Pleiotropic genes for metabolic syndrome and inflammation

Aldi T Kraja¹, Daniel I Chasman², Kari E North³, Alexander P Reiner⁴, Lisa R Yanek⁵, Tuomas O Kilpeläinen⁶, Jennifer A Smith⁷, Abbas Dehghan⁸, Josée Dupuis⁹, Andrew D Johnson¹⁰, Mary F Feitosa¹¹, Fasil Tekola-Ayele¹², Audrey Y Chu¹³, Ilja M Nolte¹⁴, Zari Dastani¹⁵, Andrew Morris¹⁶, Sarah A Pendergrass¹⁷, Yan V Sun¹⁸, Marylyn D Ritchie¹⁹, Ahmad Vaez²⁰, Honghuang Lin²¹, Symen Ligthart²², Letizia Marullo²³, Rebecca Rohde²⁴, Yaming Shao²⁵, Mark A Ziegler²⁶, Hae Kyung Im²⁷; Cross Consortia Pleiotropy Group; Cohorts for Heart and; Aging Research in Genetic Epidemiology; Genetic Investigation of Anthropometric Traits Consortium; Global Lipids Genetics Consortium; Meta-Analyses of Glucose; Insulin-related traits Consortium; Global BPgen Consortium; ADIPOGen Consortium; Women's Genome Health Study; Howard University Family Study; Renate B Schnabel²⁸, Torben Jørgensen²⁹, Marit E Jørgensen³⁰, Torben Hansen³¹, Oluf Pedersen³², Ronald P Stolk³³, Harold Snieder³⁴, Albert Hofman³⁵, Andre G Uitterlinden³⁶, Oscar H Franco³⁷, M Arfan Ikram³⁸, J Brent Richards³⁹, Charles Rotimi⁴⁰, James G Wilson⁴¹, Leslie Lange⁴², Santhi K Ganesh⁴³, Mike Nalls⁴⁴, Laura J Rasmussen-Torvik⁴⁵, James S Pankow⁴⁶, Josef Coresh⁴⁷, Weihong Tang⁴⁸, W H Linda Kao⁴⁹, Eric Boerwinkle⁵⁰, Alanna C Morrison⁵¹, Paul M Ridker⁵², Diane M Becker⁵³, Jerome I Rotter⁵⁴, Sharon L R Kardia⁵⁵, Ruth J F Loos⁵⁶, Martin G Larson⁵⁷, Yi-Hsiang Hsu⁵⁸, Michael A Province⁵⁹, Russell Tracy⁶⁰, Benjamin F Voight⁶¹, Dhananjay Vaidya⁶², Christopher J O'Donnell⁶³, Emelia J Benjamin⁶⁴, Behrooz Z Alizadeh⁶⁵, Inga Prokopenko⁶⁶, James B Meigs⁶⁷, Ingrid B Borecki⁶⁸

