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

Abstract

The proinflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and β-cell dysfunction, whereas higher circulating levels of IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor of IL-1β, has been suggested to improve glycemia and β-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 × 10(-21)] and rs6759676, closest gene locus IL1F10 [n = 13,994, P = 1.73 × 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 IL1RN and IL1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance.

Figure 1

Association between rs4251961 and rs6759676 and IL-1RA in the discovery analysis. Shown are genome-wide association P values for all variants that were tested in the IL-1RA association analysis and located in the IL1RN gene cluster on the chromosome 2 (chr2). A: SNP rs4251961 allele shows the strongest association with IL-1RA in the discovery analysis. B: SNP rs4251961 remains an independent hit when conditioning on rs6759676. C: SNP rs6759676 remains an independent hit when conditioning on rs4251961.

Figure 1

Association between rs4251961 and rs6759676 and IL-1RA in the discovery analysis. Shown are genome-wide association P values for all variants that were tested in the IL-1RA association analysis and located in the IL1RN gene cluster on the chromosome 2 (chr2). A: SNP rs4251961 allele shows the strongest association with IL-1RA in the discovery analysis. B: SNP rs4251961 remains an independent hit when conditioning on rs6759676. C: SNP rs6759676 remains an independent hit when conditioning on rs4251961.

Figure 2

Association of rs4251961 and rs6759676 with circulating IL-1RA, CRP, insulin levels, and HOMA-IR in individual studies included in the discovery and replication analysis. A and B: IL-1RA. C and D: CRP. E and F: Insulin. G and H: HOMA-IR. All analyses were adjusted for age, sex, BMI, waist-to-hip ratio, and smoking. FE, fixed effects; FR1997, FINRISK 1997; RE, random effects.