Single Nucleotide Polymorphisms In IL1RN Research Articles

IL1 genes polymorphism and the risk of renal cell carcinoma in Chinese Han population.

Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. However, with the lack of diagnostic screening biomarkers, early diagnosis of RCC is challenging. Our study was investigated the association of IL1 gene polymorphisms and RCC risk. We conducted a case-control study of 291 RCC cases and 463 controls to evaluation the IL1RN of single nucleotide polymorphisms (SNPs) on RCC risk. We selection of 16 SNPs in IL1RN, IL1A, IL1B genes were analyzed. Using the chi-squared (χ2) test and genetic model analysis, we found an association with RCC risk for five SNPs [rs3783550 (IL1A), rs3783546 (IL1A), rs1609682 (IL1A), rs3783521 (IL1A), and rs1143623 (IL1B)] and increased the risk of RCC. Stratified analyses show that smoking, not drinking and age>55 populations relative to nonsmoking, drinking and age<55 more susceptible. Our study suggested that IL1B and IL1A may involve in the development of RCC in Chinese Han population.

The interleukin-1β-511 T > C (rs16944) gene polymorphism is associated with risk of developing silent myocardial ischemia in diabetic patients

Silent myocardial ischemia (SMI) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. Considering the prominent role of IL-1β, IL-1F10 and IL-1RN as regulators of the inflammatory process and vascular physiology, the aim of the present study was to analyze whether IL-1β, IL-1F10 and IL-1RN single nucleotide polymorphisms (SNPs) are associated with SMI. One polymorphism was associated with risk of SMI. Under co-dominant, recessive and additive models, the IL-1β-511 T>C polymorphism was associated with increased risk of SMI when compared to healthy controls (OR=4.68, 95%CI=2.21–9.92, pCCo-dom=0.0048; OR=3.97, 95%CI=1.97–7.99, pCRec=0.0024; OR=2.02, 95%CI=1.41–2.90, pCAdd=0.0024, respectively). All models were adjusted for gender, age and smoking. Linkage disequilibrium analysis showed four haplotypes (CTCC, CCTC, CCCT and CTCC) with increased frequency in SMI patients when compared to healthy controls (OR=2.53, 95%CI=1.47–4.36, pC=0.0009, OR=2.34, 95%CI=1.15–4.74, pC=0.02, OR=2.44, 95%CI=1.14–5.18, pC=0.02, OR=5.11, 95%CI=1.37–19.05, pC=0.01, respectively). In summary, our data suggest that the IL-1β-511 T>C polymorphism plays an important role in the development of SMI in diabetic patients. In addition, in our study was possible to distinguish one protective and four risk haplotypes for development of SMI.

Stroke, IL-1ra, IL1RN, Infection and Outcome

Infection is a common phenomenon following stroke, and adversely affects outcome. Previous studies suggest that interleukin-1 receptor antagonist (IL-1ra) and single nucleotide polymorphisms (SNPs) in the IL1RN gene might influence the risk of post-stroke infection and outcome. In this study, we addressed the effects of the rs4251961 SNP in IL1RN on infection risk and outcome. Subjects with acute ischemic stroke were enrolled within 72 h of symptom onset and followed up to 1 year. Plasma IL-1ra was measured at multiple time points and outcome assessed at 1, 3, 6, and 12 months. Active surveillance for infection occurred while subjects were hospitalized. Subjects were genotyped for the IL1RN rs4251961 polymorphism. In the population of 113 subjects for this study, those with the minor C allele of rs4251961 polymorphism in IL1RN were more likely to be Caucasian, hypertensive, and to be afflicted with coronary heart disease. Higher plasma IL-1ra was associated with an increased risk of infection (other than pneumonia), and the minor C allele of rs4251961 was independently associated with a decreased risk of infection (other than pneumonia). Initial plasma IL-1ra was not predictive of long-term outcome, but patients with the minor C allele of rs4251961 were more likely to experience good (modified Rankin Score <2) long-term outcome. These data indicate that IL-1ra and IL1RN may influence the risk of infection after stroke, but this influence seems limited to infections other than pneumonia. Further studies are needed to better understand the complexities of immune regulation on infection and outcome after stroke.

