Interleukin-1 Gene Cluster Research Articles

Associations of the Interleukin‐1 Gene Locus Polymorphisms with Risk to Hip and Knee Osteoarthritis: Gender and Subpopulation Differences

Genetic predisposition to the complex hereditary disease like osteoarthritis (OA) of the large joints (hip and knee) includes the interleukin-1 gene (IL-1) cluster on chromosome 2. Using a case-control study with 500 OA patients (240 knee and 260 hip OA patients, all with joint replacement), we analysed frequencies of IL-1 gene cluster polymorphisms in Croatian Caucasian population. The control samples came from 531 healthy individuals including blood donors. We genotyped two single nucleotide polymorphisms in the IL-1 gene locus at IL-1A (-889, C>T, rs1800587) and IL-1B (+3594, C>T, rs1143634) and compared their frequencies between patients and controls. We predicted haplotypes by combining current data with our previous results on gene polymorphisms (IL-1B, rs16944 and the IL-1 receptor antagonist gene [IL-1RN] variable number tandem repeat [VNTR]) for the same population. Haplotype analyses revealed gender disparities and showed that women carriers of the 1-2-1-1 haplotype [IL-1A(rs1800587) - IL-1B(rs1143634) - IL-1B(rs16944) - IL-1RN(VNTR)] had sixfold lower risk to develop knee OA. However, carriers of the 1-1-1-2 haplotype of both sexes had over twofold higher predisposition to hip OA. Our results differ from some earlier studies in Caucasian subpopulations, which may be due to the fact that this is the first study to separate genders in assessing the IL-1-locus genetic risk of OA. The results suggest that inflammatory mediators like IL-1 might be implicated in the pathogenesis of primary OA in large joints and that as yet unidentified gender-specific factors exist in a Croatian Caucasian population.

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.

Interleukin 1 gene cluster SNPs (rs1800587, rs1143634) influences post‐orthodontic root resorption in endodontic and their contralateral vital control teeth differently

To investigate whether the genetic variants of the interleukin-1 gene cluster (IL1) are associated with a possible genetically induced variability in post-orthodontic external apical root resorption (EARR) in root filled teeth and their control counterparts with vital pulps. One hundred and forty-six maxillary premolars were evaluated radiographically following orthodontic treatment. Genetic screening was performed on orthodontic patients for two single-nucleotide polymorphisms (SNPs: rs1800587 and rs1143634) in the IL1 gene cluster. Subjects were divided into two groups according to the presence or absence of radiographic post-orthodontic EARR (>2 mm) in root filled teeth and their controls with vital pulps. Logistic regression analysis was performed to obtain an adjusted estimation between EARR and IL1 polymorphisms. Allelic frequencies, genotype distributions, and adjusted odds ratio (OR), at 95% confidence interval, were also calculated. Whilst no clear statistical association was found for gene variations in IL1A, a sound association was found in the comparative analysis of subjects homozygous [2/2(TT)] for the IL1B gene, which resulted in a two times increased risk of suffering post-orthodontic EARR in root filled teeth [OR, 2.032 (P = 0.031); CI,1.99-14.77] when compared with their controls with vital pulps. There was, however, a shared predisposition to EARR in controls with vital pulps and root filled teeth of subjects homozygous for allele 1 [OR, 5.05 (P = 0.002)] and [OR, 2.77 (P = 0.037)], respectively. Genetic variations in the interleukin-1β gene (rs1143634) predispose root filled teeth to EARR for matched pairs secondary to orthodontic treatment in a different way from their control teeth with vital pulps in subjects homozygous for allele 2 [2/2(TT)].

Interleukin-1 gene cluster variants and recurrent pregnancy loss among North Indian women: retrospective study and meta-analysis

