordell, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), LeidenUniversity Medical Centre, Department of Epidemiology, The Netherlands Cancer Institute, Institute of Genetic Medicine, Newcastle University [Newcastle], National Institute of Public Health, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Tartu, Institute of Molecular and Cell Biology, Department of Gerontology and Geriatrics, Leiden University Medical Center (LUMC), deCODE genetics [Reykjavik], Christian-Albrechts University of Kiel, University of Calabria, Delft University of Technology (TU Delft), Department of Cardiovascular Sciences, Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospitals Leicester, Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Iowa [Iowa City], DIMES: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University Hospital, Institute for Ageing and Health, University of Glasgow, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO Institute for Health and Care Research, VU University Amsterdam Medical Center, Landspitali National University Hospital of Iceland, University of Iceland, McGill University = Université McGill [Montréal, Canada], Genome Quebec Innovation Centre, Institut de Génomique, Belfast Health and Social Care Trust, Estonian Biocentre, Partenaires INRAE, Aarhus University [Aarhus], School of Social and Community Medicine, Erasmus University Rotterdam, Mayo Clinic, BHF Glasgow Cardiovascular Research Centre, University Medical Center Schleswig-Holstein, Institute of Cardiovascular and Medical Sciences, Sophia Children's Hospital, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Augustinus Foundation, Avera Institute for Human Genetics (AIHG), AXA Research Fund, Belfast City Hospital Trust Fund, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007], Biotechnology and Biological Sciences Research Council (BBSRC), Bristol-Myers Squibb, Center for Inherited Disease Research (CIDR), Centre for Medical Systems Biology (CMSB), CERA Foundation, Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG), Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR) [11-107308], Danish National Research Foundation (DNRF), Department of Health and Social Services (Northern Ireland), DFG-Cluster of Excellence 'Inflammation at Interfaces', Dunhill Medical Trust [R124/0509], Egmont Foundation, Estonian Science Foundation [7859], Estonian Government [SF0180142s08], European Research Council (ERC) [230374], European Science Foundation (ESF) [EU/QLRT-2001-01254], European Union [FP5-QLK6-CY-2001-00128, FP6-LIFESCIHEALTH-36894, FP6-LSH M-CT-2004-503270, FP7-HEALTH-2007-B-223004, FP7-HEALTH-F4-2007-201413, FP7-HEALTH-F4-2008-202047, FP7-HEALTH-2009-single-stage-242244, FP7-HEALTH-2010-two-stage-259679], Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL, Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH) [MH081802], GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254], Guy's & St Thomas' NHS Foundation Trust, Health Foundation, Heart and Lung foundation [20070481], Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007], Institut National de la Recherche Agronomique (INRA), Institut National de la Sante et de la Recherche Medicale (INSERM), King's College London, Medical Research Council (MRC) [G0500997, G0601333], Ministere de l'Enseignement superieur et de la Recherche (MESR), National Institutes of Health (NIH)/National Institute of Aging (NIA) [P01AG08761, R01D0042157-01A, U01DK066134], National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, NBIC BioAssist [NWO-NBIC/BioAssist/RK/2008.024], Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810], Netherlands Genomics Initiative (NGI), Netherlands Heart Foundation (NHF) [2001 D 032], Netherlands Organization for Scientific Research (NWO, MagW/ZonMW) [904-61-090, 904-61-193, 480-04-004, 400-05-717, Spinozapremie 56-464-14192, 175.010.2005.011, 911-03-012, 985-10-002, Addiction-31160008, Middelg-root-911-09-032], Netspar - Living longer for a good health, NHS North of Tyne (Newcastle Primary Care Trust), Pharmacy Foundation, Regione Autonoma della Sardegna, Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06], Swedish Research Council [M-2005-1112], Tampere University Hospital and Academy of Finland, Danish Interdisciplinary Research Council, Health Foundation (Helsefonden), Ministry for Higher Education, National Program for Research Infrastructure [09-063256], March of Dimes Birth Defects Foundation, Swedish Foundation for Strategic Research (SSF), Unilever Discover Colworth, Universite Paris 13, University of Tartu [SP1GVAR-ENG], Velux Foundation, VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), Wellcome Trust [084762, 085475, 087436], IDEAL [FP7-HEALTH-2010-two-stage-259679], Research and Education into Ageing-0153, European Regional Development Fund, Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, McNerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE., Leiden Univ, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands [ 2 ] Leiden Univ, Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands [ 3 ] Leiden Univ, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands [ 4 ] Leiden Univ, Dept Cardiol, NL-2300 RC Leiden, Netherlands [ 5 ] Leiden Univ, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands [ 6 ] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands [ 7 ] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands [ 8 ] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England [ 9 ] Univ So Denmark, Inst Publ Hlth, DK-5000 Odense C, Denmark [ 10 ] Univ So Denmark, Inst Clin Res, Dept Gynecol & Obstet, DK-5000 Odense C, Denmark [ 11 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 12 ] Odense Univ Hosp, Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark [ 13 ] Fdn Jean Dausset CEPH, F-75010 Paris, France [ 14 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 15 ] Univ Tartu, Estonian Genome Ctr, Tartu 51010, Estonia [ 16 ] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia [ 17 ] deCODE Genet, Populat Gen, IS-101 Reykjavik, Iceland [ 18 ] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany [ 19 ] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany [ 20 ] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy [ 21 ] Delft Univ Technol, Delft Bioinformat Lab, NL-2600 GA Delft, Netherlands [ 22 ] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England [ 23 ] Glenfield Hosp, Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England [ 24 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England [ 25 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland [ 26 ] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA [ 27 ] Univ Bologna, Dept Expt Diagnost & Specialty Med, I-40126 Bologna, Italy [ 28 ] Univ Bologna, Interdepartmental Ctr L Galvani, I-40126 Bologna, Italy [ 29 ] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England [ 30 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland [ 31 ] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland [ 32 ] Max Planck Inst Demograf Forsch, Lab Stat Demog, D-18057 Rostock, Germany [ 33 ] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands [ 34 ] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands [ 35 ] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland [ 36 ] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland [ 37 ] CEA, Inst Genom, F-91057 Evry, France [ 38 ] McGill Univ, Montreal, PQ H3G 1A4, Canada [ 39 ] Genome Quebec Innovat Ctr, Montreal, PQ H3G 1A4, Canada [ 40 ] Belfast Hlth & Social Care Trust, Cytogenet Lab, Belfast BT8 8BH, Antrim, North Ireland [ 