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1. Genetic variation in the C-reactive protein gene and arterial stiffness: The Rotterdam Study

Author

M.P.S. Sie, F.U.S. Mattace-Raso, I. Kardys, M.P.M. de Maat, A.G. Uitterlinden, A. Hofman, A.P.G. Hoeks, R.S. Reneman, R. Asmar, C.M. van Duijn, and J.C.M. Witteman

Subjects
C-reactive protein, Polymorphism, Arterial stiffness, Pulse wave velocity, Distensibility coefficient, Pulse pressure, Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background and aim: Arterial stiffness increases with age and has been found to predict cardiovascular disease. C-reactive protein (CRP) is an inflammation marker and has been found to be associated with arterial stiffness and risk of cardiovascular disease. Genetic factors account for part of the variance in CRP level. We studied the association of the total common variation in the CRP gene by polymorphisms 1184 C/T, 2042 C/T, 2911 C/G and haplotypes with arterial stiffness within the Rotterdam study. Methods: The study (n = 3615) was embedded in the Rotterdam Study, a prospective, population-based study among subjects aged 55 years and older. Associations of genotypes and haplotypes with CRP level and measures of arterial stiffness were examined using linear regression and analyses of variance. Measures of arterial stiffness included aortic pulse wave velocity, carotid distensibility and pulse pressure. Analyses were adjusted for age, sex, mean arterial pressure, heart rate, known cardiovascular risk factors and measures of atherosclerosis. Results: CRP level was significantly associated with pulse wave velocity (p < 0.001) and pulse pressure (p < 0.05), also after adjusting for cardiovascular risk factors. CRP level was also associated with the 1184 C/T (T-allele: higher level), the 2042 C/T (T-allele: lower level) and 2911 C/G (G-allele: higher level) polymorphisms (all p < 0.001). Genotype and haplotype analyses showed no consistent associations of genetic variation with pulse wave velocity, carotid distensibility and pulse pressure. Conclusions: No consistent associations of the CRP polymorphisms 1184 C/T, 2042 C/T, 2911 C/G and corresponding haplotypes were found with measures of arterial stiffness.

Published
2008
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2. A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms

Author

René Pool, Sabine Spijker, T. E. Galesloot, Josep Antoni Ramos-Quiroga, Barbara Franke, Jan K. Buitelaar, Marieke Klein, Catharina A. Hartman, Janita Bralten, Christel M. Middeldorp, Michel G. Nivard, Conor V. Dolan, Dina Vojinovic, Lambertus A. Kiemeney, Ilja M. Nolte, Najaf Amin, Alexander J. Groffen, V. M. Kattenberg, Alejandro Arias-Vasquez, A. den Braber, Cristina Sánchez-Mora, Iryna O. Fedko, J.J.S. Kooij, J-J Hottenga, Sita H. Vermeulen, August B. Smit, Klaasjan G. Ouwens, Dorret I. Boomsma, Martine Hoogman, C.M. van Duijn, Pieter J. Hoekstra, Harmen H.M. Draisma, Marta Ribasés, Brenda W.J.H. Penninx, P. J. van der Most, Human genetics, APH - Mental Health, Psychiatry, Neurology, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Health Behaviors & Chronic Diseases, APH - Digital Health, Epidemiology, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Functional Genomics, Molecular and Cellular Neurobiology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Biological Psychology, APH - Personalized Medicine, APH - Methodology, EMGO+ - Lifestyle, Overweight and Diabetes, Center for Neurogenomics and Cognitive Research, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Male, 0301 basic medicine, Oncology, Netherlands Twin Register (NTR), Genome-wide association study, TOMOSYN, Cohort Studies, R-SNARE Proteins, Mice, 0302 clinical medicine, Risk Factors, Epidemiology, GWAS, Prefrontal cortex, Genetics (clinical), education.field_of_study, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, ASSOCIATION, Phenotype, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, RNA, Long Noncoding, medicine.symptom, SNARE COMPLEX, Adult, medicine.medical_specialty, Genotype, Population, Nerve Tissue Proteins, Single-nucleotide polymorphism, Impulsivity, BIOBANK, Polymorphism, Single Nucleotide, ADHD symptoms, DNA, Antisense, ENVIRONMENTAL-INFLUENCES, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Animals, Humans, SNP, Adults, Genetic Predisposition to Disease, AUTISM, education, Ecology, Evolution, Behavior and Systematics, DEFICIT-HYPERACTIVITY-DISORDER, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Heritability, STXBP5-AS1 gene, Genetics, Population, HEK293 Cells, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, RNA, SCALES, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10 −7 ) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in “SNAP” (Soluble NSF attachment protein) Receptor” (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r 2 = − 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.

Published
2019
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3. Predicting biological age based on the BBMRI-NL 1H-NMR metabolomics repository

Author

C.M. van Duijn, Simon P. Mooijaart, J.J.H. Barkey Wolf, Joop Jukema, B.W.J.H. Penninx, Mihai G. Netea, Bbmri-Nl, A. H. Zwinderman, Coen D.A. Stehouwer, Joris Deelen, P. Eline Slagboom, Leen M 't Hart, Marcel J. T. Reinders, H.E.D. Suchiman, D.I. Boomsma, Naveed Sattar, Stella Trompet, Marian Beekman, Ingrid Meulenbelt, Hailiang Mei, Alexandra Zhernakova, I. C. C. van der Horst, Eric Boersma, Folkert W. Asselbergs, M.M.J. van Greevenbroek, Mohammad Arfan Ikram, A.M.J.M. van den Maagdenberg, Morris A. Swertz, Petra J. M. Elders, E. B. van den Akker, Mariska Slofstra, Rob G H H Nelissen, Charlotte E. Teunissen, Margreet Kloppenburg, C.J.H. van der Kallen, W.E. van Spil, Gisela M. Terwindt, Davy Cats, P. van der Harst, Johanna M. Geleijnse, and Cisca Wijmenga

Subjects
Data access, Increased risk, Metabolomics, Biological age, Metabolome, Disease, Chronological age, Computational biology, Biology, Metabolomics data
Abstract

The blood metabolome incorporates cues from the environment as well as the host’s genetic background, potentially offering a holistic view of an individual’s health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared to one’s chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.

