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Herder, C.* ; Nuotio, M.L.* ; Shah, S.* ; Blankenberg, S.* ; Brunner, E.J.* ; Carstensen, M.* ; Gieger, C. ; Grallert, H. ; Jula, A.* ; Kähönen, M.* ; Kettunen, J.* ; Kivimaki, M.* ; Koenig, W.* ; Kristiansson, K.* ; Langenberg, C.* ; Lehtimäki, T.* ; Luotola, K.* ; Marzi, C. ; Müller, C.* ; Peters, A. ; Prokisch, H. ; Raitakari, O.* ; Rathmann, W.* ; Roden, M.* ; Salmi, M.* ; Schramm, K. ; Swerdlow, D.I.* ; Tabak, A.G.* ; Thorand, B. ; Wareham, N.J.* ; Wild, P.S.* ; Zeller, T.* ; Hingorani, A.D.* ; Witte, D.R.* ; Kumari, M.* ; Perola, M.* ; Salomaa, V.*

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

Diabetes 63, 4343-4359 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 63, Issue: 12, Pages: 4343-4359 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
Institute of Lung Health and Immunity (LHI)
German Center for Diabetes Reseach (DZD)