41 ] Estonian Bioctr, EE-51010 Tartu, Estonia [ 42 ] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark [ 43 ] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England [ 44 ] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA [ 45 ] Univ Glasgow, Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland [ 46 ] Univ Kiel, PopGen Biobank, D-24105 Kiel, Germany [ 47 ] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany [ 48 ] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CA Rotterdam, Netherlands [ 49 ] Univ Paris 04, UREN, U557, INSERM, F-93017 Bobigny, France [ 50 ] U1125 Inra, F-93017 Bobigny, France [ 51 ] Cnam, F-93017 Bobigny, France [ 52 ] Univ Paris 13, CRNH IdF, F-93017 Bobigny, France [ 53 ] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr, DK-2200 Copenhagen N, Denmark [ 54 ] Inst Prevent Med, DK-2000 Copenhagen, Denmark [ 55 ] Frederiksberg Univ Hosp, DK-2000 Copenhagen, Denmark [ 56 ] Interuniv Cardiol Inst Netherlands, NL-3501 DG Utrecht, Netherlands [ 57 ] Bellaria Hosp, IRCCS Inst Neurol Sci, I-40139 Bologna, Italy [ 58 ] CNR, ISOF, I-40129 Bologna, Italy, Epidemiology, Surgery, Internal Medicine, Child and Adolescent Psychiatry / Psychology, ProdInra, Migration, Vrije Universiteit Amsterdam [Amsterdam] (VU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Amsterdam, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes
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Male ,Netherlands Twin Register (NTR) ,Disease/genetics ,Lífslíkur ,Longevity/genetics ,[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Genetic Linkage ,Genome-wide association study ,0302 clinical medicine ,Prospective Studies ,Genetics (clinical) ,Genetics ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Association Studies Articles ,Age Factors ,Chromosome Mapping ,Genetic Loci/physiology ,General Medicine ,3. Good health ,Europe ,Phenotype ,Cardiovascular Diseases ,Hypertension ,Chromosomes, Human, Pair 5 ,Female ,Human Longevity, genetics, meta-analysis ,Aging/genetics ,Cardiology and Cardiovascular Medicine ,HUMAN AGING ,Longevity ,European Continental Ancestry Group ,Population ,HUMAN GENETICS ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,FAMILIAL LONGEVITY ,White People ,03 medical and health sciences ,Gene mapping ,SDG 3 - Good Health and Well-being ,Cardiovascular Diseases/genetics ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Humans ,Allele ,education ,Molecular Biology ,Aged ,030304 developmental biology ,Genetic association ,Öldrun ,Genome, Human ,Arfgengi ,Minor allele frequency ,Ageing ,Genetic Loci ,Chromosomes, Human, Pair 19 ,Hypertension/genetics ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genome-Wide Association Study - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (
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- 2014
14. Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project
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C. Gilbault, G. Pelicci, Marian Beekman, Axel Skytthe, Serena Dato, A. Skouteri, Konstantinos Voutetakis, Luca Deiana, Ciriaco Carru, Ewa Sikora, Claudio Franceschi, Friederike Flachsbart, Leena Peltonen, James W. Vaupel, P. Laiho, Joanna Collerton, V. Bezrukov, Stefan Schreiber, Michel Poulain, Karen Davies, Irene Maeve Rea, Mikko Hurme, Giuseppe Passarino, Federica Sevini, Katarzyna Broczek, Outi Törnwall, Antti Hervonen, Elisa Cevenini, Hélène Blanché, Bernard Jeune, Maria Scurti, Rodolfo Cotichini, Jean-Marie Robine, Erica Haimes, A.J.M. de Craen, Thomas B. L. Kirkwood, R. Masciulli, José Remacle, Lene Christiansen, Dorota Janiszewska, F. Balard, Almut Nebel, A. Leon, P.E. Slagboom, Lars Bolund, A. Marchisio, Liana Spazzafumo, Marja Jylhä, Virgilia Toccaceli, G. De Benedictis, Markus Perola, Olivier Toussaint, Jutta Gampe, M A Stazi, Silvana Valensin, Peter Kristensen, Kaare Christensen, Efstathios S. Gonos, University of Southern Denmark (SDU), University of Bologna/Università di Bologna, Laboratoire Lorrain de Sciences Sociales (2L2S), Université de Lorraine (UL), Institut National de la Santé et de la Recherche Médicale (INSERM), Netherlands Consortium for Healthy Ageing, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Institute of Gerontology [Kiev], Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Beijing Genomics Institute [Shenzhen] (BGI), Institute of Human Genetics [Aarhus], Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Medical University of Warsaw - Poland, Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Odense University Hospital (OUH), Newcastle University [Newcastle], Istituto Superiore di Sanità (ISS), Universiteit Leiden, Università della Calabria [Arcavacata di Rende] (Unical), Institute of Clinical Molecular Biology, Kiel University, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Université Catholique de Louvain = Catholic University of Louvain (UCL), National Hellenic Research Foundation [Athens], Tampere School of Public Health, University of Tampere [Finland], University of Aarhus, The National Institute for Health and Welfare, National Institute for Health and Welfare [Helsinki], Research Innovation [Italy], IFOM Institute of Milan, Queen's University [Belfast] (QUB), Eppendorf Array Technologies, CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto Nazionale Ricovero e Cura Anziani, Université de Namur [Namur] (UNamur), European Project: 26813,GEHA, University of Bologna, Istituto Superiore di Sanita [Rome], University of Calabria, The Queen’s University of Belfast, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), Skytthe A., Valensin S., Jeune B., Cevenini E., Balard F., Beekman M., Bezrukov V., Blanche H., Bolund L., Broczek K., Carru C., Christensen K., Christiansen L., Collerton J.C., Cotichini R., de Craen A.J., Dato S., Davies K., De Benedictis G., Deiana L., Flachsbart F., Gampe J., Gilbault C., Gonos E.S., Haimes E., Hervonen A., Hurme M.A., Janiszewska D., Jylha M., Kirkwood T.B., Kristensen P., Laiho P., Leon A., Marchisio A., Masciulli R., Nebel A., Passarino G., Pelicci G., Peltonen L., Perola M., Poulain M., Rea I.M., Remacle J., Robine J.M., Schreiber S., Scurti M., Sevini F., Sikora E., Skouteri A., Slagboom P.E., Spazzafumo L., Stazi M.A., Toccaceli V., Toussaint O., Tornwall O., Vaupel J.W., Voutetakis K., Franceschi C., GEHA consortium [Pini Elisa, Palmas Maria Giustina, Panourgia Maria Panagiota], balard, frédéric, and GEnetics for Healthy Aging - GEHA - 26813 - OLD
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Research design ,Gerontology ,Male ,Questionnaires ,Aging ,Genetic Linkage ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Biochemistry ,Nonagenarian sib pairs ,[SHS]Humanities and Social Sciences ,0302 clinical medicine ,Endocrinology ,Cognition ,Surveys and Questionnaires ,80 and over ,Medicine ,ComputingMilieux_MISCELLANEOUS ,media_common ,Genetics ,Aged, 80 and over ,0303 health sciences ,Life style ,Longevity ,Middle Aged ,HEALTHY AGING ,[SDV] Life Sciences [q-bio] ,Europe ,Research Design ,Extreme longevity tracking ,Female ,[SHS] Humanities and Social Sciences ,media_common.quotation_subject ,Article ,03 medical and health sciences ,Healthy ageing ,Humans ,Family ,Molecular Biology ,Life Style ,030304 developmental biology ,Genetic association ,Aged ,nonagenarian sib pair ,business.industry ,Patient Selection ,Cell Biology ,Multicenter study ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity. In 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7years the number of families with all participating siblings aged 95years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.