Published
2019
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4. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Tina Shah, E. C. M. van Leeuwen, Jingjing Liang, Susan M. Ring, Alexander Teumer, P Anugu, Salman M. Tajuddin, Aaron Isaacs, Jorgen Engmann, Marcus Dörr, Kenneth Rice, Anne B. Newman, Sonia Shah, Lenore J. Launer, Diana Kuh, Panos Roussos, P. De Vries, Bo Hedblad, Xiaofeng Zhu, Walter Palmas, John E. Deanfield, Debbie A Lawlor, Ganesh Chauhan, Dennis O. Mook-Kanamori, André G. Uitterlinden, Sudha Seshadri, Ilja M. Nolte, Elmo Mannarino, Daniel H. O'Leary, Susan R. Heckbert, Bogdan Pasaniuc, Solomon K. Musani, Rebecca Hardy, Rainer Malik, Lesca M. Holdt, Lars Lind, Reinhold Schmidt, R. de Mutsert, Aroon D. Hingorani, Riccardo E. Marioni, P. Amouyel, Albert V. Smith, Janne Pott, Eric E. Schadt, Lyytikäinen L-P., Raymond Noordam, Stéphanie Debette, Oscar H. Franco, Vincent Plagnol, Gerardo Heiss, Brenda W.J.H. Penninx, SG Wannamethee, Carl D. Langefeld, Stella Trompet, C.M. van Duijn, Tessel E. Galesloot, Peter K. Joshi, Maryam Kavousi, Juan P. Casas, Joanna M. Wardlaw, P. Giral, Julian Halcox, Björkegren Jlm., U de Faire, Andries J. Smit, Christina L. Wassel, Christopher J. O'Donnell, Matthew Traylor, Uwe Völker, Mika Kivimäki, Jenna Price, Quenna Wong, Chris Finan, Wayne D. Rosamond, Markus Loeffler, Harry Campbell, L Lu, Jerome I. Rotter, Joop Jukema, Karl Gertow, Edith Hofer, Hugh S. Markus, Albert Hofman, Peter H. Whincup, James G. Wilson, Michelle K. Evans, Enzo Grossi, Matthias Sitzer, Martin Dichgans, Oscar L. Rueda-Ochoa, J. C. Bis, Klodian Dhana, Ralph Burkhardt, Harold Snieder, Kiemeney Lalm., Daniel Teupser, A C Morrison, Markus Scholz, Ulf Schminke, Richard W Morris, Meena Kumari, Caroline Dale, Helena Schmidt, Sara Hägg, Niina Pitkänen, Fabrizio Veglia, Donald W. Bowden, Olli T. Raitakari, Joachim Thiery, Anders Hamsten, Muralidharan Sargurupremraj, Hwang S-J., Elena Tremoli, Stela McLachlan, Amanda J. Cox, Kent D. Taylor, Frank Beutner, Henry Völzke, Terho Lehtimäki, Abbas Dehghan, Ruth C. Lovering, Rachael P. Huntley, Mike A. Nalls, Jemma C. Hopewell, Erik Ingelsson, Claudia Giambartolomei, Bruce M. Psaty, Annie Britton, A Seldenrijk, Bengt Sennblad, Olle Melander, J. de Graaf, Adolfo Correa, Fernando Rivadeneira, Oscar Franzén, Laura M. Raffield, Alan B. Zonderman, Rona J. Strawbridge, Thomas W. Winkler, Ian J. Deary, Misa Graff, Wendy S. Post, Andrew Wong, T.B. Harris, Yasaman Saba, Arno Ruusalepp, James F. Wilson, Vilmundur Gudnason, Eric Boerwinkle, Damiano Baldassarre, Cristiano Fava, S.E. Humphries, Sudhir Kurl, Rainer Rauramaa, Christophe Tzourio, Xuejiang Guo, Nora Franceschini, Xiaoling Zhang, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: CARIM - R1.01 - Blood proteins & engineering, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Giambartolomei, Claudia [0000-0003-2786-1225], Huntley, Rachael P [0000-0001-6718-3559], Lovering, Ruth C [0000-0002-9791-0064], Tajuddin, Salman M [0000-0002-7919-8528], Winkler, Thomas W [0000-0003-0292-5421], Nolte, Ilja M [0000-0001-5047-4077], Scholz, Markus [0000-0002-4059-1779], Joshi, Peter K [0000-0002-6361-5059], Isaacs, Aaron [0000-0001-5037-4834], Correa, Adolfo [0000-0002-9501-600X], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Newman, Anne B [0000-0002-0106-1150], Sennblad, Bengt [0000-0002-4360-8003], Baldassarre, Damiano [0000-0002-2766-8882], Kuh, Diana [0000-0001-7386-2857], Schadt, Eric E [0000-0002-7892-8808], Rivadeneira, Fernando [0000-0001-9435-9441], Jukema, J Wouter [0000-0002-3246-8359], Rice, Kenneth [0000-0002-3071-7278], Dhana, Klodian [0000-0002-6397-7009], Dichgans, Martin [0000-0002-0654-387X], Traylor, Matthew [0000-0001-6624-8621], Kivimaki, Mika [0000-0002-4699-5627], Roussos, Panos [0000-0002-4640-6239], Amouyel, Philippe [0000-0001-9088-234X], Burkhardt, Ralph [0000-0003-1924-1202], Morris, Richard W [0000-0001-7240-4563], Hägg, Sara [0000-0002-2452-1500], Lawlor, Deborah A [0000-0002-6793-2262], Wilson, James F [0000-0001-5751-9178], Wardlaw, Joanna M [0000-0002-9812-6642], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Gudnason, Vilmundur [0000-0001-5696-0084], Apollo - University of Cambridge Repository, Psychiatry, APH - Mental Health, APH - Digital Health, Epidemiology, Internal Medicine, and Experimental Immunology

Subjects
0301 basic medicine, Candidate gene, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], General Physics and Astronomy, Genome-wide association study, Coronary Disease, VARIANTS, Carotid Intima-Media Thickness, Coronary artery disease, Protein-Lysine 6-Oxidase, Risk Factors, Medicine, genetics, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, GENE-PRODUCT, cardiovascular genetics, Multidisciplinary, Kardiologi, Plaque, Atherosclerotic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cardiology, cardiovascular system, Medical genetics, CORONARY-ARTERY-DISEASE, HEART, Amino Acid Oxidoreductases, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, MEGASTROKE Consortium, Science, Quantitative Trait Loci, ADAMTS9 Protein, INTEGRATIVE ANALYSIS, Locus (genetics), 610 Medicine & health, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 360 Social problems & social services, Internal medicine, MD Multidisciplinary, Humans, Erfðafræði, intima media thickness, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, Medicinsk genetik, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Intima-media thickness, genome-wide association studies, quantitative trait loci, lcsh:Q, atherosclerosis, Lod Score, hjarta, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans., The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.

Published
2018
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5. Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Author

Marcus E. Kleber, Lu Chen, Farmaki A-E., Tom R. Gaunt, C.M. van Duijn, Gianluigi Zaza, Charles Kooperberg, Abbas Dehghan, Oscar H. Franco, Jian'an Luan, Matthew T. Maurano, Mattia Frontini, Nicole Soranzo, Giovanni Malerba, George Dedoussis, Tao Jiang, Heather Elding, Michela Traglia, Raha Pazoki, Robert A. Scott, Maria Sabater-Lleal, Mattias Frånberg, J L Min, Daniela Toniolo, Valentina Iotchkova, Paul L. Auer, Adam S. Butterworth, E. C. M. van Leeuwen, Daniel Mead, Christopher S. Franklin, Anders Hamsten, Yasin Memari, André G. Uitterlinden, William J. Astle, Lorraine Southam, Claudia Langenberg, Jie Huang, Massimiliano Cocca, Fernando Rivadeneira, Alexander P. Reiner, Patrick Deelen, John A. Morris, Giovanni Gambaro, Ioanna Ntalla, Aaron Isaacs, Genevieve Lachance, Winfried März, N J Timpson, Perry Jrb., Kalliope Panoutsopoulou, Najaf Amin, Hugh Watkins, Albert Hofman, John C. Chambers, Lude Franke, Eleftheria Zeggini, Weihua Zhang, Shin S-Y., Caterina Barbieri, Deepti Jain, Bengt Sennblad, Angela Matchan, Jaspal S. Kooner, Klaudia Walter, Morris A. Swertz, Paolo Gasparini, and F van Dijk

Subjects
Cardiometabolic risk, Genetics & Heredity, Science & Technology, Published Erratum, MEDLINE, Computational biology, Biology, 06 Biological Sciences, Genetics, UK10K Consortium, Life Sciences & Biomedicine, Imputation (genetics), 11 Medical and Health Sciences, Developmental Biology
Abstract

Correction to: Nature Genetics https://doi.org/10.1038/ng.3668, published online 26 September 2016. In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.

Published
2018

6. Genes, pathways, and animal models in primary open-angle glaucoma

Author

C.M. van Duijn, Robert Willemsen, Wishal D. Ramdas, H Springelkamp, Caroline C W Klaver, Adriana I. Iglesias, MUMC+: AB Oogheelkunde Atrium (9), MUMC+: MA Oogheelkunde (9), UM Sports, Oogheelkunde, RS: FHML non-thematic output, Epidemiology, Ophthalmology, and Erasmus MC other

Subjects
Retinal Ganglion Cells, medicine.medical_specialty, Intraocular pressure, genetic structures, Open angle glaucoma, Optic Disk, Optic disk, Glaucoma, Genome-wide association study, Review, Biology, Polymorphism, Single Nucleotide, Retinal ganglion, Optic neuropathy, SDG 3 - Good Health and Well-being, Ophthalmology, Optic Nerve Diseases, medicine, Animals, Humans, Genetic Association Studies, Intraocular Pressure, Genetic association, medicine.disease, eye diseases, Disease Models, Animal, sense organs, Glaucoma, Open-Angle, Genome-Wide Association Study
Abstract

Glaucoma is an optic neuropathy characterized by loss of retinal ganglion cells (RGCs) and consequently visual field loss. It is a complex and heterogeneous disease in which both environmental and genetic factors play a role. With the advent of genome-wide association studies (GWASs), the number of loci associated with primary open-angle glaucoma (POAG) have increased greatly. There has also been major progress in understanding the genes determining the vertical cup-disc ratio (VCDR), disc area (DA), cup area (CA), intraocular pressure (IOP), and central corneal thickness (CCT). In this review, we will update and summarize the genetic loci associated so far with POAG, VCDR, DA, CA, IOP, and CCT. We will describe the pathways revealed and supported by genetic association studies, integrating current knowledge from human and experimental data. Finally, we will discuss approaches for functional genomics and clinical translation.

Published
2015
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7. Association of heat shock proteins with all-cause mortality

Author

K. L. Lunetta, C.M. van Duijn, A.G. Uitterlinden, Stefania Bandinelli, Linda Broer, A. M. Arnold, Yongmei Liu, Marcus Dörr, Joanne M. Murabito, W. Hoffmann, Toshiko Tanaka, Thomas Kocher, Albert Hofman, Ellen W. Demerath, Albert V. Smith, Jerome I. Rotter, David Karasik, Bruce M. Psaty, Vilmundur Gudnason, Robert C. Kaplan, Ben A. Oostra, Kurt Lohman, Lenore J. Launer, G. J. Tranah, Luigi Ferrucci, S. Walter, H. Wallaschofski, M. E. Garcia, Nora Franceschini, Henning Tiemeier, Tamara B. Harris, Douglas P. Kiel, Gil Atzmon, G. Homuth, A.B. Newman, Epidemiology, Child and Adolescent Psychiatry / Psychology, Internal Medicine, and Clinical Genetics

Subjects
Aging, Genotype, Transcription, Genetic, Longevity, Population, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Cause of Death, Heat shock protein, Humans, Promoter Regions, Genetic, education, Genotyping, Heat-Shock Proteins, Retrospective Studies, 030304 developmental biology, Aged, 80 and over, Genetics, 0303 health sciences, education.field_of_study, Heat shock proteins, General Medicine, All-cause mortality, United States, 3. Good health, Hsp70, Heat shock factor, HEAT shock factor 2, Ageing, Immunology, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Forecasting
Abstract

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality. Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9417-7) contains supplementary material, which is available to authorized users.