Affiliations

¹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: aldi@wustl.edu.
² Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: dchasman@research.bwh.harvard.edu.
³ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: kari_north@unc.edu.
⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: apreiner@u.washington.edu.
⁵ Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: lryanek@jhmi.edu.
⁶ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: tuomas.kilpelainen@sund.ku.dk.
⁷ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. Electronic address: smjenn@umich.edu.
⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.dehghan@erasmusmc.nl.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA. Electronic address: dupuis@bu.edu.
¹⁰ National Heart, Lung and Blood Institute (NHLBI) Division of Intramural Research and NHLBI's Framingham Heart Study, Framingham, MA, USA. Electronic address: johnsonad2@nhlbi.nih.gov.
¹¹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mfeitosa@wustl.edu.
¹² Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: fasil.ayele2@nih.gov.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: aychu@partners.org.
¹⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: i.m.nolte@umcg.nl.
¹⁵ Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University Montreal, Quebec, Canada. Electronic address: zari.dastani@mail.mcgill.ca.
¹⁶ The Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: andrew.morris@well.ox.ac.uk.
¹⁷ Department of Biochemistry and Molecular Biology, Eberly College of Science and The Huck Institutes of the Life Sciences, The Pennsylvania State University, PA, USA. Electronic address: sap29@psu.edu.
¹⁸ Department of Epidemiology, Rollins School of Public Health, and Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA. Electronic address: yan.v.sun@emory.edu.
¹⁹ Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA. Electronic address: marylyn.ritchie@psu.edu.
²⁰ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: a.vaez@umcg.nl.
²¹ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: hhlin@bu.edu.
²² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: s.ligthart@erasmusmc.nl.
²³ The Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. Electronic address: lety@well.ox.ac.uk.
²⁴ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: rohde@email.unc.edu.
²⁵ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: yaming_shao@unc.edu.
²⁶ Division of Biostatistics, MSIBS Program, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: MZiegler23@WUSTL.EDU.
²⁷ Department of Health Studies, University of Chicago, IL, USA. Electronic address: haky@uchicago.edu.
²⁸ Department of General and Interventional Cardiology University Heart Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: schnabelr@gmx.de.
²⁹ Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. Electronic address: tojo@glo.regionh.dk.
³⁰ Steno Diabetes Center, Gentofte, Denmark. Electronic address: maej@steno.dk.
³¹ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: torben.hansen@sund.ku.dk.
³² The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: oluf@sund.ku.dk.
³³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: r.p.stolk@umcg.nl.
³⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: h.snieder@umcg.nl.
³⁵ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.hofman@erasmusmc.nl.
³⁶ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.g.uitterlinden@erasmusmc.nl.
³⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: o.franco@erasmusmc.nl.
³⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: m.a.ikram@erasmusmc.nl.
³⁹ Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University Montreal, Quebec, Canada; Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Canada; Department of Twin Research, King's College, London, UK. Electronic address: brent.richards@mcgill.ca.
⁴⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: rotimic@mail.nih.gov.
⁴¹ University of Mississippi, Medical Center, MS, USA. Electronic address: jgwilson2@umc.edu.
⁴² Department of Genetics, University of North Carolina, NC, USA. Electronic address: leslie_lange@med.unc.edu.
⁴³ Department of Internal Medicine, University of Michigan, MI, USA. Electronic address: sganesh@med.umich.edu.
⁴⁴ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, USA. Electronic address: nallsm@mail.nih.gov.
⁴⁵ Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: ljrtorvik@northwestern.edu.
⁴⁶ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. Electronic address: panko001@umn.edu.
⁴⁷ Department of Medicine, Epidemiology, Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: coresh@jhu.edu.
⁴⁸ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. Electronic address: tang0097@umn.edu.
⁴⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: wkao@jhsph.edu.
⁵⁰ Human Genetics Center, University of Texas - Houston Health Science Center at Houston, Houston, TX, USA. Electronic address: Eric.Boerwinkle@uth.tmc.edu.
⁵¹ Human Genetics Center, University of Texas - Houston Health Science Center at Houston, Houston, TX, USA. Electronic address: Alanna.C.Morrison@uth.tmc.edu.
⁵² Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: pridker@partners.org.
⁵³ Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: DBecker607@aol.com.
⁵⁴ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute (LA BioMed), Harbor-UCLA Medical Center, Torrance, CA, USA. Electronic address: jrotter@labiomed.org.
⁵⁵ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. Electronic address: skardia@umich.edu.
⁵⁶ The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: ruth.loos@mssm.edu.
⁵⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Mathematics and Statistics, Boston University, Boston, MA, USA. Electronic address: mlarson@bu.edu.
⁵⁸ Hebrew Senior Life Institute for Aging Research, Harvard Medical School and Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA. Electronic address: YiHsiangHsu@hsl.harvard.edu.
⁵⁹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mprovince@wustl.edu.
⁶⁰ University of Vermont College of Medicine, Burlington, VT, USA. Electronic address: russell.tracy@med.uvm.edu.
⁶¹ Department of Pharmacology, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: bvoight@upenn.edu.
⁶² Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dvaidya1@jhmi.edu.
⁶³ National Heart, Lung and Blood Institute (NHLBI) Division of Intramural Research and NHLBI's Framingham Heart Study, Framingham, MA, USA. Electronic address: odonnellc@nhlbi.nih.gov.
⁶⁴ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Cardiology and Preventive Medicine Sections, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: emelia@bu.edu.
⁶⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: b.z.alizadeh@umcg.nl.
⁶⁶ Department of Genomics of Common Diseases, School of Public Health, Imperial College London, London W12 0NN, UK. Electronic address: i.prokopenko@imperial.ac.uk.
⁶⁷ General Medicine Division, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jmeigs@partners.org.
⁶⁸ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: iborecki@wustl.edu.