The aim of this study was to determine whether or not interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) and IL-1 receptor antagonist (IL-1RA) polymorphisms are associated with risk of unexplained recurrent pregnancy loss (RPL) among North Indian women. This retrospective case–control study examine 200 well-characterized RPL cases for IL-1 gene cluster variants, determined by restriction fragment length polymorphism-PCR. The observed allele, genotype and haplotype distributions were compared with those obtained from 300 ethnically matched negative controls. Invariant distribution of IL-1 gene cluster single-nucleotide polymorphisms was observed among RPL cases and controls. Meta-analysis of IL-1β −511, +3953 and IL-1RN 86-bp variable number tandem repeat from the reported literature and this study did not reveal any significant association with the risk of RPL. In conclusion, no significant difference between RPL and control groups was observed at the allele, genotype or haplotype levels when tested for association using the dominant, recessive and additive models of inheritance for IL-1 gene cluster variants. As far as is known, this is the first report from India pertaining to IL-1 gene cluster variants’ association with the risk of RPL from North India.One of the most unfortunate complications of incomplete motherhood is recurrent pregnancy loss (RPL) particularly of unknown aetiology. RPL is defined as the loss of three or more consecutive pregnancies before the 24th week of gestation. Both genetic and environmental factors may play a role in the maintenance of pregnancy. From a traditional immunological perspective, survival of the semi-allogenic fetus is dependent on suppression of the maternal immune response. However, the function of immune cells changes during pregnancy, no generalized suppression of the maternal immune response has been recorded. Cytokines in the interleukin-1 system (IL-1α, IL-1β and receptor antagonist (IL-1RA)) are produced at the fetal–maternal interface during early pregnancy and are believed to influence the immune responsiveness of Th1/Th2 cells and has been implicated in the establishment of successful pregnancy. This study examines IL-1 gene cluster variants among well-characterized RPL patients and compares them with those of healthy controls. IL-1 gene cluster single-nucleotide polymorphisms were found to be invariably distributed among RPL patients and controls. Meta-analysis of results of IL-1β −511, IL-1β +3953 and IL-1RN 86-bp variable number tandem repeat studies in RPL, as reported previously, also did not show any effect of these variations on the risk of occurrence of the disease.

IL1 gene polymorphisms in enthesitis related arthritis category of juvenile idiopathic arthritis (ERA-JIA)

Cytokine gene loci are one of the potential susceptibility factors in immuno-inflammatory diseases. Interleukin1 (IL-1) is a major monocyte derived proinflammatory cytokine that mediates tissue damage and cartilage loss in chronic arthritis. IL-1 locus has been linked to various autoimmune diseases, but data on juvenile idiopathic arthritis (JIA) is limited. Ninety-four patients with enthesitis related arthritis (ERA) category of JIA (ILAR criteria) were included in the study. One hundred eighty-five healthy blood donors were used as controls. IL-1Ra VNTR polymorphism was done by PCR using specific primers, and allele assignment was done on product size obtained on 2% agarose gel. IL-1α-889 and IL-β-511 polymorphism was done using PCR-RFLP method. Among 94 patients, 87 were males, and the mean age at onset of disease was 11.8 + 1.8 years; 17 had history of uveitis, and 13 had positive family history. Forty-two had enthesitis, and 51 had inflammatory back pain; all had arthritis. Seventy-six were HLA B27 positive. All three loci genotypes were in the Hardy-Weinberg equilibrium in controls. There was no difference in genotype frequency among patients and controls for IL-1Ra, IL-1α-889 and IL-β-511. IL1*RN2 homozygosity was more common in patients, whereas carriage rate for IL1*RN1 was less frequent in patients. Haplotype frequencies were also similar in both groups. IL-1 gene cluster is not a susceptibility locus for ERA.

Lack of association between polymorphisms in the interleukin-1 gene cluster and familial thrombophilia

IntroductionInflammation and venous thrombosis are intimately linked, and there is evidence that levels of inflammatory cytokines influence risk of venous thrombosis. We investigated the hypothesis that allelic variation within the IL-1 gene cluster, which encompasses the genes encoding the inflammatory cytokines IL-1α and IL-1β and the competitive IL-1 receptor antagonist, is associated with venous thrombosis among patients with heritable thrombophilia. Subjects and MethodsGenomic DNA samples from 181 index cases with heritable thrombophilia and 323 control subjects were genotyped for four SNPs, and four microsatellite markers located within the IL-1 gene cluster. The distributions of SNP genotypes and of microsatellite marker alleles were then compared between the patient and control groups. ResultsThere was no significant difference in the distribution of alleles between the patients and control subjects for any of the four microsatellite loci studied. Likewise, the distribution of genotypes for each of the four SNPs investigated was similar among the cases and control subjects. Haplotype analysis showed no difference in the estimated frequencies of any of the IL-1 gene cluster haplotypes between the patients and control subjects. ConclusionsOur findings in this study suggest that inherited variation within the IL-1 gene cluster is not associated with thrombosis among patients with heritable thrombophilia and that alterations in inflammatory cytokines encoded by loci in the IL-1 gene cluster are more likely to occur as a result, rather than a cause, of venous thrombosis.