Published
2012
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8. EVI5 is a risk gene for multiple sclerosis

Author

S V Ramagopalan, R Q Hintzen, Y S Aulchenko, I A Hoppenbrouwers, C.M. van Duijn, George C. Ebers, B.A. Oostra, Neurology, Epidemiology, and Clinical Genetics

Subjects
Adult, Male, Canada, Multiple Sclerosis, Genotype, Immunology, Population, Cell Cycle Proteins, Locus (genetics), Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Risk Factors, Odds Ratio, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, education, Gene, Genetics (clinical), Netherlands, education.field_of_study, Multiple sclerosis, GTPase-Activating Proteins, Nuclear Proteins, Reproducibility of Results, Odds ratio, medicine.disease, Genes, Chromosomes, Human, Pair 1, Case-Control Studies, Female
Abstract

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P = 0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P = 0.03 and OR 1.15; P = 0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Published
2008

9. Transforming-growth factor beta(1) Leu10Pro polymorphism and breast cancer morbidity

Author

Albert Hofman, A. M. González-Zuloeta Ladd, Jan Willem Coebergh, C. Siemes, B.H.Ch. Stricker, Jacqueline C. M. Witteman, C.M. van Duijn, A. Arias-Vásquez, A.G. Uitterlinden, Epidemiology, and Internal Medicine

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Genotype, Breast Neoplasms, medicine.disease_cause, Logistic regression, Disease-Free Survival, Transforming Growth Factor beta1, Rotterdam Study, Breast cancer, Gene Frequency, SDG 3 - Good Health and Well-being, Internal medicine, Perception and Action [DCN 1], Determinants in Health and Disease [EBP 1], medicine, Humans, Allele, Survival analysis, Aged, Netherlands, Aged, 80 and over, Polymorphism, Genetic, business.industry, medicine.disease, Confidence interval, Endocrinology, Regression Analysis, Female, business, Carcinogenesis, Functional Neurogenomics [DCN 2]
Abstract

Contains fulltext : 52445.pdf (Publisher’s version ) (Closed access) TGF-beta1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-beta1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1-2.0) against non-carriers. Our data suggest that the TGF-beta1 Leu10Pro polymorphism might play a role in breast cancer risk.

Published
2007
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10. Identification of novel genes related to airway obstruction in never-smokers

Author

Judith M. Vonk, Hendrika Boezen, Guy Brusselle, K. De Jong, C.M. van Duijn, C. C. van Diemen, Lies Lahousse, Dirkje S. Postma, and D. A. van der Plaat

Subjects
Oncology, Genetics, medicine.medical_specialty, COPD, business.industry, Single-nucleotide polymorphism, Airway obstruction, medicine.disease, respiratory tract diseases, Pathogenesis, Rotterdam Study, FEV1/FVC ratio, Internal medicine, medicine, Genetic predisposition, business, Gene
Abstract

Background: Although a striking proportion (25-45%) of patients with chronic obstructive pulmonary disease (COPD) are never-smokers, most genetic susceptibility studies have not focussed on this group exclusively. Objective: This study aims to identify common genetic variants associated with airway obstruction in never-smokers by performing a genome-wide association (GWA) study on the ratio of FEV 1 to FVC (FEV 1 /FVC). Methods: We used linear regression to analyse the association between 227,981 genotyped single nucleotide polymorphisms (SNPs) and the level of FEV 1 /FVC in 5,070 never-smokers of the LifeLines study. Results were verified in never-smokers of two other cohorts, namely the Vlagtwedde-Vlaardingen study (n = 432) and the Rotterdam study I (n = 408). Results: Seven top SNPs were associated with the level of FEV 1 /FVC (p-value -5 ) in never-smokers of the LifeLines study and were verified in the two other cohorts. Although the SNPs did not reach genome-wide significance in the meta-analysis (p-value -7 ) of the three cohorts, we observed similar directions and magnitudes of effects for four SNPs. We identified two novel SNPs, located in introns of AGAP1 , which is involved in membrane trafficking and cytoskeleton dynamics, and PACSIN2 which plays a role in vesicle formation and transport. The other two SNPs are located nearby HHIP and in an intron of FAM13A , previously identified in GWA studies on COPD (in smokers). Discussion: In never-smokers, we found associations of airway obstruction with both novel genetic variants and with genetic variants previously identified in GWA studies on COPD. This could indicate that these genes play a role in the pathogenesis of non-smoking related COPD.

Published
2015
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11. CLEC4M and STXBP5 gene variations contribute to vonWillebrand factor level variation in von Willebrand disease

Author

Y.V. Sanders, J.G. van der Bom, A. Isaacs, M.H. Cnossen, M.P.M. de Maat, B.A.P. Laros-van Gorkom, K. Fijnvandraat, K. Meijer, C.M. van Duijn, E.P. Mauser-Bunschoten, J. Eikenboom, F.W.G. Leebeek, M. Coppens, A. Kors, J. de Meris, M.R. Nijziel, R.Y.J. Tamminga, P.F. Ypma, F.J.W. Smiers, B. Granzen, K. Hamulyák, P. Brons, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, MUMC+: MA Heelkunde (9), Nutrition and Movement Sciences, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Hematology, Epidemiology, Pediatrics, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, Paediatric Infectious Diseases / Rheumatology / Immunology, Vascular Medicine, Vascular Ageing Programme (VAP), Cardiovascular Centre (CVC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Receptors, Cell Surface/genetics, Male, single nucleotide, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Von Willebrand factor, von Willebrand factor, PHENOTYPE, Gastroenterology, polymorphism, CLINICAL MARKERS, BLOOD-GROUP, 80 and over, Nerve Tissue Proteins/genetics, Child, von Willebrand Factor/analysis, Aged, 80 and over, Blood Coagulation/genetics, Pathophysiology, von Willebrand Disease, Type 1/blood, Child, Preschool, cardiovascular system, Blood Coagulation Tests, medicine.medical_specialty, Type 1/blood, Single-nucleotide polymorphism, Hemorrhage, Receptors, Cell Surface, Lectins, C-Type/genetics, DIAGNOSIS, ABO blood group system, Hemorrhage/blood, Humans, human, Blood Coagulation, Aged, Infant, von Willebrand Disease, Type 2/blood, medicine.disease, Cross-Sectional Studies, CLEC4M protein, Polymorphism, single nucleotide, Cell Adhesion Molecules, Biomarkers, STXBP5 protein, DETERMINANTS, C-Type/genetics, R-SNARE Proteins/genetics, R-SNARE Proteins, Gene Frequency, Risk Factors, Lectins, hemic and lymphatic diseases, Receptors, Non-U.S. Gov't, MCMDM-1VWD, Netherlands, Genetics, RISK, biology, Von Willebrand disease, Research Support, Non-U.S. Gov't, Hematology, Middle Aged, Multicenter Study, Molecular Diagnostic Techniques, Female, Cell Adhesion Molecules/genetics, von Willebrand disease, circulatory and respiratory physiology, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Nerve Tissue Proteins, von Willebrand Disease, Type 2, Research Support, von Willebrand Disease, Type 1, Young Adult, Internal medicine, Genetic variation, medicine, Journal Article, MANAGEMENT, Lectins, C-Type, Genetic Predisposition to Disease, Allele, Preschool, PLASMA-LEVELS, Genetic Association Studies, Cell Surface/genetics, Type 2/blood, business.industry, Confidence interval, THROMBOSIS, STXBP5 protein, human, biology.protein, CLEC4M protein, human, business, Biomarkers/blood
Abstract

Item does not contain fulltext BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to -0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.

