Abstract 5095: Association of Genetic Variation in the IL-1 Gene with Diabetes and Glucose Homeostasis

Abstract

To examine the associations of genetic variation in the interleukin 1 (IL-1) cluster with diabetes and glucose homeostasis. We determined 15 single nucleotide polymorphisms in the IL-1α, IL-1β and IL-1 receptor antagonist (IL1RN) genes in a Finnish population sample of 6,771 individuals. Fasting glucose and insulin were determined from all participants. Indices of insulin resistance and beta cell function were calculated using the homeostasis model assessment (HOMA-IR and HOMA-β cell). Two-hour oral glucose tolerance tests (OGTT) with insulin and glucose measurements at 30 min and 120 min were carried out on a subsample of 1,390 participants. Replication of the findings on prevalent diabetes was tested in another independent material of 972 European myocardial infarction (MI) survivors (AIRGENE). Replication of the associations with fasting insulin, glucose and HOMA-IR was searched from the publicly available Framingham SNP Health Association Resource (SHARe) database. In multivariate models haplotypic variation in the IL-1β SNPs rs1143634, rs3917356 and rs16944 was associated with prevalent diabetes among Health 2000 participants: rate ratio (RR) 1.54 (95% CI 1.03–2.30, p=0.037), comparing participants with two copies of the ACG haplotype with participants with no copy of the haplotype. This association was replicated among the European MI survivors: RR 2.09 (1.17–3.76, p=0.013). The same haplotype was associated with HOMA-IR (p=0.007), fasting insulin (p=0.021) and in the OGTT subsample with area under the glucose curve (AUC glucose) (p=0.0002). Rs1143634 was the tagging SNP of this haplotype and showed associations consistent with the haplotypic analyses. In the Framingham SNP Health Association Resource (SHARe) genome-wide data rs1374284 of the IL-1β gene is associated with fasting insulin and HOMA-IR (p=3.56e-4 and p=1.51e-4, respectively). Rs1374284 is in high LD with the rs1143634 (r2>0.80) most probably reflecting the same signal as observed in our study. Genetic variation in the IL-1 cluster is associated with prevalent diabetes and several measures of glucose homeostasis. The associations seem consistent in several populations of white European ancestry.