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PLoS One. 2015 Mar 26;10(3):e0119752. doi: 10.1371/journal.pone.0119752. eCollection 2015.

Modulation of genetic associations with serum urate levels by body-mass-index in humans.

Huffman JE1, Albrecht E2, Teumer A3, Mangino M4, Kapur K5, Johnson T6, Kutalik Z5, Pirastu N7, Pistis G8, Lopez LM9, Haller T10, Salo P11, Goel A12, Li M13, Tanaka T14, Dehghan A15, Ruggiero D16, Malerba G17, Smith AV18, Nolte IM19, Portas L20, Phipps-Green A21, Boteva L1, Navarro P1, Johansson A22, Hicks AA23, Polasek O24, Esko T25, Peden JF12, Harris SE26, Murgia F20, Wild SH27, Tenesa A28, Tin A13, Mihailov E10, Grotevendt A29, Gislason GK30, Coresh J31, D'Adamo P7, Ulivi S32, Vollenweider P33, Waeber G33, Campbell S1, Kolcic I24, Fisher K10, Viigimaa M34, Metter JE14, Masciullo C8, Trabetti E17, Bombieri C17, Sorice R16, Döring A35, Reischl E36, Strauch K37, Hofman A15, Uitterlinden AG15, Waldenberger M36, Wichmann HE38, Davies G9, Gow AJ9, Dalbeth N39, Stamp L40, Smit JH41, Kirin M27, Nagaraja R42, Nauck M29, Schurmann C3, Budde K29, Farrington SM1, Theodoratou E27, Jula A43, Salomaa V11, Sala C8, Hengstenberg C44, Burnier M45, Mägi R10, Klopp N46, Kloiber S47, Schipf S48, Ripatti S49, Cabras S50, Soranzo N51, Homuth G3, Nutile T16, Munroe PB6, Hastie N1, Campbell H27, Rudan I52, Cabrera C53, Haley C28, Franco OH15, Merriman TR21, Gudnason V18, Pirastu M20, Penninx BW54, Snieder H19, Metspalu A10, Ciullo M16, Pramstaller PP23, van Duijn CM55, Ferrucci L14, Gambaro G56, Deary IJ9, Dunlop MG1, Wilson JF27, Gasparini P7, Gyllensten U57, Spector TD4, Wright AF1, Hayward C1, Watkins H58, Perola M59, Bochud M60, Kao WH31, Caulfield M6, Toniolo D8, Völzke H48, Gieger C2, Köttgen A61, Vitart V1.

Author information

1
Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, United Kingdom.
2
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
3
Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
4
King's College London, St. Thomas' Hospital Campus, London, United Kingdom.
5
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
6
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
7
Institute for Maternal and Child Health-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) "Burlo Garofolo", Trieste, Italy; University of Trieste, Trieste, Italy.
8
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
9
Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom.
10
Estonian Genome Center, University of Tartu, Tartu, Estonia.
11
Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland.
12
Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
13
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
14
Clinical Research Branch, National Institute on Aging, Baltimore, MD, United States of America.
15
Member of Netherlands Consortium for Healthy Aging (NCHA) sponsored by Netherlands Genomics Initiative (NGI), Leiden, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
16
Institute of Genetics and Biophysics "A. Buzzati-Traverso"-Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
17
Biology and Genetics section, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
18
Icelandic Heart Association Research Institute, Kopavogur, Iceland; University of Iceland, Reykjavik, Iceland.
19
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
20
Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
21
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
22
Uppsala Clinical Research Center, Uppsala University Hospital, Upsalla, Sweden; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 751 85, Sweden.
23
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy; Affiliated Institute of the University of Lübeck, Lübeck, Germany.
24
Faculty of Medicine, University of Split, Croatia, Soltanska 2, Split, 21000, Croatia.
25
Estonian Genome Center, University of Tartu, Tartu, Estonia; Broad Institute, Cambridge, MA, United States of America; Children's Hospital Boston, Boston, MA, United States of America.
26
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom.
27
Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
28
Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, United Kingdom; Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom.
29
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
30
Icelandic Heart Association Research Institute, Kopavogur, Iceland.
31
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America; Welch Center for Prevention, Epidemiology and Clinical Research, John Hopkins University, Baltimore, MD, United States of America.
32
Institute for Maternal and Child Health-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) "Burlo Garofolo", Trieste, Italy.
33
Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
34
Tallinn University of Technology, Department of Biomedical Engineering, Chair of Medical Physics, Tallinn, Estonia; Centre of Cardiology, North Estonia Medical Centre, Tallinn, Estonia.
35
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
36
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
37
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
38
Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Klinikum Grosshadern, Munich, Germany.
39
Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
40
Department of Medicine, University of Otago, Christchurch, New Zealand.
41
Department of Psychiatry/EMGO Institute, VU University Medical Centre, Amsterdam, the Netherlands.
42
Laboratory of Genetics, National Institute on Aging (NIA), Baltimore, MD, United States of America.
43
Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Turku, Finland.
44
University Hospital Regensburg, Regensburg, Germany.
45
Department of Medicine, Nephrology Division, Lausanne University Hospital, Lausanne, Switzerland.
46
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany.
47
Max Planck Institute of Psychiatry, Munich, Germany.
48
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
49
Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Turku, Finland; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; University of Helsinki, Institute of Molecular Medicine, Helsinki, Finland.
50
Department of Mathematics and Informatics, Università di Cagliari, Cagliari, Italy; Department of Statistics, Universidad Carlos III de Madrid, Madrid, Spain.
51
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
52
Faculty of Medicine, University of Split, Croatia, Soltanska 2, Split, 21000, Croatia; Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
53
Queen Mary, University of London, London, United Kingdom.
54
Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
55
Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
56
Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy.
57
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 751 85, Sweden.
58
on behalf of PROCARDIS; Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
59
Estonian Genome Center, University of Tartu, Tartu, Estonia; Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland; University of Helsinki, Institute of Molecular Medicine, Helsinki, Finland.
60
University Institute of Social and Preventive Medicine, Lausanne, Switzerland.
61
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America; Renal Division, Freiburg University Hospital, Freiburg, Germany.

Abstract

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

PMID:
25811787
PMCID:
PMC4374966
DOI:
10.1371/journal.pone.0119752
[Indexed for MEDLINE]
Free PMC Article

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