Lack of Association of Interleukin-1 Gene Cluster Polymorphisms with Angiographically Documented Coronary Artery Disease: Demonstration of Association with Hypertension in the Polish Population

Inflammation plays a key role in the development of atherosclerosis. We investigated associations between the interleukin-1β gene (IL1B) and IL-1 receptor antagonist (IL1RN ) polymorphisms and their haplotypes, with coronary artery disease (CAD), severity of CAD (single vessel, SVD vs. multivessel disease, MVD) and hypertension. Three hundred eighteen individuals were submitted to coronary angiography. Of these, 201 patients with ≥50% occlusion in at least one major coronary artery comprised the CAD group; the control group (non-CAD) consisted of the remaining 117 subjects. The genotypes of IL1B C(-31)T and IL1RN VNTR were determined by polymerase chain reaction (PCR). Allele (-31)C of the IL1B gene was significantly associated with hypertension (p= 0.046). There was no association of hypertension with IL1RN genotype. The association between the number of IL1B C alleles and prevalence of hypertension was similar in univariate (OR 1.383; 95% CI 1.002-1.909; p= 0.048) and multivariate (OR 1.429; 95% CI 1.021-1.999; p= 0.036) analysis. We did not observe a significant association between CAD and genotypes or alleles of IL1B C(-31)T/IL1RN VNTR or their haplotypes. No associations were found between IL1B C(-31)T or IL1RN VNTR genotypes, alleles or haplotypes and the severity of CAD when subgroups with SVD and MVD were compared. No association was found between polymorphisms of IL1B C(-31)T/IL1RN VNTR or their haplotypes and CAD. However, the data suggest that allele (-31)C of IL1B may be a risk factor for hypertension in the Polish population with CAD in the western Pomeranian region of Poland.

Single nucleotide polymorphisms in interleukin-1gene cluster and subgingival colonization with Aggregatibacter actinomycetemcomitans in patients with aggressive periodontitis

Periodontitis is initiated by the subgingival occurrence of periodontopathogens. It is triggered by a specific host-dependent immune response that is influenced by genetic predisposition. Polymorphisms in the interleukin-1 (IL-1) gene cluster have been suggested to influence the pathogenesis of periodontitis. A total of 159 periodontitis patients (chronic disease: n = 73, aggressive disease: n = 86) and 89 periodontitis-free controls were included in the study. Polymorphisms IL-1α (rs1800587), IL-1β (rs16944, rs1143634), IL-1 receptor (rs2234650), and IL-1 receptor antagonist (rs315952) were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP). Subgingival bacterial colonization was assessed using a polymerase chain reaction/DNA probe test (micro-Ident). Haplotype block structure was determined using Haploview 4.2. Statistical analyses were performed applying SPSS 17.0 considering dominant, recessive, and codominant genetic models. In this case-control study, no association between genomic variants of the IL-1 gene cluster and the incidence of severe periodontitis could be shown. Carriers of the rare genotypes of rs1800587 ( p corr = 0.009), rs1143634 ( p corr = 0.009) and composite genotype (rs1800587+rs1143634) ( p corr = 0.031) had a twofold higher risk for subgingival occurrence of Aggregatibacter actinomycetemcomitans. In forward stepwise binary logistic regression analyses considering age, gender, smoking, and approximal plaque index as potential confounders these significant associations were demonstrated. Despite the genetic background of IL-1 gene cluster could be shown to be associated with subgingival colonization of A actinomycetemcomitans, there is no evidence that it is an independent risk indicator for periodontitis.

IL1B -511(G>A) and IL1RN (VNTR) allelic polymorphisms and susceptibility to knee osteoarthritis in Croatian population

Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1β (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G -511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population (P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease.

