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Association of Variation in the Interleukin-1 Gene Family with Diabetes and Glucose Homeostasis

Department of Medicine (K.L., M.S.N.), Helsinki University Central Hospital, Helsinki 00290, Finland; Department of Chronic Disease Prevention (R.P., A.P.), 00300 Helsinki; Health and Functional Capacity (A.J.), 20720 Turku; and Environmental Epidemiology (T.L.), 70701 Kuopio, National Institute for Health and Welfare, Finland; Wihuri Research Institute (M.A.), 00140 Helsinki, Finland; National Institute for Health and Welfare and FIMM, Institute for Molecular Medicine Finland (M.A., I.S., M.P.), 00014 Helsinki, Finland; Department of Medicine (L.M.), University Hospital of Kuopio, 70211 Kuopio, Finland; Department of Clinical Physiology (M.K.), Tampere University Hospital and Medical School, University of Tampere, 33521 Tampere, Finland; Department of Internal Medicine and Biocenter Oulu (Y.A.K.), University of Oulu and Clinical Research Center, Oulu University Hospital, 90014 Oulu, Finland; Institute of Epidemiology (A.P.), Helmholtz Zentrum München, 85764 Neuherberg, Germany; and Department of Chronic Disease Prevention (V.S.), National Institute for Health and Welfare, 00271 Helsinki, Finland

Address all correspondence and requests for reprints to: Kari Luotola, Department of Medicine, HUCH-Helsinki University Central Hospital, Box 340 HUS, FI-00029 Helsinki, Finland. E-mail: kari.luotola{at}helsinki.fi; or Veikko Salomaa, THL-National Institute for Health and Welfare, P.O.B. 30 FI-00271 Helsinki, Finland. E-mail: veikko.salomaa{at}thl.fi.

Objective: Proinflammatory cytokine IL-1β is capable of decreasing insulin-induced glucose transport. Therefore, we hypothesized that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and diabetes.

Design and Outcome Measures: Fifteen haplotype-tagging single-nucleotide polymorphisms in the IL-1, IL-1β, and IL-1 receptor antagonist genes were determined in a Finnish population survey (n = 6771). Glucose and insulin concentrations were measured, and indices of insulin resistance and β-cell function were calculated using the homeostasis model assessment. Two-hour oral glucose tolerance tests were carried out on a subsample of 1390 participants. Associations with prevalent diabetes were tested for replication in a sample of European myocardial infarction survivors (n = 972).

Results: The minor allele of the IL-1β rs1143634(GA) was associated with higher blood glucose than the major allele: 5.37, 5.41, and 5.48 mmol/liter for the GG, AG, and AA genotypes, respectively (multivariate adjusted P for trend <0.0001; Bonferroni corrected P = 0.00096). The 2-h glucose was also higher (6.45 and 7.20 mmol/liter for the GG vs. AA; P = 0.003, Bonferroni corrected P = 0.045). The haplotype ACG of rs1143634, rs3917356, and rs16944 associated with higher glucose, higher homeostasis model assessment for insulin resistance index, higher 2-h insulin, and prevalent diabetes (adjusted rate ratio = 1.54; 95% confidence interval = 1.03–2.30; P = 0.037). The association with prevalent diabetes was replicated among European myocardial infarction survivors (rate ratio = 2.09; 95% confidence interval = 1.17–3.76; P = 0.013).

Conclusions: These results suggest that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and prevalent diabetes.