Genetic Variation Within the Interleukin-1 Gene Cluster and Ischemic Stroke

Evidence is emerging that inflammation plays a key role in the pathophysiology of ischemic stroke (IS). The aim of this study was to investigate whether genetic variation in the interleukin-1α, interleukin-1β, and interleukin-1 receptor antagonist genes (IL1A, IL1B, and IL1RN) is associated with IS and/or any etiologic subtype of IS. Twelve tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which comprises 844 patients with IS and 668 control subjects. IS subtypes were defined according to the Trial of Org 10172 in Acute Stroke Treatment criteria in SAHLSIS. The Lund Stroke Register and the Malmö Diet and Cancer study were used as a replication sample for overall IS (in total 3145 patients and 1793 control subjects). The single nucleotide polymorphism rs380092 in IL1RN showed an association with overall IS in SAHLSIS (OR, 1.21; 95% CI, 1.02-1.43; P=0.03), which was replicated in the Lund Stroke Register and the Malmö Diet and Cancer study sample. An association was also detected in all samples combined (OR, 1.12; 95% CI, 1.04-1.21; P=0.03). Three single nucleotide polymorphisms in IL1RN (including rs380092) were nominally associated with the subtype of cryptogenic stroke in SAHLSIS, but the statistical significance did not remain after correction for multiple testing. Furthermore, increased plasma levels of interleukin-1 receptor antagonist were observed in the subtype of cryptogenic stroke compared with controls. This comprehensive study, based on a tagSNP approach and replication, presents support for the role of IL1RN in overall IS.

Anti-Inflammatory Markers Are Associated with Glomerular Filtration Rate In Adults with Sickle Cell Disease.

AbstractAbstract 1652Sickle cell disease (SCD) is characterized by increased systemic inflammation. Further, in a significant number of adult SCD patients, renal dysfunction and failure occur and are risk factors for early mortality. While some evidence supports a relationship between inflammation and renal dysfunction in the general population, this association has not yet been established in SCD. Recently, inflammatory biomarkers including TNFα (tumor necrosis factor alpha), C reactive protein (CRP), interleukin 6 (IL-6), and CD40 ligand (CD40L) were shown to be associated with chronic kidney disease (CKD) in a cohort of offspring of European descent participating in the Framingham study. Inflammatory markers were increased and glomerular filtration rates (GFR) were decreased in those with CKD compared to individuals with normal kidney function (Upadhyay, et al. 2010). Increased CRP has also been associated with CKD in African Americans participating in the Jackson Heart study (Fox, et al. 2010). Our goal was to determine if single nucleotide polymorphisms (SNPs) in inflammatory genes are associated with GFR in our population of SCD patients. To test this, we analyzed 55 haplotype tagging SNPs within 14 pro- and anti-inflammatory genes in 675 DNA samples from SCD patients ascertained from Duke University, University of North Carolina-Chapel Hill, and Emory University. SNP genotyping was performed using Taqman genotyping assays from Applied Biosystems. Genetic associations with GFR were examined using allele tests and multiple regression analysis (SAS version 9.1.3, Cary, NC). After controlling for age, gender, and use of hydroxyurea, SNPs in IL-1RN (rs452204), IL-10 (rs3024498), IL-12B (rs2195940), and IL-13 (rs1295687 and rs2069744) were significantly associated with GFR, with nominal p values ranging from 0.048 to 0.01. The two IL-13 SNPs were not found to be in linkage disequilibrium (LD) with each other (r2=0.017). After correcting for multiple testing, the SNPs in IL-10, IL-12B, and IL-13 (rs1295687 only) remained significant, with p values of 0.0134, 0.0084 and 0.0123, respectively. We then used regression analyses to test for pairwise interactions among all five of the SNPs, including each as a main effect in our analyses. Significant interactions were observed between rs1295687 in IL-13 and SNPs in IL-1RN (p=0.0174), IL-10 (p=0.0014), and rs2069744, also in IL-13 (p=0.0054). However, there was no significant interaction between IL-12B and any other SNP. The functional significance of these SNPs is presently unknown. All of the markers are located in introns except for the IL-10 marker, which is located in the 3' untranslated region of the gene. Our findings in SCD support previous data from the general population showing associations among inflammatory markers, GFR and renal dysfunction. Interestingly, the SNPs which displayed significant interactions in the prediction of GFR are all located in anti-inflammatory genes (IL-13, IL-1RN and IL-10). In one previous study, macrophages that were stimulated with IL-4 and IL-13 ex vivo to produce IL-10, instead of TNFα and interferon gamma (IFNγ), protected against in vivo renal injury when infused into severe combined immunodeficiency (SCID) mice with doxorubicin-induced nephropathy (Wang, et al. 2007). The role of genetic factors that correlate with changes in GFR in adults with SCD requires replication in additional patient cohorts. Most importantly, our findings suggest that further investigation into the role of pro-inflammatory and anti-inflammatory pathways in the deterioration of kidney function in SCD is warranted. Disclosures:Telen:GlycoMimetics: Consultancy.

