IL-1RN Variable Number Tandem Repeat Research Articles

Association of IL1RN VNTR polymorphism with chikungunya infection: A study from Western India.

Chikungunya, caused by the chikungunya virus (CHIKV) mostly presents as acute and chronic articular inflammatory manifestations. Interleukin 1 receptor antagonist (IL-1RN) is a potent endogenous competitive inhibitor of IL-1α and 1β and has an anti-inflammatory role. The present study evaluated the possible association of IL1RN variable number tandem-repeat (VNTR) alleles and genotypes, and CHIKV stimulated IL-1RN cytokine production with resistance and/or susceptibility to chikungunya infection and disease state in 224 patients withchikungunya (61 patients withacute chikungunya and 163 patients with chronic chikungunya) and 355 healthy controls. Polymerase chain reaction, CHIKV stimulated cytokine assay and luminex platform were used for assessing polymorphism and protein levels respectively. The study revealed a significant association of IL1RN*1/*1 genotype under recessive genetic model with the risk of developing chikungunya infection. Our findings also indicated that IL1RN *2 allele under dominant mode was associated with protection to chronic chikungunya. The results also revealed a higher production of IL-1 RN protein in patients with chronic chikungunya. To conclude, the results suggest the association of ILRN VNTR polymorphism and IL-RN protein levels with chronic chikungunya.

IL1 gene polymorphisms in relation to external apical root resorption concurrent with orthodontia

External apical root resorption (EARR) is permanent shortening of the end of the tooth root. It is a common clinical complication of orthodontic treatment. Polymorphisms in the interleukin 1 (IL1) gene cluster have been related to an increased EARR risk. The aim of this study was to analyze possible associations of IL1 gene variants with EARR in Czech population. In this case-control study, 32 patients with EARR (age 15.0 ± 4.1 years) and 74 controls (age 15.2 ± 5.3 years) were genotyped using PCR-based methods for IL1A (-889C/T), IL1B (+3953C/T), and IL1RN [IL1 receptor antagonist, variable number tandem repeat (VNTR)] gene polymorphisms. While no statistical significant differences in the IL1A and IL1B genotype, allele and reconstructed IL1 haplotype frequencies between patients with EARR and controls were found, marginally significant differences were observed in the frequencies of IL1RN variant (P = 0.05 for *22 genotype and P = 0.06 for a short (2) allele). In addition, significant associations between IL1RN*12, *22 genotypes and the short (2) allele and EARR were identified in the subgroup of girls (P = 0.04 and P = 0.02, P = 0.02). Although no significant role of IL1A (-889C/T) and IL1B (+3953C/T) variants in EARR was confirmed, IL1RN VNTR may be associated with EARR, especially in girls.

Interleukin‐1B and interleukin‐1 RN polymorphisms and gastric carcinoma risk: A meta‐analysis

We aimed to explore the role of interleukin (IL)-1B cluster gene polymorphisms at positions -511, -31, and +3954 and the receptor IL-1RN variable number tandem repeat polymorphisms in the susceptibility to gastric carcinoma through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. The desirable data were extracted and registered into databases. Studies that deviated from Hardy-Weinberg equilibrium were excluded. Eighteen studies were ultimately eligible for the meta-analysis of IL1B-511, 21 studies for IL1B-31, 10 studies for IL1B+3954, and 20 studies for IL1RN variable number tandem repeat genetic polymorphisms, respectively. Original groups were collapsed and re-grouping was adopted in line with the most probably appropriate genetic models. Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and biases across studies were estimated. The pooled odds ratios (95% confidence intervals, P-value) associated with IL-1B -511 T carriers versus CC genotypes and with RN *2 carriers versus L/L were 1.23 (1.04-1.45, P = 0.015) and 1.26 (1.06-1.51, P = 0.010), respectively, for overall gastric carcinoma; 1.31 (1.04-1.64, P = 0.020) and 1.47 (1.21-1.79, P = 0.000), respectively, for non-cardia gastric cancer; 1.55 (1.05-2.28, P = 0.026) and 1.66 (1.23-2.25, P = 0.001), respectively, for intestinal type gastric carcinoma; and 1.33 (1.04-1.71, P = 0.023) and 1.31 (1.07-1.61, P = 0.010), respectively, in Caucasians for overall gastric carcinoma. The pooled odds ratio (95% confidence interval, P-value) regarding IL-1B-31 CC plus TT versus CT was 0.73 (0.60-0.89, P = 0.002) for intestinal type gastric carcinoma. Genotyping methods and publication time could constitute the sources of heterogeneity across studies. Publication biases were not found. IL-1B -511 T allele and IL-1 RN *2 VNTR are significantly associated with an increased risk of developing gastric carcinoma and even more significantly with non-cardia gastric carcinoma or with intestinal-type gastric carcinoma. Both are significantly associated with an increased risk of developing gastric carcinoma among Caucasians, but not among Asians or Hispanics.