Coding Single-Nucleotide Polymorphisms of Interleukin-1 Gene Cluster Are Not Associated with Kawasaki Disease in the Korean Population

This study aimed to examine whether coding single-nucleotide polymorphisms (cSNPs) of the interleukin-1 gene cluster [interleukin-1-alpha (IL1α), IL1β, IL-1-receptor antagonist (IL1RN)] are genetic markers of susceptibility to Kawasaki disease (KD) in the Korean population. The study enrolled 109 KD patients and 287 healthy control subjects. Four cSNPs [rs17561 (Ala114Ser) of IL1α, rs1143634 (Phe105Phe) of IL1β, and rs419598 (Ala23Ala) and rs315952 (Ser96Ser) of IL1RN] were genotyped using the restriction fragment-length polymorphism (RFLP) and direct sequencing. The KD patients were divided into two groups according to the presence of coronary artery lesions (CALs). For genetic analysis, SNPStats, HapAnalyzer, Helixtree, and SNPAnalyzer were used. The allele and genotype frequencies of the IL1 gene cluster polymorphisms in the KD patients had a pattern similar to that in the control subjects. Furthermore, no association was observed between four cSNPs of the IL1 gene cluster and the development of CALs in KD. These results suggest that the IL1 gene cluster may not be associated with susceptibility to KD and the development of CALs in the Korean population.

Allele, genotype, and composite genotype effects of IL-1A +4845 and IL-1B +3954 polymorphisms for chronic periodontitis in an Indian population

The pro-inflammatory cytokine interleukin-1 (IL-1) is a key modulator of host responses to microbial infection and a major modulator of extracellular matrix catabolism and bone resorption, and polymorphisms in the IL-1 gene cluster have been associated with an increased risk of developing severe adult periodontitis. A case control study was performed to determine the role of IL-1A+4845 and IL-1B+3954 polymorphisms in the predisposition to chronic periodontitis. The study was conducted with 103 unrelated participants recruited from Manipal College of Dental Sciences, Manipal, which included 51 chronic periodontitis patients and 52 normal periodontally healthy individuals. Extensive clinical data were collected, bone loss was the major outcome variable and smokers and diabetics were excluded from the study to eliminate the influence of these risk factors. Genomic DNA was isolated from the blood samples of participants for genotyping IL-1A+4845 and IL-1B+3954 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism and the data statistically analyzed. Allele 2 of the IL-1A+4845 polymorphism was carried by 38% of all participants; of these only 6 were homozygous for the allele. Allele 2 of the IL-1B+3954 was carried by 21% of the subjects; only 1 was homozygous for allele 2. The composite genotype was carried by 31% of the cases and by 38% of the controls. Overall, 35% participants carried the composite IL-1 genotype. No statistically significant association was found for the distributions. The distribution of the IL-1 positive composite genotype is in concordance with the frequencies reported in the Caucasians. Association was not found for the effect of allele, genotype, composite genotype, and haplotypes of IL-1A+4845 and IL-1B+3954 polymorphisms with periodontitis. Its utility as a risk marker in this population was not borne out by the study.

Genetic screening test for psoriatic arthritis and UVB irradiation potential responders: A new tool to identify psoriasis subpopulation patients?

Psoriatic arthritis (PsA) is a psoriasis-associated inflammatory disease of the joints and enthuses. The occurrence of PsA is linked to the complex interplay of gene environment, and immune system. Genetic factors have long been recognized to play an important role in PsA. Genes within the major histocompatibility complex (MHC) region have been shown to be associated with PsA. These include genes coded in the HLA region, (especially Class I antigens) and non-HLA genes (i.e., MHC class I chain-related antigen A, MICA, and TNF-α genes). Association studies in PsA have also identified a number of genes outside MHC region, including interleukin-1 (IL-1) gene cluster, killer-cell immunoglobulin-like receptors (KIRs), and IL-23R genes. Established systemic treatments for moderate-severe psoriasis and PsA may be potentially dangerous and usually time consuming for the patient and often expensive for the National Health Systems. Tests which could predict which subset of psoriatic patients could develop the most severe forms of the disease (i.e., PsA) or will respond to well-established (UVB irradiation) or other systemic treatments are now required. The goal of genetic test screening is to rapidly and safely identify subjects for preventive or early treatment or extended surveillance prior to the onset of signs and symptoms. Genetic tests today represent a reliable investigation procedure which could rapidly and consistently improve the diagnostic ability of the dermatologist and contribute to the early and correct treatment of the different subsets of PsA.