Published
2015

12. Differential Roles of Angiotensinogen and Angiotensin Receptor type 1 Polymorphisms in Breast Cancer Risk

Author

Mojgan Yazdanpanah, Jan Willem Coebergh, C.M. van Duijn, A. Arias Vásquez, A. M. González-Zuloeta Ladd, Albert Hofman, B.H.Ch. Stricker, C. Siemes, Epidemiology, and Internal Medicine

Subjects
Cancer Research, Angiotensin receptor, medicine.medical_specialty, Genotype, DNA Mutational Analysis, Angiotensinogen, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Disease-Free Survival, Receptor, Angiotensin, Type 1, Body Mass Index, Rotterdam Study, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, Prevalence, Perception and Action [DCN 1], Determinants in Health and Disease [EBP 1], medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Aged, Netherlands, Aged, 80 and over, Hazard ratio, Case-control study, DNA, Odds ratio, Middle Aged, medicine.disease, Angiotensin II, Endocrinology, Oncology, Case-Control Studies, Female, Functional Neurogenomics [DCN 2], Follow-Up Studies
Abstract

Contains fulltext : 52360.pdf (Publisher’s version ) (Closed access) While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

Published
2006
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13. ACE polymorphisms

Author

F.A. Sayed-Tabatabaei, B.A. Oostra, A. Isaacs, C.M. van Duijn, J.C.M. Witteman, Epidemiology, and Clinical Genetics

Subjects
Polymorphism, Genetic, Physiology, Humans, Peptidyl-Dipeptidase A, Cardiology and Cardiovascular Medicine
Abstract

Angiotensin converting enzyme (ACE) plays an essential role in two physiological systems, one leading to the production of angiotensin II and the other to the degradation of bradykinin. The wide distribution and multifunctional properties of these peptides suggest that ACE could be involved in various pathophysiological conditions. The discovery that ACE levels are under genetic control ushered in a new era of investigation; most studies focused on an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene as a marker for a functional polymorphism. Recently, many single nucleotide polymorphisms were detected in the gene and the search for the locations of functional polymorphisms became a topic of extensive investigation. Nevertheless, association studies on the I/D polymorphism and clinical outcomes continued, mostly with conflicting results. This article reviews the current state of knowledge regarding ACE polymorphisms and suggests that a functional polymorphism is most likely located between intron 18 and the 3′ UTR. The potential existence of another functional polymorphism in the 5′ UTR, however, cannot be excluded. This review also presents an overview of ACE function in different pathophysiological systems, and summarizes previous reports on ACE and clinical outcomes. Although findings on the I/D polymorphism and disorders like diabetic nephropathy and Alzheimer disease can be considered conclusive, reports on most of the cardiovascular phenotypes are still controversial. Genotypic and phenotypic misclassifications, insufficient power in some studies, and the presence of interaction with other genes or environmental factors are possible explanations for the contradictory findings.

Published
2006

14. Common genetic variants influence human subcortical brain structures

Author

D.P. Hibar, J.L. Stein, M.E. Renteria, A. Arias-Vasquez, S. Desrivieres, N. Jahanshad, R. Toro, K. Wittfeld, L. Abramovic, M. Andersson, B.S. Aribisala, N.J. Armstrong, M. Bernard, M.M. Bohlken, M.P. Boks, A. den Braber, Y. Milaneschi, I.O. Fedko, J.J. Hottenga, G.W. Montgomery, D. van 't Ent, G.E. Davies, R.S. Kahn, B.W.J.H. Penninx, D.I. Boomsma, R.M. Brouwer, H.E. Hulshoff Pol, C.M. van Duijn, J.C. Bis, V. Gudnason, S. Seshadri, M. Arfan Ikram, The Alzheimer’s Disease Neuroimaging Initiative and others

Published
2015

15. A genome-wide linkage study of individuals with high scores on NEO personality traits

Author

Tatiana I. Axenovich, Anatoly V. Kirichenko, Maaike Schuur, Yurii S. Aulchenko, Najaf Amin, C.M. van Duijn, B.A. Oostra, Aaron Isaacs, A C J W Janssens, Irina V. Zorkoltseva, Elena S. Gusareva, Neurology, Epidemiology, and Clinical Genetics

Subjects
Male, Personality Inventory, Genetic Linkage, Consciousness/physiology, Developmental psychology, Cohort Studies, Extraversion, Psychological, Chromosomes, Human, Big Five personality traits, Child, Emotional Intelligence, Netherlands, Genetics, Genetic Linkage/genetics, education.field_of_study, Human/genetics, Middle Aged, Neuroticism, Anxiety Disorders, Aggression, Psychiatry and Mental health, Phenotype, Genome-Wide Association Study/methods, Female, Personality Assessment Inventory, Psychology, Personality, Agreeableness, Adult, Adolescent, Consciousness, DNA Copy Number Variations, Genotype, Population, Aggression/physiology, DNA Copy Number Variations/genetics, Chromosomes, Cellular and Molecular Neuroscience, Young Adult, Personality/genetics, Openness to experience, Humans, education, Molecular Biology, Extraversion, Family Health, Extraversion and introversion, Chromosomes, Human/genetics, Conscientiousness, Psychological, Anxiety Disorders/genetics, Genome-Wide Association Study
Abstract

The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD) = 5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and 12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P-value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques. Molecular Psychiatry (2012) 17, 1031-1041; doi:10.1038/mp.2011.97; published online 9 August 2011

Published
2012
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16. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

Author

A. G. Uitterlinden, S. Y. Shin, Massimo Mangino, N. Dahmen, Lambertus A. Kiemeney, Dorret I. Boomsma, Arfan Ikram, B.A. Oostra, D. F. Gudbjartsson, Germaine C. Verwoert, Aravinda Chakravarti, Vilmundur Gudnason, Stefan Walter, J. C. Keers, Unnur Thorsteinsdottir, F. J.A. Van Rooij, Henning Tiemeier, Grant W. Montgomery, P. Sulem, Rajesh Rawal, Tim D. Spector, Erich Wichmann, Enda M. Byrne, Nicholas G. Martin, J. C. M. Witteman, Sebastian E. Baumeister, Najaf Amin, Christopher J Hammond, C.M. van Duijn, Astrid Petersmann, Julie Johnson, Aaron Isaacs, Georgia Chenevix-Trench, A. C. J. W. Janssens, Alexander Teumer, J. M. Vink, Ilja M. Nolte, Y S Aulchenko, Angela Doering, Linda Broer, A. C. Heath, B. H.R. Wolfenbuttel, Bruce M. Psaty, Harold Snieder, Fernando Rivadeneira, Kari Stefansson, Albert Hofman, Naomi R. Wray, J. J. Hottenga, Hans-Jörgen Grabe, Rainer Biffar, Daniel Levy, Science in Healthy Ageing & healthcaRE (SHARE), Life Course Epidemiology (LCE), Faculteit Medische Wetenschappen/UMCG, Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, Neuroscience Campus Amsterdam - Addictive Behavior, EMGO+ - Lifestyle, Overweight and Diabetes, Epidemiology, Public Health, Hematology, Internal Medicine, Department of Strategic Management and Entrepreneurship, Child and Adolescent Psychiatry / Psychology, and Clinical Genetics

Subjects
Netherlands Twin Register (NTR), PSYCHOMOTOR PERFORMANCE, Male, Linkage disequilibrium, Parkinson's disease, Gene Expression, Genome-wide association study, BLOOD-PRESSURE, Aetiology, screening and detection [ONCOL 5], CAFFEINE CONSUMPTION, Caffeine/pharmacology, chemistry.chemical_compound, 0302 clinical medicine, PARKINSONS-DISEASE, Polymorphism (computer science), CYP1A2 GENOTYPE, European Continental Ancestry Group/genetics, Parkinson Disease/genetics, NRCAM, GENE-EXPRESSION, Genetics, 0303 health sciences, Genetic Predisposition to Disease/genetics, Parkinson Disease, Single Nucleotide, HUMAN BRAIN, 3. Good health, Drinking/genetics, Antigens, Neoplasm/genetics, Psychiatry and Mental health, Genome-Wide Association Study/methods, Female, Original Article, Caffeine, Cell Adhesion Molecules/genetics, MESSENGER-RNA, Protein-Serine-Threonine Kinases/genetics, coffee, Drinking, TYPE-2 DIABETES-MELLITUS, Single-nucleotide polymorphism, Gene Expression/drug effects, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, White People, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cytochrome P-450 CYP1A2/genetics, Antigens, Neoplasm, Cytochrome P-450 CYP1A2, CAB39L, Cytochrome P-450 CYP1A1, CYP1A1/CYP1A2, Humans, Genetic Predisposition to Disease, Antigens, Polymorphism, Molecular Biology, Gene, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Genetic association, Neoplasm/genetics, Cytochrome P-450 CYP1A1/genetics, Coffee/genetics, Gene Expression Profiling, Gene expression profiling, chemistry, Apoptosis Regulatory Proteins/genetics, Gene Expression Profiling/methods, Apoptosis Regulatory Proteins, AGED FINNISH MEN, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Genome-Wide Association Study, P450
Abstract

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N = 18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values = 1.6 x 10(-11) and 2.7 x 10(-11)), which were also in strong linkage disequilibrium (r(2) = 0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value = 3.9 x 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value = 7.1 x 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value = 2.2 x 10(-05)) and Parkinson's disease pathways (P-value = 3.6 x 10(-05)). Molecular Psychiatry (2012) 17, 1116-1129; doi: 10.1038/mp.2011.101; published online 30 August 2011

