Genetic Determinants of Circulating Interleukin-1 Receptor Antagonist Levels and Their Association With Glycemic Traits

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.