Investigation of the interleukin-1 gene cluster polymorphisms in Jordanian patients with chronic and aggressive periodontitis

Objective Interleukin-1 (IL-1) is a proinflammatory cytokine that is highly elevated in response to bacterial biofilms and is a potential risk factor for periodontal diseases. IL-1 gene polymorphisms have been associated with the IL-1 level. The aim of this study was to investigate if IL-1 gene cluster polymorphisms are associated with chronic (CP) and aggressive (AgP) periodontitis in a Jordanian population. Methods A total of 100 CP, 80 AgP patients and 80 controls were genotyped using PCR for IL-1RN-86-bp VNTR and PCR-RFLP for IL-1A-889, IL-1B-511, -35, +3953, and IL-1RN +8006, +9589, +11100 SNPs. The distribution of alleles and genotypes between groups was compared using χ 2 analysis. Estimation of haplotype frequencies was carried out using the EH programme. Results The IL-1RN8006 SNP and the IL-1RN-VNTR were associated with CP but not with AgP. The C allele and TC genotype of IL-1RN8006 were increased in CP ( P corr = 0.002, 0.00026 respectively). The A1 allele and A1/A1 genotype of the IL1-RN-VNTR were significantly increased in CP ( P corr = 0.0007, <0.0001 respectively). The CA1 haplotype formed by both markers was present in 29 CP patients but not in any of the controls ( P < 0.0001). No significant differences were found in the distribution of allele and genotype frequencies of the other markers between CP and AgP cases and controls. Conclusions IL-1RN 8006 and IL-1RN VNTR were associated with CP but not AgP in a Jordanian population, whilst other investigated markers in IL-1A, IL-1B and IL-1RN were not associated with either CP or AgP.

Interleukin 1 receptor antagonist polymorphisms are associated with the risk of developing acute coronary syndrome in Mexicans

Inflammation plays an essential role in the development and progression of atherosclerotic lesions. Cytokines of the interleukin-1 family are central regulators in immunoinflammatory mechanisms. In the present work, the role of interleukin 1 ( IL-1) and IL-1 receptor antagonist ( IL-1RN) gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS) was evaluated. Six polymorphisms in the IL-1 gene cluster members were genotyped by 5′ exonuclease TaqMan genotyping assays in 289 ACS patients and 248 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis. Statistically significant associations were found between three polymorphisms of the IL-1RA gene (rs419598, rs315951, and rs2234663) and the development ACS. The polymorphism RN.4T> C (rs419598) was associated with hypertension, previous myocardial infarction, and major adverse cardiac events. To establish the functional effect of the IL-1RN6/ 2 (rs315951) polymorphism (principal IL-1RN polymorphism associated with ACS in our study), monocytes were obtained from a group of 27 healthy individuals and the production of IL-1 receptor antagonist (IL-1Ra) was determined. Monocytes from individuals with rs315951 CC genotype showed similar production of IL-1Ra as individuals with GG and CG genotypes. The analysis of linkage disequilibrium of the IL-1RA polymorphisms showed four out of eight different possible allele combinations with differences between the studied groups. Patients with ACS showed increased frequency of “ T1C” haplotype when compared to healthy controls. The results suggest that IL-1RN gene polymorphisms could be involved in the risk of developing ACS in Mexican individuals.

Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study

To assess whether genetic variation in the interleukin-1 (IL-1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL-1beta or IL-1 receptor antagonist (IL-1Ra). Innate ex vivo IL-1beta and IL-1Ra production upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radiographic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single-nucleotide polymorphisms (SNPs) encompassing the IL-1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analysis were performed to assess the relationship between the IL-1 gene cluster SNPs, innate ex vivo cytokine production, and OA. Among subjects in the GARP Study, the haplotype variable-number tandem repeat in intron 2/T+8006C/T+11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL-1beta upon LPS stimulation (P = 0.026) and with ROA at the highest number of joint locations. These results show that genetic variation at the IL-1 gene cluster is associated with lower IL-1beta bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms.

