Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits

  1. Veikko Salomaa37,**
  1. 1Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  2. 2German Center for Diabetes Research (DZD e.V.), partner site Düsseldorf, Germany
  3. 3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  4. 4Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland
  5. 5Centre of Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St Lucia, Australia
  6. 6Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
  7. 7German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg, Lübeck, Kiel, Germany
  8. 8Department of Epidemiology and Public Health, University College London, London, UK
  9. 9Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  10. 10Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  11. 11Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  12. 12German Center for Diabetes Research (DZD e.V.), partner site Munich, Germany
  13. 13National Institute for Health and Welfare, Turku, Finland
  14. 14Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland
  15. 15Computational Medicine, Institute of Health Sciences, University of Oulu and Oulu University Hospital, Oulu, Finland
  16. 16Department of Internal Medicine II – Cardiology, University of Ulm Medical Center, Ulm, Germany
  17. 17MRC Epidemiology Unit, Cambridge University, Cambridge, UK
  18. 18Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
  19. 19Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
  20. 20Department of Obstetrics and Gynecology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
  21. 21German Center for Cardiovascular Research (DZHK e.V.), partner site Munich, Germany
  22. 22Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
  23. 23Institute of Human Genetics, Technical University Munich, Munich, Germany
  24. 24Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  25. 25Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
  26. 26Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  27. 27Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
  28. 28MediCity Research Laboratory, University of Turku, Finland
  29. 29Department of Medical Microbiology and Immunology, University of Turku, Finland
  30. 30Institute of Cardiovascular Sciences, University College London, London, UK
  31. 311st Department of Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary
  32. 32Department of Medicine 2, University Medical Center Mainz, Mainz, Germany
  33. 33Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
  34. 34German Center for Cardiovascular Research (DZHK), partner site RhineMain, Mainz, Germany
  35. 35Centre de Recherche Public de la Santé, Strassen, Luxembourg
  36. 36Estonian Genome Center, University of Tartu, Tartu, Estonia
  37. 37Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  1. Corresponding author: Christian Herder. E-mail: christian.herder{at}ddz.uni-duesseldorf.de

Abstract

The pro-inflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and beta-cell dysfunction, whereas higher circulating IL-1 receptor antagonist (IL-1RA – an endogenous inhibitor of IL-1β - has been suggested to improve glycemia and beta-cell function in patients with type 2 diabetes. In order 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 7 discovery and 4 replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL-1RN locus, n=13,955, P=2.76x10-21; and rs6759676, closest gene locus IL1F10, n=13,994, P=1.73x10-17). 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 and lower homeostasis model assessment insulin resistance (HOMA-IR). In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL-1RN and IL-1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.

  • Received May 9, 2014.
  • Accepted June 20, 2014.

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