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- 2011
15. Human longevity and 11p15.5: a study in 1321 centenarians
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Stefan Schreiber, Hélène Blanché, Sandro Sorbi, Friederike Flachsbart, Eline Slagboom, Mourad Sahbatou, Giuseppe Passarino, Almut Nebel, Marian Beekman, Claudio Franceschi, Francesco Lescai, Lescai F., Blanché H., Nebel A., Beekman M., Sahbatou M., Flachsbart F., Slagboom E., Schreiber S., Sorbi S., Passarino G., and Franceschi C.
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Male ,media_common.quotation_subject ,Longevity ,Short Report ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,White People ,Genetic variation ,Genotype ,Genetics ,SNP ,Humans ,Longevity, genetics ,Genetics (clinical) ,Genetic association ,media_common ,Aged ,Aged, 80 and over ,European Continental Ancestry Group, genetics ,Chromosomes, Human, Pair 11 ,Genetic Variation ,Middle Aged ,Human genetics ,Chromosomal region ,Female - Abstract
The 11p15.5 chromosomal region (2.8 Mb) is of particular interest as it encloses five genes (HRAS1, SIRT3, 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 1140 younger subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 SNPs. No significant results (P
- Published
- 2009
16. Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.
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Torres GG, Nygaard M, Caliebe A, Blanché H, Chantalat S, Galan P, Lieb W, Christiansen L, Deleuze JF, Christensen K, Strauch K, Müller-Nurasyid M, Peters A, Nöthen MM, Hoffmann P, Flachsbart F, Schreiber S, Ellinghaus D, Franke A, Dose J, and Nebel A
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- Aged, 80 and over, Alleles, Case-Control Studies, Exome genetics, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Longevity genetics, Phosphoric Monoester Hydrolases genetics, Phosphotransferases (Alcohol Group Acceptor) genetics
- Abstract
Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP)., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.)
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- 2021
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17. DNA methylation QTL analysis identifies new regulators of human longevity.
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Szymczak S, Dose J, Torres GG, Heinsen FA, Venkatesh G, Datlinger P, Nygaard M, Mengel-From J, Flachsbart F, Klapper W, Christensen K, Lieb W, Schreiber S, Häsler R, Bock C, Franke A, and Nebel A
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- Aged, 80 and over, DNA Methylation genetics, Epigenesis, Genetic genetics, Epigenome genetics, Female, Gene Expression Regulation genetics, Genome, Human genetics, Humans, Male, Mitochondrial Precursor Protein Import Complex Proteins, Apolipoproteins E genetics, DNA-Binding Proteins genetics, Endonucleases genetics, Longevity genetics, Membrane Transport Proteins genetics, Nectins genetics
- Abstract
Human longevity is a complex trait influenced by both genetic and environmental factors, whose interaction is mediated by epigenetic mechanisms like DNA methylation. Here, we generated genome-wide whole-blood methylome data from 267 individuals, of which 71 were long-lived (90-104 years), by applying reduced representation bisulfite sequencing. We followed a stringent two-stage analysis procedure using discovery and replication samples to detect differentially methylated sites (DMSs) between young and long-lived study participants. Additionally, we performed a DNA methylation quantitative trait loci analysis to identify DMSs that underlie the longevity phenotype. We combined the DMSs results with gene expression data as an indicator of functional relevance. This approach yielded 21 new candidate genes, the majority of which are involved in neurophysiological processes or cancer. Notably, two candidates (PVRL2, ERCC1) are located on chromosome 19q, in close proximity to the well-known longevity- and Alzheimer's disease-associated loci APOE and TOMM40. We propose this region as a longevity hub, operating on both a genetic (APOE, TOMM40) and an epigenetic (PVRL2, ERCC1) level. We hypothesize that the heritable methylation and associated gene expression changes reported here are overall advantageous for the LLI and may prevent/postpone age-related diseases and facilitate survival into very old age., (© The Author(s) 2020. Published by Oxford University Press.)
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- 2020
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18. Blood coagulation: a powerful bactericidal mechanism of human innate immunity.
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Minasyan H and Flachsbart F
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- Anti-Bacterial Agents, Humans, Immunity, Innate, Oxyhemoglobins metabolism, Blood Coagulation, Blood Platelets physiology, Erythrocytes physiology, Infections immunology, Macrophages physiology, Neutrophils physiology
- Abstract
Infection proliferates and disseminates rapidly and so innate immunity should react effectively and fast. Innate immunity mechanisms depend upon fluid dynamics and are different in compartments with slow (the tissues) and rapid (the bloodstream) liquid flow. In the tissues, coagulation initiated by clotting factors, platelets and erythrocytes, is prompt and effective mechanism of the first line of antibacterial defense. Resident macrophages, transmigrated neutrophils, monocytes, NETs and platelets are the second line of the defense. In the bloodstream the first line of innate immunity defense are erythrocytes that kill pathogens by oxygen, released from oxyhemoglobin (oxycytosis); the second line of the defense is coagulation that in case of overactivation may cause disseminated intravascular coagulation (DIC). Blood coagulation is the fastest mechanism of infection confinement and inactivation. It is the first and the last line of innate immunity defense and occurs both in the tissues and the bloodstream.