PMID: 24981077
PMCID: PMC4122618
DOI: 10.1016/j.ymgme.2014.04.007

Meta-Analysis

Pleiotropic genes for metabolic syndrome and inflammation

Aldi T Kraja et al. Mol Genet Metab. 2014 Aug.

. 2014 Aug;112(4):317-38.

doi: 10.1016/j.ymgme.2014.04.007. Epub 2014 May 9.

Authors

Affiliations

¹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: aldi@wustl.edu.
² Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: dchasman@research.bwh.harvard.edu.
³ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: kari_north@unc.edu.
⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: apreiner@u.washington.edu.
⁵ Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: lryanek@jhmi.edu.
⁶ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: tuomas.kilpelainen@sund.ku.dk.
⁷ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. Electronic address: smjenn@umich.edu.
⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.dehghan@erasmusmc.nl.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA. Electronic address: dupuis@bu.edu.
¹⁰ National Heart, Lung and Blood Institute (NHLBI) Division of Intramural Research and NHLBI's Framingham Heart Study, Framingham, MA, USA. Electronic address: johnsonad2@nhlbi.nih.gov.
¹¹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mfeitosa@wustl.edu.
¹² Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: fasil.ayele2@nih.gov.
¹³ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: aychu@partners.org.
¹⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: i.m.nolte@umcg.nl.
¹⁵ Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University Montreal, Quebec, Canada. Electronic address: zari.dastani@mail.mcgill.ca.
¹⁶ The Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: andrew.morris@well.ox.ac.uk.
¹⁷ Department of Biochemistry and Molecular Biology, Eberly College of Science and The Huck Institutes of the Life Sciences, The Pennsylvania State University, PA, USA. Electronic address: sap29@psu.edu.
¹⁸ Department of Epidemiology, Rollins School of Public Health, and Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA. Electronic address: yan.v.sun@emory.edu.
¹⁹ Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA. Electronic address: marylyn.ritchie@psu.edu.
²⁰ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: a.vaez@umcg.nl.
²¹ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: hhlin@bu.edu.
²² Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: s.ligthart@erasmusmc.nl.
²³ The Welcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. Electronic address: lety@well.ox.ac.uk.
²⁴ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: rohde@email.unc.edu.
²⁵ Department of Epidemiology and Carolina Center for Genome Sciences, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA. Electronic address: yaming_shao@unc.edu.
²⁶ Division of Biostatistics, MSIBS Program, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: MZiegler23@WUSTL.EDU.
²⁷ Department of Health Studies, University of Chicago, IL, USA. Electronic address: haky@uchicago.edu.
²⁸ Department of General and Interventional Cardiology University Heart Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: schnabelr@gmx.de.
²⁹ Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. Electronic address: tojo@glo.regionh.dk.
³⁰ Steno Diabetes Center, Gentofte, Denmark. Electronic address: maej@steno.dk.
³¹ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: torben.hansen@sund.ku.dk.
³² The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: oluf@sund.ku.dk.
³³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: r.p.stolk@umcg.nl.
³⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: h.snieder@umcg.nl.
³⁵ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.hofman@erasmusmc.nl.
³⁶ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: a.g.uitterlinden@erasmusmc.nl.
³⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: o.franco@erasmusmc.nl.
³⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: m.a.ikram@erasmusmc.nl.
³⁹ Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University Montreal, Quebec, Canada; Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Canada; Department of Twin Research, King's College, London, UK. Electronic address: brent.richards@mcgill.ca.
⁴⁰ Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: rotimic@mail.nih.gov.
⁴¹ University of Mississippi, Medical Center, MS, USA. Electronic address: jgwilson2@umc.edu.
⁴² Department of Genetics, University of North Carolina, NC, USA. Electronic address: leslie_lange@med.unc.edu.
⁴³ Department of Internal Medicine, University of Michigan, MI, USA. Electronic address: sganesh@med.umich.edu.
⁴⁴ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, USA. Electronic address: nallsm@mail.nih.gov.
⁴⁵ Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: ljrtorvik@northwestern.edu.
⁴⁶ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. Electronic address: panko001@umn.edu.
⁴⁷ Department of Medicine, Epidemiology, Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: coresh@jhu.edu.
⁴⁸ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. Electronic address: tang0097@umn.edu.
⁴⁹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: wkao@jhsph.edu.
⁵⁰ Human Genetics Center, University of Texas - Houston Health Science Center at Houston, Houston, TX, USA. Electronic address: Eric.Boerwinkle@uth.tmc.edu.
⁵¹ Human Genetics Center, University of Texas - Houston Health Science Center at Houston, Houston, TX, USA. Electronic address: Alanna.C.Morrison@uth.tmc.edu.
⁵² Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: pridker@partners.org.
⁵³ Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: DBecker607@aol.com.
⁵⁴ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute (LA BioMed), Harbor-UCLA Medical Center, Torrance, CA, USA. Electronic address: jrotter@labiomed.org.
⁵⁵ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. Electronic address: skardia@umich.edu.
⁵⁶ The Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: ruth.loos@mssm.edu.
⁵⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Department of Mathematics and Statistics, Boston University, Boston, MA, USA. Electronic address: mlarson@bu.edu.
⁵⁸ Hebrew Senior Life Institute for Aging Research, Harvard Medical School and Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA. Electronic address: YiHsiangHsu@hsl.harvard.edu.
⁵⁹ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mprovince@wustl.edu.
⁶⁰ University of Vermont College of Medicine, Burlington, VT, USA. Electronic address: russell.tracy@med.uvm.edu.
⁶¹ Department of Pharmacology, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA, USA; Department of Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: bvoight@upenn.edu.
⁶² Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: dvaidya1@jhmi.edu.
⁶³ National Heart, Lung and Blood Institute (NHLBI) Division of Intramural Research and NHLBI's Framingham Heart Study, Framingham, MA, USA. Electronic address: odonnellc@nhlbi.nih.gov.
⁶⁴ National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; Cardiology and Preventive Medicine Sections, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Electronic address: emelia@bu.edu.
⁶⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: b.z.alizadeh@umcg.nl.
⁶⁶ Department of Genomics of Common Diseases, School of Public Health, Imperial College London, London W12 0NN, UK. Electronic address: i.prokopenko@imperial.ac.uk.
⁶⁷ General Medicine Division, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jmeigs@partners.org.
⁶⁸ Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: iborecki@wustl.edu.