Published
2011
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17. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

Author

James F. Wilson, Leena Peltonen, Ida Surakka, D S Postma, Albert Hofman, Jouke-Jan Hottenga, Johan G. Eriksson, Ulla Sovio, Dennis O. Mook-Kanamori, Joachim Heinrich, Beverley M. Shields, Nicholas J. Timpson, George Dedoussis, A. H. Wijga, Paul F. O'Reilly, Chen C-M., Hong Xiang Zhang, Jarvelin M-R., Marika Kaakinen, Nabila Bouatia-Naji, Chris Power, Paul Elliott, A Pouta, Jonathan P. Bradfield, Andrew T. Hattersley, Marjan Kerkhof, Inga Prokopenko, Fernando Rivadeneira, Steegers Eap., Linda S. Adair, Jaddoe Vwv., Craig E. Pennell, Philippe Froguel, Panagiotis Deloukas, Dorret I. Boomsma, Anja Taanila, Hartikainen A-L., Julie A. Marsh, Holly Jmp., Nicole M. Warrington, Mirna Kirin, Bridget A. Knight, Rachel M. Freathy, Gonneke Willemsen, E. Widen, Timothy M. Frayling, André G. Uitterlinden, Gerard H. Koppelman, Diana L. Cousminer, Judith B. Borja, de Geus Ejc., Adaikalavan Ramasamy, Amanda J. Bennett, Jianhua Zhao, Matthew W. Gillman, Mark I. McCarthy, Cecilia M. Lindgren, Karen L. Mohlke, Coin Ljm., Joel N. Hirschhorn, Nigel W. Rayner, Y S Aulchenko, Carla M. T. Tiesler, Christopher J. Groves, Susan M. Ring, Lyle J. Palmer, G. Davey Smith, C.M. van Duijn, Beate Glaser, Wendy L. McArdle, J. Laitinen, Reedik Mägi, Hakon Hakonarson, David M. Evans, David P. Strachan, Diane J. Berry, Grant Sfa., Neelam Hassanali, Leslie A. Lange, Pimphen Charoen, Helen N. Lyon, Stavroula Kanoni, Elina Hyppönen, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute for Asthma and COPD (GRIAC), Freathy, Rachel M, Mook-Kanamori, Dennis O, Sovio, Ulla, Prokopenko, Inga, Hypponen, Elina, McCarthy, Mark I, Biological Psychology, EMGO+ - Mental Health, Erasmus MC other, Epidemiology, Gastroenterology & Hepatology, Internal Medicine, Obstetrics & Gynecology, Public Health, and Medical Research Council (MRC)

Subjects
Netherlands Twin Register (NTR), Male, Genome-wide association study, Type 2 diabetes, Cohort Studies, 0302 clinical medicine, Pregnancy, Ethnicity, Birth Weight, GESTATIONAL-AGE, Genetics & Heredity, 0303 health sciences, Gestational age, 11 Medical And Health Sciences, 3. Good health, Isoenzymes, HEAD CIRCUMFERENCE, Wellcome Trust Case Control Consortium, Female, Life Sciences & Biomedicine, Adenylyl Cyclases, Adenylate Cyclase, EXPRESSION, medicine.medical_specialty, Genotype, Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Birth weight, Ethnic Groups, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, ISOFORMS, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Early Growth Genetics (EGG) Consortium, Internal medicine, Diabetes mellitus, Cyclins, Genetics, medicine, Humans, Genetic Predisposition to Disease, COHORT, GENOME-WIDE ASSOCIATION, Alleles, METAANALYSIS, 030304 developmental biology, Fetus, Science & Technology, Models, Genetic, ADENYLYL-CYCLASE, 06 Biological Sciences, medicine.disease, GENE, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Meta-Analyses of Glucose and Insulin-related traits Consortium, TYPE-2 DIABETES RISK, Developmental Biology
Abstract

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 × 10 35) and rs9883204 in ADCY5 (P = 7 × 10 15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113g (95% CI 89-137g) lighter at birth than the 24% with zero or one alleles (P trend = 7 × 10 30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy. © 2010 Nature America, Inc. All rights reserved.

Published
2010
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18. Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

Author

Tatiana I. Axenovich, Maksim Struchalin, Manfred Kayser, Yu. S. Aulchenko, Nadezhda M. Belonogova, B.A. Oostra, C.M. van Duijn, Irina V. Zorkoltseva, Anatoly V. Kirichenko, Epidemiology, Genetic Identification, and Clinical Genetics

Subjects
Adult, Male, Linkage disequilibrium, Genotype, Genetic Linkage, Population, DNA Mutational Analysis, Population genetics, Quantitative trait locus, Biology, Genetic linkage, Genetics, Humans, education, Genetics (clinical), Netherlands, education.field_of_study, Models, Genetic, Genetic heterogeneity, Reproducibility of Results, Complex segregation analysis, Heritability, Body Height, Pedigree, Genetics, Population, Phenotype, Female, Lod Score, Software
Abstract

Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait's variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.

Published
2009

19. Meta-analyses of genetic studies on major depressive disorder

Author

A. M. González-Zuloeta Ladd, A C J W Janssens, Jurgen Del-Favero, Stephan Claes, B.A. Oostra, Sandra Lopez-Leon, C.M. van Duijn, Epidemiology, and Clinical Genetics

Subjects
Polymorphism, Single Nucleotide, Genetic determinism, Cellular and Molecular Neuroscience, Genotype, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Sequence Deletion, Genetic association, Genetics, Depressive Disorder, Major, Dopamine Plasma Membrane Transport Proteins, Membrane Glycoproteins, Polymorphism, Genetic, biology, Membrane Transport Proteins, Odds ratio, medicine.disease, Psychiatry and Mental health, Methylenetetrahydrofolate reductase, Meta-analysis, biology.protein, Major depressive disorder, Psychology, GNB3
Abstract

The genetic basis of major depressive disorder (MDD) has been investigated extensively, but the identification of MDD genes has been hampered by conflicting results from underpowered studies. We review all MDD case-control genetic association studies published before June 2007 and perform meta-analyses for polymorphisms that had been investigated in at least three studies. The study selection and data extraction were performed in duplicate by two independent investigators. The 183 papers that met our criteria studied 393 polymorphisms in 102 genes. Twenty-two polymorphisms (6%) were investigated in at least three studies. Seven polymorphisms had been evaluated in previous meta-analyses, 5 of these had new data available. Hence, we performed meta-analyses for 20 polymorphisms in 18 genes. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistically significant associations were found for the APOE varepsilon2 (OR, 0.51), GNB3 825T (OR, 1.38), MTHFR 677T (OR, 1.20), SLC6A4 44 bp Ins/Del S (OR, 1.11) alleles and the SLC6A3 40 bpVNTR 9/10 genotype (OR, 2.06). To date, there is statistically significant evidence for six MDD susceptibility genes (APOE, DRD4, GNB3, MTHFR, SLC6A3 and SLC6A4).

Published
2008

20. CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathies

Author

Anna Ladogana, Miguel Calero, N. Cuadrado-Corrales, Uta Heinemann, Eva Mitrova, C.M. van Duijn, Pascual Sánchez-Juan, Albert Saiz, Dana Slivarichova, Alison Green, Vittorio Mellina, Theodoros Sklaviadis, Katharina Stoeck, Jerzy Kulczycki, K Hess, Raquel Sánchez-Valle, Richard Knight, Inga Zerr, Erasmus MC other, and Epidemiology

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, animal diseases, Oligoclonal IgG, Creutzfeldt-Jakob Syndrome, Monocytes, Prion Diseases, 03 medical and health sciences, Leukocyte Count, 0302 clinical medicine, Cerebrospinal fluid, mental disorders, Medicine, Humans, In patient, Lymphocyte Count, 030304 developmental biology, Total protein, Aged, Aged, 80 and over, 0303 health sciences, Sporadic CJD, business.industry, Homozygote, Oligoclonal Bands, Osmolar Concentration, Genetic Variation, Cerebrospinal Fluid Proteins, Middle Aged, Virology, nervous system diseases, 3. Good health, Europe, Neurology, Csf analysis, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Patients with suspected Creutzfeldt-Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC-supported multinational study. Raised white cell counts of >5 cells/microl were found in three of 298 patients with sporadic CJD, with two cell counts of 7 cells/microl and one of 20 cells/microl. Total protein concentrations of >0.9 g/l were found in five of 438 patients with sporadic CJD, although none had a concentration of >1 g/l. CSF oligoclonal IgG was detected in eight of 182 sporadic CJD patients. Of the patients with other TSEs, six had elevated cell counts ranging from 6 to 14 cells/microl but none had total protein concentrations of >0.9 g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests.