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- 2019
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19. On a Western diet, APOEɛ4 is associated with low innate immune sensing, but not APOEɛ3.
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Dose J, Schloesser A, Torres GG, Venkatesh G, Häsler R, Flachsbart F, Lieb W, Nebel A, Rimbach G, and Huebbe P
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- Acute-Phase Proteins metabolism, Alkaline Phosphatase metabolism, Animals, Carrier Proteins metabolism, Feces chemistry, Female, Genotype, Humans, Lipopolysaccharide Receptors metabolism, Liver enzymology, Male, Membrane Glycoproteins metabolism, Mice, Apolipoprotein E3 genetics, Apolipoprotein E4 genetics, Diet, Western, Immunity, Innate, Toll-Like Receptors blood
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- 2018
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20. Publisher Correction: Identification and characterization of two functional variants in the human longevity gene FOXO3.
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Flachsbart F, Dose J, Gentschew L, Geismann C, Caliebe A, Knecht C, Nygaard M, Badarinarayan N, ElSharawy A, May S, Luzius A, Torres GG, Jentzsch M, Forster M, Häsler R, Pallauf K, Lieb W, Derbois C, Galan P, Drichel D, Arlt A, Till A, Krause-Kyora B, Rimbach G, Blanché H, Deleuze JF, Christiansen L, Christensen K, Nothnagel M, Rosenstiel P, Schreiber S, Franke A, Sebens S, and Nebel A
- Abstract
The original version of this Article contained an error in the spelling of the author Robert Häsler, which was incorrectly given as Robert Häesler. This has now been corrected in both the PDF and HTML versions of the Article.
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- 2018
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21. Identification and characterization of two functional variants in the human longevity gene FOXO3.
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Flachsbart F, Dose J, Gentschew L, Geismann C, Caliebe A, Knecht C, Nygaard M, Badarinarayan N, ElSharawy A, May S, Luzius A, Torres GG, Jentzsch M, Forster M, Häsler R, Pallauf K, Lieb W, Derbois C, Galan P, Drichel D, Arlt A, Till A, Krause-Kyora B, Rimbach G, Blanché H, Deleuze JF, Christiansen L, Christensen K, Nothnagel M, Rosenstiel P, Schreiber S, Franke A, Sebens S, and Nebel A
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- Age Factors, Aged, Aged, 80 and over, Alleles, CCCTC-Binding Factor genetics, CCCTC-Binding Factor metabolism, Computer Simulation, Female, Forkhead Box Protein O3 genetics, Haplotypes genetics, Humans, Insulin-Like Growth Factor I metabolism, Introns genetics, Male, Middle Aged, RNA, Messenger metabolism, Serum Response Factor genetics, Serum Response Factor metabolism, Forkhead Box Protein O3 physiology, Longevity genetics, Polymorphism, Single Nucleotide genetics, White People genetics
- Abstract
FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.
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- 2017
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22. Association of Polymorphisms in Connective Tissue Growth Factor and Epidermal Growth Factor Receptor Genes With Human Longevity.
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Donlon TA, Morris BJ, He Q, Chen R, Masaki KH, Allsopp RC, Willcox DC, Tranah GJ, Parimi N, Evans DS, Flachsbart F, Nebel A, Kim DH, Park J, and Willcox BJ
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- Aged, 80 and over, Asian People genetics, Genetic Variation, Humans, Male, Polymorphism, Single Nucleotide, United States epidemiology, White People genetics, Connective Tissue Growth Factor genetics, ErbB Receptors genetics, Longevity genetics
- Abstract
Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p < .05 level for 2 SNPs in CTGF and 7 in EGFR. Two in CTGF and two in EGFR remained significant after Bonferroni correction. The SNPs of both CTGF and EGFR were in a haplotype block in each respective gene. Haplotype analysis confirmed the suggestive association found by χ2 analysis. We noted an excess of heterozygotes among the longevity cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2017
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23. Genetic interplay between human longevity and metabolic pathways - a large-scale eQTL study.
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Häsler R, Venkatesh G, Tan Q, Flachsbart F, Sinha A, Rosenstiel P, Lieb W, Schreiber S, Christensen K, Christiansen L, and Nebel A
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- Adult, Aged, Aged, 80 and over, Denmark, Genome, Human, Genotype, Germany, High-Throughput Nucleotide Sequencing, Humans, Longitudinal Studies, Middle Aged, Quantitative Trait, Heritable, Twins, Dizygotic, Twins, Monozygotic, Longevity genetics, Metabolic Networks and Pathways genetics, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcriptome
- Abstract
Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study (eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
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- 2017
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24. Gursharan Singh Chhatwal.
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Anand JK and Flachsbart F
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- Germany, History, 20th Century, History, 21st Century, Humans, India, Microbiology history
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- 2017
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25. Immunochip analysis identifies association of the RAD50/IL13 region with human longevity.
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Flachsbart F, Ellinghaus D, Gentschew L, Heinsen FA, Caliebe A, Christiansen L, Nygaard M, Christensen K, Blanché H, Deleuze JF, Derbois C, Galan P, Büning C, Brand S, Peters A, Strauch K, Müller-Nurasyid M, Hoffmann P, Nöthen MM, Lieb W, Franke A, Schreiber S, and Nebel A
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- Acid Anhydride Hydrolases, Chromosomes, Human, Pair 5 genetics, Genetic Loci, Humans, DNA Repair Enzymes genetics, DNA-Binding Proteins genetics, Genome-Wide Association Study, Interleukin-13 genetics, Longevity genetics, Longevity immunology, Oligonucleotide Array Sequence Analysis
- 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., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
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- 2016
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26. Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation.
