Journal
DIABETES
Volume 63, Issue 12, Pages 4343-4359Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db14-0731
Keywords
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Categories
Funding
- Medical Research Council [K013351, G0501184]
- British Heart Foundation [RG/07/008/23674]
- Stroke Association
- National Heart, Lung, and Blood Institute [R01-HL-036310]
- National Institute on Aging [5R01-AG-13196]
- Agency for Health Care Policy and Research [HS06516]
- John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health
- National Institute for Health and Welfare (THL), Finland
- European Community's Seventh Framework Programme, project Bioshare [261433]
- ENGAGE Consortium
- Academy of Finland [250207, 283045, 266199, 129494, 139635, 134309, 126925, 121584, 124282, 129378, 117797, 41071]
- Orion-Farmos Research Foundation
- Finnish Medical Foundation
- Finnish Foundation for Cardiovascular Research
- Academy of Finland's Responding to Public Health Challenges Research Programme (SALVE) Pubgensense [129322]
- Finnish Centre for Pensions (ETK)
- Social Insurance Institution of Finland (KELA)
- Local Government Pensions Institution (KEVA)
- Helmholtz Zentrum Munchen
- German Research Center for Environmental Health
- German Federal Ministry of Education and Research
- State of Bavaria
- Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW)
- German Federal Ministry of Health (BMG)
- German Research Foundation (DFG) [RA 459/2-1]
- German Federal Ministry of Education and Research (BMBF) [0315494A, BMBF 01KU0908A, ANR 09 GENO 106 01, BMBF 01EO1003]
- National Genome Network NGFNplus Atherogenomics [01GS0834]
- government of Rheinland-Pfalz (Stiftung Rheinland-Pfalz fur Innovation) [AZ 961-386261/733]
- Johannes Gutenberg-University of Mainz
- National Genome Network NGFNplus by German Federal Ministry of Education and Research (BMBF) [01GS0833, 01GS0831]
- Agence Nationale de la Recherche, France [BMBF 01KU0908A, ANR 09 GENO 106 01]
- Social Insurance Institution of Finland
- Kuopio, Tampere, and Turku University Hospital Medical Funds
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Foundation of Cardiovascular Research
- Finnish Cultural Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- [HEALTH-F4-2007-201413]
- ESRC [ES/J023299/1, ES/K005146/1, ES/H029745/1] Funding Source: UKRI
- MRC [MR/K013351/1, G0501184, MC_UU_12015/1] Funding Source: UKRI
- British Heart Foundation [RG/07/008/23674, RG/13/2/30098, RG/10/12/28456] Funding Source: researchfish
- Economic and Social Research Council [ES/H029745/1, ES/J023299/1, ES/K005146/1] Funding Source: researchfish
- Medical Research Council [MR/K013351/1, MC_UU_12015/1, MR/K006584/1, MC_U106179471, G0501184] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10135] Funding Source: researchfish
- Academy of Finland (AKA) [266199, 266199] Funding Source: Academy of Finland (AKA)
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The proinflammatory cytokine interleukin (IL)-1 beta is implicated in the development of insulin resistance and beta-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1 beta, has been suggested to improve glycemia and b-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 x 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 x 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 IL-1RN and IL-1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.
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