title: Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits.
abstract: The proinflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and β-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1β, has been suggested to improve glycemia and β-cell function in patients with type 2 diabetes. To elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of seven discovery and four replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL1RN locus [n = 13,955, P = 2.76 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 10(-17)]). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin levels and lower HOMA insulin resistance. In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
authors: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany christian.herder@ddz.uni-duesseldorf.de.
authors: Christian
authors: C
authors: Herder
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
authors: Marja-Liisa
authors: ML
authors: Nuotio
authors: Centre of Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, QLD, Australia.
authors: Sonia
authors: S
authors: Shah
authors: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany.
authors: Stefan
authors: S
authors: Blankenberg
authors: Department of Epidemiology and Public Health, University College London, London, U.K.
authors: Eric J
authors: EJ
authors: Brunner
authors: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany.
authors: Maren
authors: M
authors: Carstensen
authors: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Christian
authors: C
authors: Gieger
authors: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), partner site, Munich, Germany.
authors: Harald
authors: H
authors: Grallert
authors: National Institute for Health and Welfare, Turku, Finland.
authors: Antti
authors: A
authors: Jula
authors: Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors: Mika
authors: M
authors: Kähönen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland Computational Medicine, Institute of Health Sciences, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Johannes
authors: J
authors: Kettunen
authors: Department of Epidemiology and Public Health, University College London, London, U.K.
authors: Mika
authors: M
authors: Kivimäki
authors: Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
authors: Wolfgang
authors: W
authors: Koenig
authors: Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
authors: Kati
authors: K
authors: Kristiansson
authors: Department of Epidemiology and Public Health, University College London, London, U.K. MRC Epidemiology Unit, Cambridge University, Cambridge, U.K.
authors: Claudia
authors: C
authors: Langenberg
authors: Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Department of Obstetrics and Gynecology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors: Kari
authors: K
authors: Luotola
authors: Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), partner site, Munich, Germany.
authors: Carola
authors: C
authors: Marzi
authors: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany.
authors: Christian
authors: C
authors: Müller
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), partner site, Munich, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Munich, Germany.
authors: Annette
authors: A
authors: Peters
authors: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors: Holger
authors: H
authors: Prokisch
authors: Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors: Olli
authors: O
authors: Raitakari
authors: Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors: Wolfgang
authors: W
authors: Rathmann
authors: Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
authors: Michael
authors: M
authors: Roden
authors: National Institute for Health and Welfare, Turku, Finland MediCity Research Laboratory, University of Turku, Turku, Finland Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors: Marko
authors: M
authors: Salmi
authors: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors: Katharina
authors: K
authors: Schramm
authors: Institute of Cardiovascular Sciences, University College London, London, U.K.
authors: Daniel
authors: D
authors: Swerdlow
authors: Department of Epidemiology and Public Health, University College London, London, U.K. 1st Department of Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary.
authors: Adam G
authors: AG
authors: Tabak
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Barbara
authors: B
authors: Thorand
authors: MRC Epidemiology Unit, Cambridge University, Cambridge, U.K.
authors: Nick
authors: N
authors: Wareham
authors: Department of Medicine 2, University Medical Center Mainz, Mainz, Germany Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Rhine-Main, Mainz, Germany.
authors: Philipp S
authors: PS
authors: Wild
authors: Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany.
authors: Tanja
authors: T
authors: Zeller
authors: Institute of Cardiovascular Sciences, University College London, London, U.K.
authors: Aroon D
authors: AD
authors: Hingorani
authors: Centre de Recherche Public de la Santé, Strassen, Luxembourg.
authors: Daniel R
authors: DR
authors: Witte
authors: Department of Epidemiology and Public Health, University College London, London, U.K.
authors: Meena
authors: M
authors: Kumari
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Markus
authors: M
authors: Perola
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors: Veikko
authors: V
authors: Salomaa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D065840:Protective Factors; D055815:Young Adult
chemical_list: C430241:IL1F10 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D002097:C-Reactive Protein