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Hoffmann S, Clauss S, Berger IM, Weiß B, Montalbano A, Röth R, Bucher M, Klier I, Wakili R, Seitz H, Schulze-Bahr E, Katus HA, Flachsbart F, Nebel A, Guenther SP, Bagaev E, Rottbauer W, Kääb S, Just S, and Rappold GA
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- Adolescent, Animals, Cohort Studies, DNA Mutational Analysis, Female, Humans, Male, Mice, Middle Aged, Mutation, Missense, Polymerase Chain Reaction, Transfection, Young Adult, Zebrafish, Atrial Fibrillation genetics, Genetic Predisposition to Disease genetics, Homeodomain Proteins genetics
- Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with a strong genetic component. Molecular pathways involving the homeodomain transcription factor Shox2 control the development and function of the cardiac conduction system in mouse and zebrafish. Here we report the analysis of human SHOX2 as a potential susceptibility gene for early-onset AF. To identify causal variants and define the underlying mechanisms, results from 378 patients with early-onset AF before the age of 60 years were analyzed and compared to 1870 controls or reference datasets. We identified two missense mutations (p.G81E, p.H283Q), that were predicted as damaging. Transactivation studies using SHOX2 targets and phenotypic rescue experiments in zebrafish demonstrated that the p.H283Q mutation severely affects SHOX2 pacemaker function. We also demonstrate an association between a 3'UTR variant c.*28T>C of SHOX2 and AF (p = 0.00515). Patients carrying this variant present significantly longer PR intervals. Mechanistically, this variant creates a functional binding site for hsa-miR-92b-5p. Circulating hsa-miR-92b-5p plasma levels were significantly altered in AF patients carrying the 3'UTR variant (p = 0.0095). Finally, we demonstrate significantly reduced SHOX2 expression levels in right atrial appendages of AF patients compared to patients with sinus rhythm. Together, these results suggest a genetic contribution of SHOX2 in early-onset AF.
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- 2016
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27. Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibility for autoimmune blistering diseases.
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Recke A, Vidarsson G, Ludwig RJ, Freitag M, Möller S, Vonthein R, Schellenberger J, Haase O, Görg S, Nebel A, Flachsbart F, Schreiber S, Lieb W, Gläser R, Benoit S, Sárdy M, Eming R, Hertl M, Zillikens D, König IR, Schmidt E, and Ibrahim S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Autoimmune Diseases genetics, Blister genetics, Case-Control Studies, Child, Child, Preschool, DNA Copy Number Variations genetics, Female, GPI-Linked Proteins genetics, GPI-Linked Proteins immunology, Gene Expression immunology, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Granulocytes metabolism, Humans, Infant, Infant, Newborn, Male, Middle Aged, Reactive Oxygen Species immunology, Reactive Oxygen Species metabolism, Receptors, IgG genetics, Autoimmune Diseases immunology, Blister immunology, DNA Copy Number Variations immunology, Granulocytes immunology, Receptors, IgG immunology
- Abstract
Low-affinity Fcγ receptors (FcγR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcγR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcγR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcγR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcγR. In a two-stage study, we analyzed whether the FcγR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcγR genes affect FcγR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcγR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcγR genotype association patterns, pointing towards different disease etiologies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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28. Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis.
- Author
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Debrabant B, Soerensen M, Flachsbart F, Dato S, Mengel-From J, Stevnsner T, Bohr VA, Kruse TA, Schreiber S, Nebel A, Christensen K, Tan Q, and Christiansen L
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, DNA Damage, DNA Repair Enzymes genetics, Female, Humans, Male, Middle Aged, DNA Repair genetics, Longevity genetics, Polymorphism, Single Nucleotide
- 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.
- Published
- 2014
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29. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.
- Author
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Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, Mcnerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, and Slagboom PE
- Subjects
- Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases genetics, Chromosome Mapping, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Female, Genome-Wide Association Study, Humans, Hypertension genetics, Male, Phenotype, Prospective Studies, White People, Genetic Loci physiology, Longevity genetics
- Abstract
The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated., (© The Author 2014. Published by Oxford University Press.)
- Published
- 2014
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30. SLC23A1 polymorphism rs6596473 in the vitamin C transporter SVCT1 is associated with aggressive periodontitis.
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de Jong TM, Jochens A, Jockel-Schneider Y, Harks I, Dommisch H, Graetz C, Flachsbart F, Staufenbiel I, Eberhard J, Folwaczny M, Noack B, Meyle J, Eickholz P, Gieger C, Grallert H, Lieb W, Franke A, Nebel A, Schreiber S, Doerfer C, Jepsen S, Bruckmann C, van der Velden U, Loos BG, and Schaefer AS
- Subjects
- Adult, Aged, 80 and over, Alveolar Bone Loss genetics, Case-Control Studies, Chronic Periodontitis genetics, Female, Gene Frequency genetics, Genetic Variation genetics, Genotype, Humans, Male, Middle Aged, Sex Factors, Smoking, Aggressive Periodontitis genetics, Polymorphism, Single Nucleotide genetics, Sodium-Coupled Vitamin C Transporters genetics
- Abstract
Aim: Identification of variants within genes SLC23A1 and SLC23A2 coding for vitamin C transporter proteins associated with aggressive (AgP) and chronic periodontitis (CP)., Material and Methods: Employment of three independent case-control samples of AgP (I. 283 cases, 979 controls; II. 417 cases, 1912 controls; III. 164 cases, 357 controls) and one sample of CP (1359 cases, 1296 controls)., Results: Stage 1: Among the tested single-nucleotide polymorphisms (SNPs), the rare allele (RA) of rs6596473 in SLC23A1 showed nominal significant association with AgP (p = 0.026, odds ratio [OR] 1.26, and a highly similar minor allele frequency between different control panels. Stage 2: rs6596473 showed no significant association with AgP in the replication with the German and Dutch case-control samples. After pooling the German AgP populations (674 cases, 2891 controls) to significantly increase the statistical power (SP = 0.81), rs6596473 RA showed significant association with AgP prior to and upon adjustment with the covariates smoking and gender with padj = 0.005, OR = 1.35. Stage 3: RA of rs6596473 showed no significant association with severe CP., Conclusion: SNP rs6596473 of SLC23A1 is suggested to be associated with AgP. These results add to previous reports that vitamin C plays a role in the pathogenesis of periodontitis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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31. Adjustment for smoking does not alter the FOXO3A association with longevity.