Involvement of Interleukin‐1 Genotypes in the Association of Coronary Heart Disease With Periodontitis

Epidemiologic studies demonstrated an association between periodontitis (PE) and coronary heart disease (CHD). The coexistence of the two disease entities could be dependent on mutual risk factors, and polymorphism of the interleukin (IL)-1 gene cluster associated with the severity of PE might also be involved in the pathogenesis of CHD. The study consisted of 225 dentate white subjects, including 97 patients with CHD and 128 controls. Patients with confirmed diagnoses of CHD were recruited after being discharged from a cardiology department, and controls without CHD were recruited consecutively from the Copenhagen City Heart Study. Mean alveolar bone level (ABL) was measured on radiographs. ABL was stratified into ABL1 (ABL < or = 2 mm), ABL2 (2 mm <ABL < or = 4 mm), and ABL3 (ABL >4 mm). Genotypes were analyzed by amplifying the polymorphic regions of the IL-1 gene cluster using polymerase chain reaction, followed by restriction digestion and gel electrophoresis. In the univariate analysis, allele 2 of IL-1B+3954 and IL-1B-511 was associated with ABL (P = 0.040 and P = 0.039, respectively), whereas no association was found with allele 2 of IL-1A+4845 or IL-1RN variable number tandem repeat (VNTR) (P = 0.445 and P = 0.375, respectively). A lower ABL was associated with the occurrence of allele 2 of IL-1B-511. The multiple logistic regression analysis also showed a significant association of allele 1 of IL-1B-511 with high ABL (P = 0.049) and of allele 2 of IL-1A+4845 with high ABL among individuals with CHD (P = 0.050). There was no association between any of the polymorphisms of IL-1 and CHD in the univariate or multiple analyses. However, in a binary multiple logistic regression model, carriage of allele 1 of IL-1RN VNTR was found to be associated with the occurrence of both CHD and ABL3 (P = 0.016). Allele 1 of IL-1RN VNTR may be associated with the coexistence of CHD and PE in a multiple regression model.

Determination of ancestral allele for possible human cancer-associated polymorphisms

To determine ancestral allele in possible cancer-associated polymorphisms, DNA samples from 10 chimpanzees ( Pan troglodytes) were sequenced for alleles corresponding to 17 polymorphisms: 8 short tandem repeats [IL1RN (alias IL-1RA) variable number tandem repeat (VNTR); TYMS (previously TS) VNTR; AR CAG repeat; dinucleotide repeats of UGT1A1, IGF1, IFNG (alias IFN-γ), ESR1 (alias ER-α), and EGFR] and 9 single nucleotide polymorphisms ( MMP1-1607 1G/2G, MMP3-1171 5A/6A, OGG1 Ser326Cys, ALDH2 Gly487Lys, TP53 Arg72Pro, ABCG2 Gln141Lys, MGMT Leu84Phe, SOD2 Ala-9Val, and MTHFR Ala222Val). No chimpanzee polymorphism corresponded to human IL1RN VNTR; the ancestral allele was a repeat lost in humans. Dinucleotide repeat polymorphisms of IGF1, IFNG, ESR1, and EGFR were shared by chimpanzees, but the length of repeats tended to be longer in humans than in chimpanzees. This tendency was particularly evident for IGF1. All of the SNPs tested are human-specific nucleotide changes. The ancestral allele 7A was shown to be lost in MMP3-1171 5A/6A. Thus, all of the possible cancer-associated polymorphisms tested have human-specific alleles, and the ancestral allele is lost in three polymorphisms ( IL1RN VNTR, UGT1A1 CA repeat, and MMP3-1171 5A/6A), suggesting a possible involvement of human-specific alleles in cancer susceptibility.