Published
2007

21. Insertion/deletion gene polymorphism of the angiotensin-converting enzyme and blood pressure changes in older adults. The Rotterdam study

Author

Michel E. Safar, Francesco U.S. Mattace-Raso, C.M. van Duijn, T.J.M. van der Cammen, Albert Hofman, Jacqueline C. M. Witteman, M P S Sie, Internal Medicine, and Epidemiology

Subjects
Male, medicine.medical_specialty, Genotype, Population, Blood Pressure, Peptidyl-Dipeptidase A, Rotterdam Study, Internal medicine, Renin–angiotensin system, Internal Medicine, medicine, Humans, education, Aged, education.field_of_study, Polymorphism, Genetic, biology, business.industry, Angiotensin-converting enzyme, Pulse pressure, Mutagenesis, Insertional, Blood pressure, Endocrinology, biology.protein, Female, sense organs, Gene polymorphism, business, Gene Deletion
Abstract

The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene may be involved in determining blood pressure changes. The aim of the present study was to assess the relationship between the ACE I/D gene and the change of blood pressure levels during follow-up. We calculated the difference between mean levels of SBP, DBP and PP obtained during the two observations as follows: BP mean levels obtained at third phase minus the BP mean levels at baseline and subsequently we investigated the association of the ACE I/D polymorphism and the mean changes of SBP, DBP and PP levels. The study was conducted within the Rotterdam Study, a population-based cohort study including subjects aged 55 years and older. Information on the II, ID and DD genotypes of the ACE gene and mean change of blood pressure levels were available in 3966 subjects. In adjusted models, subjects with the D allele had higher mean changes of systolic and pulse pressure (PP) than subjects with the I allele. The mean changes of systolic blood pressure were 6.1 (4.7-7.5), 8.2 (7.5-9.3) and 7.4 (5.9-8.5) mm Hg in subjects with the II, ID and DD genotype, respectively. The corresponding mean changes of PP through genotypes were 4.3 (3.3-5.4), 6.0 (5.3-6.7) and 5.9 (4.9-6.9) mm Hg, respectively. No difference was found for mean change of diastolic blood pressure among genotypes. In conclusion, the results of this population-based study show that the ACE ID/DD genotypes are associated with increased mean changes of systolic and PP.

Published
2007

22. GenABEL: an R library for genorne-wide association analysis

Author

Stephan Ripke, C.M. van Duijn, Yurii S. Aulchenko, Aaron Isaacs, and Epidemiology

Subjects
Statistics and Probability, Information Storage and Retrieval, Single-nucleotide polymorphism, Biology, computer.software_genre, Biochemistry, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Software, Genome-Wide Association Analysis, Humans, Computer Simulation, Molecular Biology, 030304 developmental biology, Gene Library, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Genome, business.industry, Genome, Human, Genetic data, Computational Biology, Computer Science Applications, Visualization, Computational Mathematics, Computational Theory and Mathematics, Haplotypes, Data mining, business, computer, 030217 neurology & neurosurgery
Abstract

Here we describe an R library for genome-wide association (GWA) analysis. It implements effective storage and handling of GWA data, fast procedures for genetic data quality control, testing of association of single nucleotide polymorphisms with binary or quantitative traits, visualization of results and also provides easy interfaces to standard statistical and graphical procedures implemented in base R and special R libraries for genetic analysis. We evaluated GenABEL using one simulated and two real data sets. We conclude that GenABEL enables the analysis of GWA data on desktop computers.Availability: http://cran.r-project.orgContact: i.aoultchenko@erasmusmc.nl

Published
2007

23. Alzheimer's Disease: Genes, Pathogenesis and Risk Prediction

Author

C.M. Van Duijn and K. Sleegers

Subjects
Disease gene, medicine.medical_specialty, education.field_of_study, business.industry, Genetic counseling, Population, Public Health, Environmental and Occupational Health, Disease, medicine.disease, Pathogenesis, Genetic epidemiology, medicine, Dementia, Western world, Intensive care medicine, education, business, Psychiatry, Genetics (clinical)
Abstract

With the aging of western society the contribution to morbidity of diseases of the elderly, such as dementia, will increase exponentially. Thorough preventative and curative strategies are needed to constrain the increasing prevalence of these disabling diseases. Better understanding of the pathogenesis of disease will enable development of therapy, prevention and the identification of high-risk groups in the population. Here, we review the genetic epidemiology of Alzheimer's disease, the most common cause of dementia in the western world. The search for genetic risk factors, though far from completed, has been of major importance for understanding the pathogenesis of Alzheimer's disease. Although effective therapy is still awaited, these findings have led to new avenues for the development of drugs. Copyright 2002 S. Karger AG, Basel