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Däumer C, Flachsbart F, Caliebe A, Schreiber S, Nebel A, and Krawczak M
- Subjects
- Aged, Aged, 80 and over, Female, Forkhead Box Protein O3, Forkhead Transcription Factors metabolism, Genetic Variation, Genotype, Germany epidemiology, Haplotypes, Humans, Incidence, Lung Neoplasms epidemiology, Lung Neoplasms genetics, Lung Neoplasms metabolism, Male, Middle Aged, Phenotype, Retrospective Studies, Risk Factors, Smoking genetics, DNA genetics, Forkhead Transcription Factors genetics, Longevity genetics, Polymorphism, Single Nucleotide, Smoking adverse effects
- Abstract
Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer.
- Published
- 2014
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32. Investigation of complement component C4 copy number variation in human longevity.
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Flachsbart F, Caliebe A, Heinsen FA, Hemming-Karlsen T, Schreiber S, Franke A, and Nebel A
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Female, Gene Frequency, Genotype, Germany, Humans, Male, Middle Aged, Risk Factors, Young Adult, Complement C4 genetics, DNA Copy Number Variations, Longevity genetics
- Abstract
Genetic factors have been estimated to account for about 25% of the variation in an adult's life span. The complement component C4 with the isotypes C4A and C4B is an effector protein of the immune system, and differences in the overall C4 copy number or gene size (long C4L; short C4S) may influence the strength of the immune response and disease susceptibilities. Previously, an association between C4B copy number and life span was reported for Hungarians and Icelanders, where the C4B*Q0 genotype, which is defined by C4B gene deficiency, showed a decrease in frequency with age. Additionally, one of the studies indicated that a low C4B copy number might be a genetic trait that is manifested only in the presence of the environmental risk factor "smoking". These observations prompted us to investigate the role of the C4 alleles in our large German longevity sample (∼ 700 cases; 94-110 years and ∼ 900 younger controls). No significant differences in the number of C4A, C4B and C4S were detected. Besides, the C4B*Q0 carrier state did not decrease with age, irrespective of smoking as an interacting variable. However, for C4L*Q0 a significantly different carrier frequency was observed in the cases compared with controls (cases: 5.08%; controls: 9.12%; p = 0.003). In a replication sample of 714 German cases (91-108 years) and 890 controls this result was not replicated (p = 0.14) although a similar trend of decreased C4L*Q0 carrier frequency in cases was visible (cases: 7.84%; controls: 10.00%).
- Published
- 2014
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33. Polymorphisms in the superoxidase dismutase genes reveal no association with human longevity in Germans: a case-control association study.
- Author
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Gentschew L, Flachsbart F, Kleindorp R, Badarinarayan N, Schreiber S, and Nebel A
- Subjects
- Aged, 80 and over, Case-Control Studies, Female, Gene Frequency, Germany, Haplotypes, Humans, Male, Phenotype, Superoxide Dismutase-1, Longevity genetics, Polymorphism, Single Nucleotide, Superoxide Dismutase genetics
- Abstract
The role of superoxide dismutases (SODs) in aging and oxidative stress regulation has been widely studied and there is growing evidence that imbalances in these processes influence lifespan in several species. In humans, genetic polymorphisms in SOD genes may play an important role in the development of age-related diseases and genetic variation in SOD2 is thought to be associated with longevity. These observations prompted us to perform a case-control association study using a comprehensive haplotype tagging approach for the three SOD genes (SOD1, SOD2, SOD3) by testing a total of 19 SNPs in our extensive collection of 1,612 long-lived individuals (centenarians and nonagenarians) and 1,104 younger controls. Furthermore, we intended to replicate the previous association of the SOD2 SNP rs4880 with longevity observed in a Danish cohort. In our study, no association was detected between the tested SNPs and the longevity phenotype, neither in the entire long-lived sample set nor in the centenarian subgroup analysis. Our results suggest that there is no considerable influence of sequence variation in the SOD genes on human longevity in Germans.
- Published
- 2013
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34. AKT1 fails to replicate as a longevity-associated gene in Danish and German nonagenarians and centenarians.
- Author
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Nygaard M, Soerensen M, Flachsbart F, Mengel-From J, Tan Q, Schreiber S, Nebel A, Christensen K, and Christiansen L
- Subjects
- Aged, 80 and over, Denmark, Female, Genotype, Germany, Humans, Male, Models, Genetic, Longevity genetics, Polymorphism, Single Nucleotide genetics, Proto-Oncogene Proteins c-akt genetics
- Abstract
In addition to APOE and FOXO3, AKT1 has recently been suggested as a third consistent longevity gene, with variants in AKT1 found to be associated with human lifespan in two previous studies. Here, we evaluated AKT1 as a longevity-associated gene across populations by attempting to replicate the previously identified variant rs3803304 as well as by analyzing six additional AKT1 single-nucleotide polymorphisms, thus capturing more of the common variation in the gene. The study population was 2996 long-lived individuals (nonagenarians and centenarians) and 1840 younger controls of Danish and German ancestry. None of the seven SNPs tested were significantly associated with longevity in either a case-control or a longitudinal setting, although a supportive nominal indication of a disadvantageous effect of rs3803304 was found in a restricted group of Danish centenarian men. Overall, our results do not support AKT1 as a universal longevity-associated gene.
- Published
- 2013
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35. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
- Author
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Beekman M, Blanché H, Perola M, Hervonen A, Bezrukov V, Sikora E, Flachsbart F, Christiansen L, De Craen AJ, Kirkwood TB, Rea IM, Poulain M, Robine JM, Valensin S, Stazi MA, Passarino G, Deiana L, Gonos ES, Paternoster L, Sørensen TI, Tan Q, Helmer Q, van den Akker EB, Deelen J, Martella F, Cordell HJ, Ayers KL, Vaupel JW, Törnwall O, Johnson TE, Schreiber S, Lathrop M, Skytthe A, Westendorp RG, Christensen K, Gampe J, Nebel A, Houwing-Duistermaat JJ, Slagboom PE, and Franceschi C
- Subjects
- Aged, Aged, 80 and over, Alleles, Chromosome Mapping, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 19, Cluster Analysis, Europe, Genetic Linkage, Genome, Human, Genome-Wide Association Study, Humans, Lod Score, Middle Aged, Mitochondrial Precursor Protein Import Complex Proteins, Siblings, Apolipoprotein C-I genetics, Apolipoproteins E genetics, Genetic Loci, Longevity genetics, Membrane Transport Proteins genetics
- Abstract
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity., (© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)
- Published
- 2013
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36. Genetic investigation of FOXO3A requires special attention due to sequence homology with FOXO3B.