IL-1 Gene Cluster is Not Linked to Aggressive Periodontitis

The interleukin-1 (IL-1) gene family has been associated with susceptibility to periodontal diseases, including aggressive periodontitis (AgP); however, the results are still conflicting. The present study investigated the association between IL-1 genes and AgP using 70 markers spanning the 1.1-Mb region, where the IL-1 gene family maps, and exploring both the linkage disequilibrium (LD) and the haplotype structure in a case-control study including 95 patients and 121 control individuals. No association between AgP and IL1A, IL1B, and IL1RN genes was found in either single-point or haplotype analyses. Also, the LD map of the region 2q13–14 under the Malécot model for multiple markers showed no causal association between AgP and polymorphisms within the region (p = 0.207). In conclusion, our findings failed to support the existence of a causative variant for generalized AgP within the 2q13–14 region in an Italian Caucasian population.

The genetic background of ankylosing spondylitis

It has long been known that the major histocompatibility complex (MHC) is essentially involved in genetic susceptibility to ankylosing spondylitis (AS). The HLA-B27 antigen has been accounted for 20 to 50% of the total genetic risk for this disease. However, susceptibility to AS cannot be fully explained by associations with the MHC. Recent studies including linkage analyses as well as candidate gene and, most recently, genome-wide association studies indicate significant associations of the interleukin-1 gene cluster, interleukin-23 receptor and ARTS1 genes as well as other possible loci with AS. In the murine model of proteoglycan-induced spondylitis, two susceptibility loci termed Pgis1 and Pgis2 were identified. Thus, AS is not a single-gene disease and the involvement of multiple non-MHC genes may account for the individual as well as geographical differences seen in AS.

IL1B polymorphisms modulate cystic fibrosis lung disease

Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for DeltaF508, and categories of "severe" (cases) or "mild" (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV(1)) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR < or =0.5 or >1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed. SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value <0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status. Our findings suggest that IL1beta is a clinically relevant modulator of CF lung disease.

Genetic polymorphisms of interleukin-1β (−511C/T) and interleukin-1 receptor antagonist (86-bpVNTR) in susceptibility to knee osteoarthritis in a Chinese Han population

Osteoarthritis (OA) is a multifactorial disorder in which genetic factors act as important contributors to its onset and progression. Associations between genetic polymorphisms of the interleukin-1 (IL-1) gene cluster and OA susceptibility have been studied continuously in different ethnic groups, yielding controversial results. This study investigated the association of interleukin-1beta (-511C/T) and interleukin-1 receptor antagonist (86-bp VNTR) polymorphisms with knee OA susceptibility in a Chinese Han population. A case-control association study was conducted. The two polymorphisms were genotyped in 453 patients who had primary symptomatic knee OA with radiographic confirmation and in 487 matched controls. Allelic and genotypic frequencies and haplotype distribution were compared between OA and control subjects. For either of the two loci, no significant difference was detected in genotype or allele distribution between knee OA and control groups (all P > 0.05). The haplotype distribution of the two loci showed no difference between the two groups, either. Furthermore, no association between the genotype of the -511 and VNTR polymorphisms and the clinical variables, age, sex, body mass index and Kellgren/Lawrence score was observed in OA patients. The genetic polymorphisms of interleukin-1beta and interleukin-1 receptor antagonist are not risk factors for OA etiology in Han Chinese.

Polymorphisms in the interleukin-1 (IL1) gene cluster are not associated with aggressive periodontitis in a large Caucasian population

Polymorphisms in the interleukin-1 (IL1) gene have been suggested to influence transcription of IL1A (interleukin-1α) and IL1B (interleukin-1β) and thereby the pathophysiology of periodontitis. This case-control association study on 415 northern European Caucasian patients with aggressive periodontitis (AgP) and 874 healthy controls was conducted to examine 10 single-nucleotide polymorphisms (SNPs) in the genes of the IL1 cluster for association with IL1A, IL1B, CKAP2L (cytoskeleton-associated protein 2-like), and IL1RN (IL-1 receptor antagonist). The results do not support an association between variants in the IL1 gene cluster and AgP. This case-control study had at least 95% power to detect genuine associations with variants carrying relative risks of at least 1.5 for heterozygous carriers and 2.25 for homozygous carriers. Previous reports of an association between IL1 promoter SNPs and periodontitis might reflect subpopulation effects and have to be interpreted with care.