Published
2002

24. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author

Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. Pearson, Pfeiffer Afh., P S Chines, N Vogelzangs, Susan Redline, Alka M. Kanaya, T B Harris, J. V. van Vliet-Ostaptchouk, Ghislain Rocheleau, Rune R. Frants, Olga D. Carlson, James G. Wilson, Melissa Garcia, Ong Rt-H., Mark J. Caulfield, Tanya M. Teslovich, Loo B-M., Beatrice Knight, Andreas Ziegler, Claudia Langenberg, Yoon Shin Cho, Paul M. Ridker, Mark J. Rieder, Praveen Sethupathy, Bert Bravenboer, J. Viikari, Matt Neville, Ioannis M. Stylianou, Andrew Walley, Jarvelin M-R., Jarred B. McAteer, Ronald M. Krauss, Augustine Kong, Oluf Pedersen, Mark J. Daly, Andrew P. Morris, Anna F. Dominiczak, Stéphane Cauchi, Michael Boehnke, Christopher J. O'Donnell, Barbara Thorand, Peter M. Nilsson, Aaron Isaacs, Deborah A. Nickerson, Roza Blagieva, Mary F. Feitosa, Nicholas J. Wareham, Robert Roberts, J S Kooner, K W van Dijk, Tiinamaija Tuomi, Paul Scheet, Lynda M. Rose, Albert V. Smith, Rafn Benediktsson, Chiara Sabatti, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Toby Johnson, Samuli Ripatti, Erik Ingelsson, Mario A. Morken, Carl G. P. Platou, Anke Tönjes, Qi Sun, Narisu Narisu, S J Bumpstead, Jose M. Ordovas, Alan B. Feranil, L Groop, P Chines, Sara M. Willems, Perry Jrb., Matthew A. Allison, Jan Scott, Cécile Lecoeur, Kastelein Jjp., Herman A. Taylor, Anyuan Cao, Christopher J. Groves, Lincoln D. Stein, Laura J. Scott, John Beilby, Kristin G. Ardlie, Christopher S. Franklin, Yoav Ben-Shlomo, B M Shields, N J Timpson, Marco Orrù, Amélie Bonnefond, Kiran Musunuru, Murielle Bochud, Udo Seedorf, Yongmei Liu, Guillaume Lettre, Lee J-Y., Alan R. Shuldiner, Ryan P. Welch, David J. Hunter, John Whitfield, Klaus Strassburger, Khaw K-T., Hartikainen A-L., Gunnar Sigurðsson, Lu Qi, Richard N. Bergman, G M Lathrop, Sigrid W. Fouchier, T van Herpt, David S. Siscovick, Igor Rudan, Richard M. Watanabe, Themistocles L. Assimes, Nicholas G. Martin, Ozren Polasek, Dhiraj Varma, K Kim, Oliver Hofmann, Nicholas D. Hastie, S Bumpstead, Jose C. Florez, Fernando Rivadeneira, Katharine R. Owen, Braxton D. Mitchell, Alisa K. Manning, Abbas Dehghan, Bruce Bartholow Duncan, Cisca Wijmenga, Timo T. Valle, Jaakko Kaprio, Mika Kivimäki, B Shields, Laila Simpson, Tim D. Spector, Paul W. Franks, Guangju Zhai, María Teresa Martínez-Larrad, Janssens Acjw., Kim L. Ward, Inês Barroso, Xiuqing Guo, Rosa Maria Roccasecca, Zari Dastani, Reijo Laaksonen, Wilmar Igl, Vincent Mooser, Niels Grarup, Cornelia Huth, Christian Gieger, Fabio Marroni, Jaakko Tuomilehto, Doney Asf., Andrew C. Edmondson, Christian Fuchsberger, Meena Kumari, David M. Nathan, Reedik Mägi, Solomon K. Musani, U de Faire, Knut Borch-Johnsen, Masahiro Koseki, Giuseppe Paolisso, Norman Klopp, Caroline S. Fox, Nelson B. Freimer, Mika Kähönen, Peter Henneman, Diana Zelenika, K Willems-Vandijk, Steven A. McCarroll, Paul Elliott, Wichmann H-E., J. C. Bis, Nita G. Forouhi, Antti Jula, Witteman Jcm., Fredrik Karpe, Joseph Hung, Antje Fischer-Rosinsky, Eric J. Brunner, Elena Gonzalez, Soumya Raychaudhuri, Jian'an Luan, Josée Dupuis, Joshua C. Randall, Taesung Park, Francis S. Collins, Lori L. Bonnycastle, Andrew A. Hicks, Peter Kovacs, Thomas Illig, Maja Barbalić, David Couper, Jaspal S. Kooner, Damien C. Croteau-Chonka, Gavin Lucas, P J Wagner, Young-Jin Kim, Yurii S. Aulchenko, Aurelian Bidulescu, Ingrid Meulenbelt, Pilar Galan, Iris M. Heid, Michael N. Weedon, Serena Sanna, Sarah H. Wild, Hivert M-F., Patricia B. Munroe, Johan G. Eriksson, Teresa Ferreira, Robert A. Scott, A. Sandbaek, Kenneth Rice, Veronique Vitart, Xin Yuan, Leslie A. Lange, Hilma Holm, Jorge R. Kizer, Timothy M. Frayling, Marika Kaakinen, Liu C-T., Petersen A-K., Peter Schwarz, G B Walters, Palmer Cna., Jean Tichet, Bernhard Paulweber, Ying Wu, Alyson Hall, Christopher T. Johansen, David Masson, Martin Ladouceur, Christie M. Ballantyne, Tai E-S., Robert Luben, Guillaume Charpentier, Angela Döring, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Mark Walker, Markus Perola, M. A. Province, Veikko Salomaa, James B. Meigs, George Davey Smith, Robert Clarke, Gerard Waeber, Stefania Bandinelli, Sally L. Ricketts, Kaisa Silander, Loos Rjf., Amanda J. Bennett, John C. Chambers, Marilyn C. Cornelis, L A Cupples, Andrew T. Hattersley, M Sandhu, Marju Orho-Melander, C M van Duijn, Olli T. Raitakari, David Meyre, Ida Surakka, Jouke-Jan Hottenga, Uh H-W., Kari Stefansson, David Melzer, P E Slagboom, Kristian Midthjell, Robert K. Semple, James P. Pirruccello, Aloysius G Lieverse, Åsa Johansson, Michael Roden, Felicity Payne, Eric J.G. Sijbrands, N P Burtt, David R. Hillman, Michael Marmot, Todd Green, Eric E. Schadt, Sijbrands Ejg., Tien Yin Wong, Coin Ljm., K B Boström, Olov Rolandsson, A D Morris, David Altshuler, Harald Grallert, L C Groop, Alan F. Wright, Karen Kapur, Xueling Sim, Philippe Froguel, K O Kyvik, T. Lauritzen, Linda S. Adair, Yavuz Ariyurek, Talin Haritunians, Toshiko Tanaka, Albert Hofman, MariaGrazia Franzosi, Nicholas L. Smith, Laura Crisponi, Andrew B. Singleton, A Uitterlinden, Bo Isomaa, Y A Kesaniemi, Anne U. Jackson, Christa Meisinger, Holly E. Syddall, Dorret I. Boomsma, Harry Campbell, Gonçalo R. Abecasis, Lyudmyla Kedenko, Christine Cavalcanti-Proença, G Crawford, Scott M. Grundy, Johnson Prv., Nuotio M-L., I Chen, J.H. Smit, Anuj Goel, M Li, David P. Strachan, Kenechi Ejebe, Beverley Balkau, Neelam Hassanali, Kristian Hveem, Pierre Meneton, R. Gwilliam, A J Swift, Caroline Hayward, J. Graessler, Carina Zabena, B. St Pourcain, Michel Marre, Margot Haun, Lyytikäinen L-P., Ben A. Oostra, Stefan Coassin, M. van Hoek, Nigel W. Rayner, John R. Thompson, Kurt Lohman, Ulla Sovio, Unnur Thorsteinsdottir, Naveed Sattar, Lyle J. Palmer, Ulf Gyllensten, A Elliott, Muredach P. Reilly, A Swift, Luigi Ferrucci, Syvänen A-C., Simon C. Potter, T.W. van Haeften, G Wu, Stefan Böhringer, Grant W. Montgomery, Edward G. Lakatta, Serkalem Demissie, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Lars Lind, Stefan R. Bornstein, Laura J. Rasmussen-Torvik, Terho Lehtimäki, Guillaume Paré, Sophie Visvikis-Siest, S C Heath, David Schlessinger, Juha Sinisalo, Kao Whl., Mark E. Cooper, Kati Kristiansson, Thomas W. Winkler, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Alex N. Parker, Nabila Bouatia-Naji, Markku S. Nieminen, Peter Vollenweider, Wendy L. McArdle, G K Hovingh, Thomas A. Buchanan, Avan Aihie Sayer, M C Zillikens, Jing Hua Zhao, Naomi Hammond, Vilmundur Gudnason, Björn Zethelius, Panos Deloukas, Jacqueline C. M. Witteman, Eric Boerwinkle, Manuel Serrano-Ríos, Anna L. Gloyn, Katherine S. Elliott, A C Fedson, Torben Jørgensen, Nicole Soranzo, Heather M. Stringham, Bruce M. Psaty, A G Uitterlinden, Stavroula Kanoni, Christian Hengstenberg, Yun Li, Olle Melander, Alan R. Tall, Manuela Uda, Magnusson Pke., Christopher W. Kuzawa, V Mooser, R. M. van Dam, Jerome I. Rotter, Greenwood Cmt., Cyrus Cooper, Pau Navarro, Min Jin Go, Nancy L. Pedersen, Serge Hercberg, Bernhard O. Boehm, Eleanor Wheeler, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Dastani, Z, Hivert, Mf, Timpson, N, Perry, Jr, Yuan, X, Scott, Ra, Henneman, P, Heid, Im, Kizer, Jr, Lyytikäinen, Lp, Fuchsberger, C, Tanaka, T, Morris, Ap, Small, K, Isaacs, A, Beekman, M, Coassin, S, Lohman, K, Qi, L, Kanoni, S, Pankow, J, Uh, Hw, Wu, Y, Bidulescu, A, Rasmussen Torvik, Lj, Greenwood, Cm, Ladouceur, M, Grimsby, J, Manning, Ak, Liu, Ct, Kooner, J, Mooser, Ve, Vollenweider, P, Kapur, Ka, Chambers, J, Wareham, Nj, Langenberg, C, Frants, R, Willems Vandijk, K, Oostra, Ba, Willems, Sm, Lamina, C, Winkler, Tw, Psaty, Bm, Tracy, Rp, Brody, J, Chen, I, Viikari, J, Kähönen, M, Pramstaller, Pp, Evans, Dm, St Pourcain, B, Sattar, N, Wood, Ar, Bandinelli, S, Carlson, Od, Egan, Jm, Böhringer, S, van Heemst, D, Kedenko, L, Kristiansson, K, Nuotio, Ml, Loo, Bm, Harris, T, Garcia, M, Kanaya, A, Haun, M, Klopp, N, Wichmann, He, Deloukas, P, Katsareli, E, Couper, Dj, Duncan, Bb, Kloppenburg, M, Adair, L, Borja, Jb, DIAGRAM+, Consortium, Magic, Consortium, Glgc, Investigator, Muther, Consortium, Wilson, Jg, Musani, S, Guo, X, Johnson, T, Semple, R, Teslovich, Tm, Allison, Ma, Redline, S, Buxbaum, Sg, Mohlke, Kl, Meulenbelt, I, Ballantyne, Cm, Dedoussis, Gv, Hu, Fb, Liu, Y, Paulweber, B, Spector, Td, Slagboom, Pe, Ferrucci, L, Jula, A, Perola, M, Raitakari, O, Florez, Jc, Salomaa, V, Eriksson, Jg, Frayling, Tm, Hicks, Aa, Lehtimäki, T, Smith, Gd, Siscovick, D, Kronenberg, F, van Duijn, C, Loos, Rj, Waterworth, Dm, Meigs, Jb, Dupuis, J, Richards, Jb, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Morris, Ad, Palmer, Cn, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Pedersen, O, Barroso, I, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Elliott, P, Rybin, D, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Lajunen, T, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sigurðsson, G, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Diagram, Consortium, Giant, Consortium, Global B., Pgen Consortium, Borecki, Ib, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Serrano Ríos, M, Lind, L, Palmer, Lj, Hu FB, 1st, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Procardis, Consortium, Buchanan, Ta, Valle, Tt, Rotter, Ji, Penninx, Bw, Boomsma, Di, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Peltonen, L, Mooser, V, Magic, Investigator, Glgc, Consortium, Musunuru, K, Smith, Av, Edmondson, Ac, Stylianou, Im, Koseki, M, Pirruccello, Jp, Chasman, Di, Johansen, Ct, Fouchier, Sw, Peloso, Gm, Barbalic, M, Ricketts, Sl, Bis, Jc, Feitosa, Mf, Orho Melander, M, Melander, O, Li, X, Cho, Y, Go, Mj, Kim, Yj, Lee, Jy, Park, T, Kim, K, Sim, X, Ong, Rt, Croteau Chonka, Dc, Lange, La, Smith, Jd, Ziegler, A, Zhang, W, Zee, Ry, Whitfield, Jb, Thompson, Jr, Surakka, I, Smit, Jh, Sinisalo, J, Scott, J, Saharinen, J, Sabatti, C, Rose, Lm, Roberts, R, Rieder, M, Parker, An, Pare, G, O'Donnell, Cj, Nieminen, M, Nickerson, Da, Montgomery, Gw, Mcardle, W, Masson, D, Martin, Ng, Marroni, F, Lucas, G, Luben, R, Lokki, Ml, Lettre, G, Launer, Lj, Lakatta, Eg, Laaksonen, R, König, Ir, Khaw, Kt, Kaplan, Lm, Johansson, Å, Janssens, Ac, Igl, W, Hovingh, Gk, Hengstenberg, C, Havulinna, A, Hastie, Nd, Harris, Tb, Haritunians, T, Hall, A, Groop, Lc, Gonzalez, E, Freimer, Nb, Erdmann, J, Ejebe, Kg, Döring, A, Dominiczak, Af, Demissie, S, de Faire, U, Caulfield, Mj, Boekholdt, Sm, Assimes, Tl, Quertermous, T, Seielstad, M, Wong, Ty, Tai, E, Feranil, Ab, Kuzawa, Cw, Taylor HA, Jr, Gabriel, Sb, Holm, H, Gudnason, V, Krauss, Rm, Ordovas, Jm, Munroe, Pb, Tall, Ar, Hegele, Ra, Kastelein, Jj, Schadt, Ee, Strachan, Dp, Reilly, Mp, Samani, Nj, Schunkert, H, Cupples, La, Ridker, Pm, Rader, Dj, Kathiresan, S., Medical Research Council (MRC), Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Semple, Robert [0000-0001-6539-3069], Griffin, Simon [0000-0002-2157-4797], Barroso, Ines [0000-0001-5800-4520], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Sandhu, Manjinder [0000-0002-2725-142X], Apollo - University of Cambridge Repository, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Other departments, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Lääketieteen yksikkö - School of Medicine, University of Tampere, Institute for Molecular Medicine Finland, Hjelt Institute (-2014), Clinicum, Department of General Practice and Primary Health Care, Department of Public Health, Haartman Institute (-2014), Transplantation Laboratory, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., and O'Leary, DH.