- Author
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Flachsbart F, Möller M, Däumer C, Gentschew L, Kleindorp R, Krawczak M, Caliebe A, Schreiber S, and Nebel A
- Subjects
- Forkhead Box Protein O3, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Sequence Homology, Forkhead Transcription Factors genetics, Longevity genetics, Pseudogenes genetics
- Abstract
Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (P(each)=0.0008). Because both SNPs are located in the 3' untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance.
- Published
- 2013
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37. Genome-wide miRNA signatures of human longevity.
- Author
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ElSharawy A, Keller A, Flachsbart F, Wendschlag A, Jacobs G, Kefer N, Brefort T, Leidinger P, Backes C, Meese E, Schreiber S, Rosenstiel P, Franke A, and Nebel A
- Subjects
- Adult, Aged, Aged, 80 and over, Aging blood, Aging genetics, Disease genetics, Down-Regulation, Female, Genetic Markers, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Reproducibility of Results, Risk Factors, Up-Regulation, Longevity genetics, MicroRNAs blood, MicroRNAs genetics
- Abstract
Little is known about the functions of miRNAs in human longevity. Here, we present the first genome-wide miRNA study in long-lived individuals (LLI) who are considered a model for healthy aging. Using a microarray with 863 miRNAs, we compared the expression profiles obtained from blood samples of 15 centenarians and nonagenarians (mean age 96.4 years) with those of 55 younger individuals (mean age 45.9 years). Eighty miRNAs showed aging-associated expression changes, with 16 miRNAs being up-regulated and 64 down-regulated in the LLI relative to the younger probands. Seven of the eight selected aging-related biomarkers were technically validated using quantitative RT-PCR, confirming the microarray data. Three of the eight miRNAs were further investigated in independent samples of 15 LLI and 17 younger participants (mean age 101.5 and 36.9 years, respectively). Our screening confirmed previously published miRNAs of human aging, thus reflecting the utility of the applied approach. The hierarchical clustering analysis of the miRNA microarray expression data revealed a distinct separation between the LLI and the younger controls (P-value < 10(-5) ). The down-regulated miRNAs appeared as a cluster and were more often reported in the context of diseases than the up-regulated miRNAs. Moreover, many of the differentially regulated miRNAs are known to exhibit contrasting expression patterns in major age-related diseases. Further in silico analyses showed enrichment of potential targets of the down-regulated miRNAs in p53 and other cancer pathways. Altogether, synchronized miRNA-p53 activities could be involved in the prevention of tumorigenesis and the maintenance of genomic integrity during aging., (© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)
- Published
- 2012
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38. Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans.
- Author
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Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, and Nebel A
- Subjects
- Aged, Aged, 80 and over, Cell Cycle Proteins, Forkhead Box Protein O1, Germany, Haplotypes, Humans, Linkage Disequilibrium, Middle Aged, Forkhead Transcription Factors genetics, Longevity genetics, Transcription Factors genetics, White People genetics
- Abstract
In mammals, the forkhead box class O (FOXO) family of transcription factors consists of the four members FOXO1, FOXO3A, FOXO4, and FOXO6. The FOXO genes are homologues of daf-16, a key regulator of the insulin-IGF1 signaling pathway and a modulator of lifespan in Caenorhabditis elegans. Recently, variants in FOXO3A have consistently been associated with human longevity in various populations worldwide. Given this confirmed finding, it is conceivable that polymorphisms in the other FOXO genes might have a similar effect on human longevity. To evaluate whether allelic variation in FOXO1, FOXO4, and FOXO6 influences the ability to become long-lived, we performed a comprehensive haplotype-tagging analysis of the three genes in a group of 1447 centenarians/nonagenarians and 1029 younger controls from Germany. This is the first investigation to analyze a possible association of human longevity with FOXO4 and FOXO6, respectively, and the largest and most comprehensive study to date to assess the genetic contribution of FOXO1 to the phenotype. Our results suggest that in Germans, none of the three genes plays a significant role in the ability to reach old age. With regard to FOXO1, this observation is supported by data from an Italian sample and is consistent with several previous reports, but appears to be in contrast to a recent study of Han Chinese. The discrepant association findings in Europeans and Chinese may be explained by their different FOXO1 linkage disequilibrium structures and could indicate a Chinese- or Asian-specific effect., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)
- Published
- 2011
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39. A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.
- Author
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Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanché H, Junge O, Wittig M, Ellinghaus D, Flachsbart F, Wichmann HE, Meitinger T, Nikolaus S, Franke A, Krawczak M, Lathrop M, and Schreiber S
- Subjects
- Aged, 80 and over, Case-Control Studies, Female, Genome-Wide Association Study, Germany, Humans, Male, Alleles, Apolipoproteins E genetics, Genetic Loci, Linkage Disequilibrium genetics, Longevity genetics, Polymorphism, Single Nucleotide
- Abstract
We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8×10(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ɛ4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
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40. Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study.
- Author
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Flachsbart F, Franke A, Kleindorp R, Caliebe A, Blanché H, Schreiber S, and Nebel A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Female, Humans, Male, Middle Aged, Models, Genetic, Tumor Suppressor Protein p53 genetics, Genetic Predisposition to Disease, Longevity genetics, Polymorphism, Single Nucleotide
- Abstract
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 pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes 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 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals 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., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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41. No or only population-specific effect of PON1 on human longevity: a comprehensive meta-analysis.
- Author
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Caliebe A, Kleindorp R, Blanché H, Christiansen L, Puca AA, Rea IM, Slagboom E, Flachsbart F, Christensen K, Rimbach G, Schreiber S, and Nebel A
- Subjects
- Apolipoprotein E4 blood, Europe, Humans, United States, Aryldialkylphosphatase genetics, Longevity genetics
- Abstract
Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet)., (2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
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42. Depletion of potential A2M risk haplotype for Alzheimer's disease in long-lived individuals.