PMID: 24981077
PMCID: PMC4122618
DOI: 10.1016/j.ymgme.2014.04.007

Abstract

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.

Keywords: Inflammatory markers; Meta-analysis; Metabolic syndrome; Pleiotropic associations; Regulome.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

All authors have no conflict of interest to declare.

Figures

**Figure 1**
Prevalence of MetS and its components and mean levels of inflammatory markers in individuals classified with and without MetS (M₁ vs. M₀). **Footnote:** Top histogram numbers represent prevalence (%) of MetS, T2D and MetS components. Bottom numbers represent number of participants for a particular trait. The inflammatory marker boxplot graph comparisons were built by using “rnorm” function in R with mean, standard deviation and sample size corresponding to subgroups with and without MetS from original (B) data. Overall, they represent 53 tests of inflammatory markers per MetS strata, summarized in Supplemental Figures 1(a–g). The number within each pair of boxplots marked by “D=” is the difference of two means of an inflammatory marker in groups of participants classified with versus without MetS. The light yellow boxed number at the bottom of the same graph marked with “p_t=” represents a p-value calculated by pooled t-test for testing if their means (M₁ vs. M₀) are different. In case the color of p_t-value box is gray, then the p-value does not pass the Bonferroni threshold p=9.43e-04.

**Figure 2**
A network of 25 pleiotropic genes with putative contributions to MetS, including inflammation. **Footnote:** In the figure they connect by GWAS phenotypic evidence and whether selected SNPs show any regulatory features based on the ENCODE database as implemented via HaploReg [50]/RegulomeDB [51] software. All phenotypic labels correspond to associations reported in the Results, Discussion, Table 5 and Suppplemental Table 5.

See this image and copyright information in PMC

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Pleiotropic genes for metabolic syndrome and inflammation

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Pleiotropic genes for metabolic syndrome and inflammation

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