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1 α ( IL1A), IL-1 β ( IL1B), and IL-1 receptor antagonist ( IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis ( P values for rs3213448, rs315952, rs315949, respectively: 5.5 x 10 −11, 1.5 x 10 −11, and 4.0 x 10 −14). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis ( P = 9.4 x 10 −7). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.

IL-1B-511 C?T Polymorphism is Associated with Increased Host Susceptibility to Helicobacter pylori Infection in Chinese

The heritability of Helicobacter pylori infection from twin studies has been reported to be 0.66. However, few data were available on the host susceptibility to H. pylori infection in Chinese. We aimed to evaluate the impact of the IL-1B and IL-1RN single-nucleotide polymorphisms (SNP) and ABO blood types on the host susceptibility to H. pylori infection. Individuals who underwent routine health check-up were enrolled. Genotyping was assessed by polymerase chain reaction (PCR) followed by direct sequencing and size fractionation using DNA from peripheral blood samples. Odds ratios (OR) for the susceptibility of H. pylori infection were computed from logistic regression models. The overall prevalence of H. pylori was 62% among the 663 healthy individuals, with 54.7, 63.5, and 66.9% in persons genotyped C/C, C/T, and T/T at IL-1B-511, respectively. Age (OR 1.05, 95% CI = 1.03-1.07, p < .001) and T carrier at IL-1B-511 (OR = 1.56, 95% CI = 1.06-2.30, p = .026) were independent factors associated with increased risks of H. pylori infection in the multivariate analysis. The risks of H. pylori infection were not related to IL-1RN SNP and ABO blood types. These findings support that a proinflammatory polymorphism at IL-1B promoter gene is associated with increased host susceptibility to H. pylori infection in Chinese.

The different expression patterns of interleukin‐1 receptor antagonist in systemic lupus erythematosus

The interleukin-1 receptor antagonist (IL1RN or IL-1Ra) is a natural antagonist of IL-1-beta. Using IL1RN as a possible marker in patients with systemic lupus erythematosus (SLE), we evaluated whether uIL1RN single nucleotide polymorphisms (SNPs) were associated with the pathogenesis of SLE in Taiwanese, and specifically whether IL1RN (rs315952) was significantly associated with end-stage renal disease. We examined IL1RN isoform expression patterns in patients with SLE to determine whether the expressions play a role in the pathogenesis of SLE. Both case-control and family-based association studies were used. For the case-control study, 104 patients with SLE and 97 normal controls were recruited, and for the family-based study, 11 families with SLE without renal disorder were recruited from the 104 patients with SLE. Eight IL1RN SNPs (rs2234678, rs2234679, rs315951, rs315952, rs419598, rs432014, rs447713, and rs451578) were selected for the family-based study. Reverse-transcriptase-polymerase chain reaction (RT-PCR) was used to determine the expression pattern of each isoform. Our results showed that IL1RN (rs315952) was significantly associated with SLE in patients without renal disorder in the family-based study, after disease stratification, but was not significantly associated with SLE in the case-control study. In the family-based study, the haplotype of IL1RN (AGCCTTAG) was significantly associated with SLE (chi2 = 11.714, P < 0.001). Using RT-PCR to determine the expression pattern of the IL1RN isoforms, we found different expression patterns between normal controls and patients with SLE, with an addition of IL1RN isoform4 or the low expression of IL1RN isoform1. We concluded that IL1RN and its isoforms were involved in the pathogenesis of SLE.