Polymorphisms Within the IL‐1 Gene Cluster: Effects on Cytokine Profiles in Peripheral Blood and Whole Blood Cell Cultures of Patients With Aggressive Periodontitis, Juvenile Idiopathic Arthritis, and Rheumatoid Arthritis

Genetic polymorphisms of cytokines have been associated with the susceptibility, severity, and clinical outcome of inflammatory diseases, such as periodontitis and chronic arthritis. An important question to address is how interleukin (IL)-1 polymorphisms affect the cytokine profiles of patients with such diseases. The study population consisted of Danish white adults, <35 years of age, who were diagnosed with localized aggressive periodontitis (LAgP, n = 18), generalized aggressive periodontitis (GAgP, n = 27), juvenile idiopathic arthritis (JIA, n = 10), and rheumatoid arthritis (RA, n = 23) and healthy individuals with no systemic or oral diseases (n = 25). Genotypes of IL-1A-889, IL-1A+4845, IL-1B-511, and IL-1B+3954 were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism, and IL-1RN variable number tandem repeat (VNTR) was detected by PCR amplification and fragment size analysis. Analysis of variance was used to evaluate the effects of IL-1 genotypes on the levels of IL-1alpha, -1beta, -1 receptor antagonist, -6, and -10; tumor necrosis factor-alpha (TNF-alpha); and lymphotoxin-alpha in peripheral blood (plasma) and in unstimulated and stimulated whole blood cell cultures from the same blood collection. The frequencies of IL-1 genotypes investigated did not differ significantly between diseased and control individuals. In LAgP patients, allele 2 of IL-1RN VNTR was associated with significantly higher levels of IL-1alpha, -6, and -10 and TNF-alpha, whereas allele 2 of IL-1B+3954 was associated with significantly lower levels of the same cytokines. In GAgP patients, a general lack of association was found. In JIA and RA patients, IL-1RN VNTR also influenced the cytokine levels. IL-1 genotypes were associated with cytokine levels in patients with aggressive periodontitis and chronic arthritis. No associations were observed in control individuals.

Genetic analysis of the interleukin-1 receptor antagonist and its homologue IL-1L1 in alopecia areata: strong severity association and possible gene interaction.

Alopecia areata is an inflammatory hair loss disease with a major genetic component. The presence of focal inflammatory lesions with perifollicular T-cell infiltrates reflects the importance of local cytokine production in the pathogenesis. In addition to its fundamental pro-inflammatory role, the interleukin-1 (IL-1) system has major effects on hair growth regulation in vitro, with the inhibitory actions of IL-1alpha and IL-1beta being opposed by the receptor antagonist IL-1ra. The novel interleukin-1 like molecule 1 (IL-1L1) which has greatest gene sequence homology with IL1RN, the gene encoding IL-1ra, is another potential IL-1 antagonist. In view of previous studies suggesting a significant role for IL1RN polymorphisms in the pathogenesis of autoimmune/inflammatory disease, we have analysed polymorphisms of IL-1ra (IL1RN+2018) and its homologue IL-1L1 (IL1L1+4734) in a case-control association study on 165 patients and a large number of matched controls. Homozygosity for the rare allele of IL1RN (IL1RN*2) was significantly associated with alopecia areata [odds ratio (OR) = 1.89, 95% CI (1.09, 3.28); P = 0.02], confirming our previous findings of significant association with the IL1RN variable number tandem repeat (VNTR). The results also revealed a novel association involving a polymorphism of the interleukin-1 receptor antagonist homologue IL1L1 at position + 4734, IL1RN+2018, and alopecia areata. The effect of a genotype combining three copies of the rare alleles at the IL1RN and IL1L1 loci conferred a more than additive increase in the risk of disease compared to IL1RN+2018 or IL1L1+4734 alone [OR 3.37 (1.60, 7.06); P = 0.002], suggesting possible synergy between the IL1RN and IL1L1 genes. This effect was stronger in patients with severe disease (alopecia totalis/universalis) [OR 4.62 (1.87, 11.40), P = 0.0022], and in those with early age at onset (< 20 years) [OR = 6.38 (2.64, 15.42), P = 0.0002]. Our results suggest that these polymorphisms within IL1RN and IL1L1 themselves or a gene in linkage disequilibrium with IL1RN and IL1L1 predispose to the more severe forms of alopecia areata.