Polymorphisms of the IL1-Receptor Antagonist Gene ( IL1RN ) Are Associated With Multiple Markers of Systemic Inflammation

Abstract

Background— Circulating levels of acute phase reactant proteins such as plasma C-reactive protein (CRP) are likely influenced by multiple genes regulating the innate immune response. Methods and Results— We screened a set of 16 inflammation-related genes for association with CRP in a large population-based study of healthy young adults (n=1627). Results were validated in 2 independent studies (n=1208 and n=4310), including a pooled analysis of all 3 studies. In the pooled analysis, the minor allele of IL1RN 1018 (rs4251961) within the gene encoding interleukin (IL)-1 receptor antagonist (IL-1RA) was significantly associated with higher mean plasma log(CRP) level ( P <1×10 −4 ). The same IL1RN 1018 allele was associated with higher mean plasma log(IL-6) levels ( P =0.004). In the pooled analysis, the minor allele of IL1RN 13888 (rs2232354) was associated with higher fibrinogen, ( P =0.001). The IL1RN 1018 and 13888 variant alleles tag a clade of IL1RN haplotypes linked to allele 1 of an 86-bp VNTR polymorphism. We confirmed that the IL1RN 1018 variant (rs4251961) was associated with decreased cellular IL-1RA production ex vivo. Conclusions— Common functional polymorphisms of the IL1RN gene are associated with several markers of systemic inflammation.

The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1

“…Additionally, they found that the IL1RN 1018 haplotype was associated with increased concentrations of IL-1b and IFN-g. These findings were recently confirmed by a study that used three independent cohorts comprising elderly individuals, young adults, and adults with severe carotid disease (16). We hypothesized that the IL1RN gene may impact on disease severity and survival in invasive pneumococcal disease through modulation of IL-1Ra levels.…”

“…Our data differ from those of Rafiq et al (15) and Reiner et al (16), who demonstrated that the C allele was associated with reduced IL-1Ra concentrations in elderly individuals, young adults, and adults with severe carotid artery disease. The subjects in Rafiq's and Reiner's studies (15,16) were healthy adults with measurements made after an overnight fast. In contrast, our subjects were children and adults in sub-Saharan Africa, with a severe acute illness, or a chronic viral infection, both of which are associated with a high mortality.…”

Inflammation and the Silent Sequelae of Stroke

“…In this same cohort of patients, we found that single nucleotide polymorphisms (SNPs) in genes that regulate inflammation were also associated with PSF [73]. Specifically, we found that PSF was associated with the C allele of IL1RN rs4251961, which is commonly associated with a decrease in IL-1ra and an increase in proinflammatory cytokines like IL-1β and CRP [74,75]. Further, we found that functional polymorphisms in Toll-like receptor 4 (TLR4) that render it less responsive to its ligands were associated with less fatigue [73].…”

“…P=0.037 a b Fig. 3 Poststroke fatigue is more prevalent in those with the C allele of IL1RN (a), which is generally associated with increased inflammation [74,75], and less prevalent in those with single nucleotide polymorphisms (SNPs) in TLR4 (b) that render the Toll-like receptor less sensitive to its agonists. FAS Fatigue Assessment Scale…”

An Application of Logistic Regression and Multifactor Dimensionality Reduction Analyses for Detecting Genotype-Phenotype Interactions Associated with Developing of Atherosclerosis in Bulgarian Cohort

“…In our study the mutant homozygote for MTHFR C677T is 9.5%, 9.5%, 16.9%, and the T allele frequency is 26%, 29% and 40%, respectively for control subjects, patients with SAP and ACS. There is only a (27,37). ILRa genotypes BB, BC, BD and DD were significantly more frequent among patients with SAP and ACS compared to control subjects (Table 2, P1=0.002 and P2=0.009).…”