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.

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…Examining common variants of the IL1RN gene revealed that the rs4251961 minor allele is associated with a lowered serum level of IL-1RN and that the rs579543 single nucleotide polymorphism (SNP) is also independently associated with IL-1RN levels, whereas the IL1RN 1018 haplotype correlates with higher concentrations of IL-1β and IFNγ 22 . These findings have been confirmed in three independent cohorts 26 , and further research has demonstrated that these factors affect the pathophysiology of human infections 27 and the risk of developing insulin resistance 28 and knee osteoarthritis 29 .…”

IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance

“…Blocking IL-1β activity with an antibody or with IL-1Ra is promising in treating type 2 diabetes [83, 87, 90]. In line with this, the IL-1Ra-increasing SNP in the IL-38 gene associated with lower fasting insulin levels and HOMA-IR [176]. Other SNPs that were found to associate with elevated IL-1Ra levels were not associated with insulin or HOMA-IR, suggesting that the association of the SNP in IL-38 with metabolic treats is independent of IL-1Ra levels.…”

“…Nevertheless, a single nucleotide polymorphism (SNP) in the IL-38 gene is associated with plasma C-reactive protein levels [175], a marker that is increased in serum of obese and type 2 diabetes patients. Interestingly, another SNP in a locus close to the IL-38 gene associates with increased circulating IL-1Ra levels [176]. Blocking IL-1β activity with an antibody or with IL-1Ra is promising in treating type 2 diabetes [83, 87, 90].…”

Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?

“…Even earlier, it has been suggested that high dose treatment with the anti-inflammatory sodium salicylate of patients with diabetes may reduce glucosuria [3]. These findings have been substantiated and extended by more recent epidemiological studies demonstrating that parameters of inflammation including leucocyte number, C-reactive protein (CrP), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra) and plasminogen activator inhibitor-1 (PAI-1) serum concentrations correlate with or predict incident type 2 diabetes [4][5][6][7][8][9]. These data are supported by intervention studies demonstrating that reducing body weight, improving glycaemic control and insulin sensitivity leads to reduced circulating markers of inflammation [10][11][12].…”