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Diabetes. 2014 Dec;63(12):4343-59. doi: 10.2337/db14-0731. Epub 2014 Jun 26.

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

Author information

1
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.
2
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
3
Centre of Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St. Lucia, QLD, Australia.
4
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.
5
Department of Epidemiology and Public Health, University College London, London, U.K.
6
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.
7
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
8
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.
9
National Institute for Health and Welfare, Turku, Finland.
10
Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
11
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.
12
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany.
13
Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
14
Department of Epidemiology and Public Health, University College London, London, U.K. MRC Epidemiology Unit, Cambridge University, Cambridge, U.K.
15
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland.
16
Department of Obstetrics and Gynecology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
17
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.
18
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany Institute of Human Genetics, Technical University Munich, Munich, Germany.
19
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.
20
Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
21
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.
22
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.
23
Institute of Cardiovascular Sciences, University College London, London, U.K.
24
Department of Epidemiology and Public Health, University College London, London, U.K. 1st Department of Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary.
25
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
26
MRC Epidemiology Unit, Cambridge University, Cambridge, U.K.
27
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.
28
Centre de Recherche Public de la Santé, Strassen, Luxembourg.
29
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.
30
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

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.

PMID:
24969107
PMCID:
PMC4237993
DOI:
10.2337/db14-0731
[Indexed for MEDLINE]
Free PMC Article

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