Subjects
Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.

Published
2012
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25. Subject Index Vol. 4, 2001

Author

Margaret Reid, Katja Aktan-Collan, Maurizio Clementi, Karen McIntosh, Romano Tenconi, Maria Feijoo, Anneke Lucassen, Claus Møldrup, Maria Soares, Anne Andermann, AD Cameron, Ari Haukkala, P.J. Marang-v.d. Mheen, Corien C. Verschuuren-Bemelmans, Donna Kirwan, Alistair Kent, M.C. van Maarle, Catherine De Vigan, Stephen Walkinshaw, Martin Bobrow, Irma Nippert, Helena Kääriäinen, Claude Stoll, Gouke J. Bonsel, Niek S. Klazinga, Eila Watson, Joan Austoker, Mariet van Diem, Marlies E. A. Stouthard, C.M. van Duijn, Theresa M. Marteau, Caroline Limbert, Sue Hall, Sixto García-Miñaur, K. Sleegers, Bernd Eiben, and Peter W. Soothill

Subjects
Gerontology, Index (economics), Public Health, Environmental and Occupational Health, Subject (documents), Psychology, Genetics (clinical)
Published
2001
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26. W48 GENETIC VARIATION WITHIN ADIPONUTRIN IS ASSOCIATED WITH LIPOPROTEIN METABOLISM AND LIVER FUNCTION

Author

C.M. van Duijn, A. Teumer, Steven C. Hunt, Zoltán Kutalik, Florian Kronenberg, Henry Völzke, Johann Willeit, Bernhard Paulweber, Y S Aulchenko, Matthias Nauck, Ted D. Adams, Stefan Kiechl, Vincent Mooser, Barbara Kollerits, Stefan Coassin, Anita Brandstätter, Angela Döring, Iris M. Heid, M. Kavousi, Claudia Lamina, and Noam D. Beckmann

Subjects
medicine.medical_specialty, education.field_of_study, General Medicine, Biology, Endocrinology, Internal medicine, Genetic variation, Internal Medicine, medicine, Lipoprotein metabolism, Adiponutrin, Liver function, Cardiology and Cardiovascular Medicine, education
Published
2010
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29. ANGIOTENSIN CONVERTING ENZYME INSERTION/DELETION POLYMORPHISM AND RISK OF HEART FAILURE IN HYPERTENSIVE SUBJECTS

Author

C.M. van Duijn, Jaap W. Deckers, H. A. P. Pols, Gysèle S. Bleumink, A. Hofrnan, B. H.C.H. Strieker, A F C Schut, J. C. M. Witteman, and Jaap Deinum

Subjects
medicine.medical_specialty, biology, Physiology, business.industry, Angiotensin-converting enzyme, medicine.disease, Endocrinology, Polymorphism (computer science), Internal medicine, Heart failure, Internal Medicine, medicine, biology.protein, Insertion deletion, Cardiology and Cardiovascular Medicine, business
Published
2004
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30. THE INFLUENCE OF GENETIC AND ENVIRONMENTAL FACTORS ON BLOOD PRESSURE VARIANCE IN A GENETICALLY ISOLATED POPULATION

Author

M. C. Zillikens, J. C. M. Witteman, A F C Schut, H. A. P. Pols, Jaap Deinum, Y S Aulchenko, B.A. Oostra, Esther A. Croes, and C.M. van Duijn

Subjects
Veterinary medicine, Isolated population, Blood pressure, Physiology, business.industry, Internal Medicine, Medicine, Variance (accounting), Cardiology and Cardiovascular Medicine, business, Biotechnology
Published
2004
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32. Reply

Author

C. Van Broeckhoven, Esther A. Croes, C.M. van Duijn, and Bart Dermaut

Subjects
Genetics, Neurology, Neurology (clinical), Disease, Biology, Prion protein, Gene
Published
2003
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35. Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons

Author

T van Herpt, Albert Hofman, Abbas Dehghan, Aloysius G Lieverse, Eric J.G. Sijbrands, M. van Hoek, Jacqueline C. M. Witteman, C.M. van Duijn, Internal Medicine, and Epidemiology

Subjects
APOC3, Male, medicine.medical_treatment, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Cohort Studies, Risk Factors, Polymorphism (computer science), Prevalence, Insulin, Prospective Studies, Promoter Regions, Genetic, Netherlands, Aged, 80 and over, education.field_of_study, Middle Aged, Type 1 diabetes, Female, medicine.medical_specialty, Population, Polymorphism, Single Nucleotide, Article, BMI, Thinness, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Internal Medicine, Humans, Hypoglycemic Agents, Genetic Predisposition to Disease, Polymorphism, Risk factor, education, Alleles, Aged, Apolipoprotein C-III, business.industry, Haplotype, Case-control study, medicine.disease, Logistic Models, Endocrinology, Diabetes Mellitus, Type 2, Haplotypes, Case-Control Studies, business
Abstract

Aims/hypothesis An APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants. Methods In the Rotterdam Study, a population-based prospective cohort (n = 7,983), Cox and logistic regression models were used to analyse the associations and interactive effects of APOC3 promoter variants (−482C > T, −455T > C) and BMI on type 2 diabetes risk and insulin treatment. Analyses were followed by replication in an independent case–control sample (1,817 cases, 2,292 controls) and meta-analysis. Results In lean participants, the −482T allele was associated with increased risk of prevalent and incident type 2 diabetes: OR −482CT 1.47 (95% CI 1.13–1.92), −482TT 1.40 (95% CI 0.83–2.35), p = 0.009 for trend; HR −482CT 1.35 (95% CI 0.96–1.89), −482TT 1.68 (95% CI 0.91–3.1), p = 0.03 for trend, respectively. These results were confirmed by replication. Meta-analysis was highly significant (−482T meta-analysis p = 1.1 × 10-4). A borderline significant interaction was observed for insulin use among participants with type 2 diabetes (−482CT*BMI p = 0.06, −455TC*BMI p = 0.02). Conclusions/interpretation At a population-based level, the influence of APOC3 promoter variants on type 2 diabetes risk varies with the level of adiposity. Lean carriers of the −482T allele had increased type 2 diabetes risk, while such an effect was not observed in overweight participants. Conversely, in overweight participants the −455C allele seemed protective against type 2 diabetes. The interaction of the variants with need for insulin treatment may indicate beta cell involvement in lean participants. Our findings suggest overlap in the genetic backgrounds of type 1 diabetes and type 2 diabetes in lean patients.

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