- Author
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Flachsbart F, Caliebe A, Nothnagel M, Kleindorp R, Nikolaus S, Schreiber S, and Nebel A
- Subjects
- Aged, Aged, 80 and over, Apolipoproteins E genetics, Humans, Alzheimer Disease genetics, Genetic Predisposition to Disease, Haplotypes genetics, Longevity genetics, alpha-Macroglobulins genetics
- Abstract
Risk alleles for age-related diseases are expected to decrease in frequency in the population strata of increasing age. Consistent with this hypothesis, earlier studies showed a depletion of the Alzheimer's disease risk factor APOE*epsilon4 in long-lived individuals (LLIs). To evaluate whether this observation also holds for a previously suggested Alzheimer's disease risk haplotype in the A2M gene, we analyzed this particular haplotype in 1042 German LLIs (aged 95-100 years) and 1040 younger individuals (aged 60-75 years). Our results show a significant depletion of this haplotype in LLIs, thus confirming it as a mortality factor in the elderly. Consequently, our data support an involvement of the suggested A2M risk haplotype in the pathogenesis of Alzheimer's disease and adds new evidence to the risk-allele depletion hypothesis.
- Published
- 2010
- Full Text
- View/download PDF
43. Human longevity and 11p15.5: a study in 1321 centenarians.
- Author
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Lescai F, Blanché H, Nebel A, Beekman M, Sahbatou M, Flachsbart F, Slagboom E, Schreiber S, Sorbi S, Passarino G, and Franceschi C
- Subjects
- Aged, Aged, 80 and over, Female, Genetic Variation, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, White People genetics, Chromosomes, Human, Pair 11, Longevity genetics
- Abstract
The 11p15.5 chromosomal region (2.8 Mb) is of particular interest as it encloses five genes (HRAS1, SIRT3, 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 1140 younger subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 SNPs. No significant results (P<0.05) 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 was 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 meta-analysis 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.
- Published
- 2009
- Full Text
- View/download PDF
44. A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians.
- Author
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Nebel A, Flachsbart F, Till A, Caliebe A, Blanché H, Arlt A, Häsler R, Jacobs G, Kleindorp R, Franke A, Shen B, Nikolaus S, Krawczak M, Rosenstiel P, and Schreiber S
- Subjects
- Aged, Aged, 80 and over, Binding Sites, Case-Control Studies, DNA Repair Enzymes metabolism, Exodeoxyribonucleases metabolism, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Germany, HeLa Cells, Humans, Jurkat Cells, Logistic Models, Male, Middle Aged, RNA, Messenger metabolism, Sex Factors, TCF Transcription Factors metabolism, Transcription Factor 7-Like 1 Protein, Transfection, Up-Regulation, DNA Repair Enzymes genetics, Exodeoxyribonucleases genetics, Longevity genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
- Abstract
Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
- Published
- 2009
- Full Text
- View/download PDF
45. Association of FOXO3A variation with human longevity confirmed in German centenarians.
- Author
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Flachsbart F, Caliebe A, Kleindorp R, Blanché H, von Eller-Eberstein H, Nikolaus S, Schreiber S, and Nebel A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Forkhead Box Protein O3, Humans, Middle Aged, Polymorphism, Single Nucleotide, Forkhead Transcription Factors genetics, Genetic Variation, Longevity genetics
- Abstract
The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.
- Published
- 2009
- Full Text
- View/download PDF
46. Common coding polymorphisms in the ABCA1 gene and risk of early-onset coronary heart disease in northern Germany.
- Author
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Nebel A, Croucher PJ, El Mokhtari NE, Flachsbart F, and Schreiber S
- Subjects
- ATP Binding Cassette Transporter 1, Female, Germany, Humans, Male, Middle Aged, Polymorphism, Genetic, Risk Factors, ATP-Binding Cassette Transporters genetics, Coronary Disease genetics
- Published
- 2007
- Full Text
- View/download PDF
47. Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men.
- Author
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Nebel A, Flachsbart F, Schäfer A, Nothnagel M, Nikolaus S, Mokhtari NE, and Schreiber S
- Subjects
- Adult, Aged, Amino Acid Substitution, Aspartic Acid chemistry, Aspartic Acid genetics, Germany, Glycine chemistry, Glycine genetics, Humans, Male, Middle Aged, Polymorphism, Genetic, Longevity genetics, Myocardial Infarction genetics, Toll-Like Receptor 4 genetics
- Abstract
In a previous study on Sicilian men, an association of the functional polymorphism Asp299Gly in the TLR4 gene was reported with longevity and a reduced risk of myocardial infarction (MI). Here, we sought to confirm the findings in our extensive collection of 273 long-lived men (95-107 years), 606 male early-onset MI patients and 594 appropriate controls from Germany. Despite sufficient statistical power to replicate the findings observed in the South Italians, our results rule out a noteworthy influence of the TLR4 polymorphism upon human longevity or MI in German men. Therefore, the previously described associations in Sicilians might reflect either population-specific or potentially false-positive results.
- Published
- 2007
- Full Text
- View/download PDF
48. [Genetic factors in longevity. Healthy living into old age--what role do genes play?].
- Author
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Flachsbart F, Nebel A, Nikolaus S, and Schreiber S
- Subjects
- Animals, DNA Repair physiology, Energy Metabolism, Germany epidemiology, Humans, Mitochondria physiology, Oxidative Stress physiology, Longevity genetics, Longevity physiology
- Published
- 2005
49. [Diagnosis of acute pulmonary embolism].
- Author
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Flachsbart F
- Subjects
- Enzyme-Linked Immunosorbent Assay, Humans, Pulmonary Embolism diagnosis
- Published
- 1998
50. [Thromboembolism--terra incognita on the map of general medicine].
- Author
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Flachsbart F
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cause of Death, Child, Child, Preschool, Diagnosis, Differential, Family Practice, Humans, Infant, Middle Aged, Pulmonary Embolism diagnosis, Pulmonary Embolism etiology, Pulmonary Embolism mortality, Retrospective Studies, Thromboembolism etiology, Thromboembolism mortality, Thromboembolism diagnosis
- Abstract
In five and a half year 1598 patients were regularly attended to. 17 patients got thromboembolism. 11 patients showed the signs of myocardial infarction, 9 patients had reversible strokes. Elder patients with risk factors in general medicine are prone to thromboembolism.
- Published
- 1993
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