Association study of interleukin‐1 family and interleukin‐6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin‐1 (IL‐1) and IL‐6 are the most potent pro‐inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL‐1 and IL‐6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL‐6 and IL‐1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL‐1α C ?889 T, IL‐1β C ?511 T, IL‐1β C +3962 T, IL‐1R C pst‐I 1970 T, IL‐1Ra C Mspa‐I11100 T, IL‐6 C ?174 G and IL‐6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence‐specific primers (PCR‐SSP). The frequency of C ?174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL‐6 gene at position ?174 which located in promoter have association with predisposition of individuals to RAS.     

CTLA-4 and IL-6 gene polymorphisms: Risk factors for recurrent pregnancy loss

The purpose of the present study was to evaluate the possible association between CTLA-4 +49A/G and IL-6 −634C/G polymorphisms, and the risk of recurrent pregnancy loss (RPL). 240 women (120 healthy controls and 120 with RPL) were enrolled in this case-control study. Genotyping was performed using a PCR-RFLP technique. In the case of polymorphic CTLA-4 +49A/G, the wild type allele G was associated with a decreased risk of RPL (OR: 0.42, 95%CI: 0.25–0.69, p = 0.001). As to IL-6 −634C/G polymorphism, a highly significant difference was observed, and those women who carry at least one mutant G allele presented a probability of developing RPL about 5 times greater than controls (OR: 5.1, 95%CI: 1.04–25.3, p = 0.04). The results indicate that polymorphisms of CTLA-4 and IL-6 genes may influence the risk of developing RPL among Iranian women, suggesting that more research on the immunogenetics of pregnancy should be conducted to confirm our results, and to declare the exact roles of studied molecules in RPL pathogenesis.     

Interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms are not associated with tubal pathology and Chlamydia trachomatis-related tubal factor subfertility

BACKGROUND: Chlamydia trachomatis infections have been associated with tubal pathology. However, not all C.trachomatis-infected women actually develop tubal pathology. Recently, host genetic factors such as the interleukin-1 gene cluster have been linked to inflammatory and infectious diseases. METHODS: Dutch Caucasian women were investigated for (i) the role of interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms in tubal pathology (group 1); and (ii) the presence of these gene polymorphisms in C.trachomatis IgG-positive women with and without tubal pathology (group 2). Group 1 consisted of women with (n = 40) or without (n = 95) tubal pathology, respectively, and group 2 of C.trachomatis IgG-positive women of whom 28 had tubal pathology at laparoscopy and 47 did not. IL-1B-511 and IL-1B+3954 gene polymorphisms were assessed by PCR-restriction fragment length polymorphism (RFLP), and the variable number of tandem repeats (VNTR) of the IL-1RN gene were assessed by a PCR-based assay. RESULTS: Neither IL-1B-511, IL-1B+3954 nor IL-1RN genotypes, allele or carrier frequencies showed significant association with tubal pathology or C.trachomatis post-infection-based tubal pathology. CONCLUSIONS: The data obtained suggest that specific IL-1 gene polymorphisms are not associated with the tubal pathology risk or to the development of C.trachomatis-based post-infectious severe sequelae.     

女性经前期复发性阿弗他溃疡患者血清IL-6、IL-8、TNF-α和sICAM-1的含量变化及其意义

目的:研究女性经前期复发性阿弗他溃疡(经前期RAU)患者血清中白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)和可溶性细胞间粘附分子-1(sICAM-1)的变化状况, 并探讨经前期RAU的发病机制。方法:用酶联免疫吸附双抗体夹心法(ELISA)检测女性经前期RAU患者外周血中IL-6、IL-8、TNF-α、sICAM-1的水平, 与正常对照组和无经前发作规律的女性RAU对照组相比。结果:经前期RAU患者的血清IL-6、IL-8、TNF-α水平不仅显著高于正常对照组(P＜0.01), 而且高于女性RAU对照组(P＜0.01)。而sICAM-1无明显变化。女性RAU患者血清中TNF-α亦高于正常对照组(P＜0.05)。结论:经前期RAU患者体内存在IL-6、IL-8、TNF-α介导的免疫功能异常, 可能对RAU局部损害起作用。     

Lack of association between IL-1 and IL-6 gene polymorphisms and myocardial infarction in Turkish population

Inflammation and genetics play a key role in the pathogenesis of atherosclerosis and its clinical result myocardial infarction (MI). Proinflammatory cytokines, IL-1 and IL-6, have been shown to play essential roles in developmental stages of coronary artery plaque formation. The aim of this study was to determine the association between IL-1 [IL-1RN, IL-1β (-511, +3953)], IL-6 [-174, -572, -597] gene polymorphisms and MI in Turkish population. A total of 402 people were participated; 235 healthy control subjects and 167 MI patients (MI<40, n: 72; MI>40, n: 95). Polymerase chain reaction (PCR) was used to determine the genotype of IL-1RN, whereas the genotypes of IL-1β (-511, +3953) and IL-6 (-174, -572, -597) were determined using PCR followed with restriction digestion analysis. There was no significant difference between MI and controls for IL-1RN, IL-1β-511, +3953 (P: 0.875, 0.608, 0.442) and IL-6 -174, -572, -597 (P: 0.977, 0.632, 0.584) gene polymorphisms. Lack of association was observed between MI at younger age (MI<40) and either IL-1RN VNTR, IL-1β-511, +3953 (P: 0.878, 0.732, 0.978) or IL-6 -174, -572, -597 (P: 0.313, 0.654, 0.552) gene polymorphisms. This study demonstrated that there was not any association between IL-1, IL-6 gene variants and MI in Turkish population. In addition, IL-1 and IL-6 gene polymorphisms did not affect MI at younger age (MI<40) or older age (MI>40). Thus, IL-1 and IL-6 single nucleotide polymorphisms may not be a risk factor for susceptibility to MI in Turkish population.     

Lack of association between pro-inflammatory cytokine (IL-6, IL-8 and TNF-alpha) gene polymorphisms and Graves' disease

Graves' disease (GD) is a common, autoimmune disease involving the thyroid gland, and it has been previously suggested that pro-inflammatory cytokines are involved in the disease's pathogenesis. The aim of this study was to test whether the interleukin (IL)-6 gene promoter region, or tumour necrosis factor (TNF)-alpha or IL-8 gene 3'-untranslated region (3'-UTR) polymorphisms could provide useful genetic markers for an individual's susceptibility to GD. A normal control group of 60 healthy people and 95 patients featuring GD were examined. Polymerase chain reaction (PCR)-based restriction analysis was performed for the three gene polymorphisms using endonucleases BsrBI, NcoI and ApaLI, respectively. We found no significant difference between the frequencies of genotype and allelic variants for the IL-6 gene promoter (-572 G/C), the TNF-alpha gene promoter (-308 A/G) and the IL-8 gene 3'-UTR (2767 A/G) for GD patients and for normal controls. Cytokines are a large group of proteins that may elicit multiple effects upon immunological reactions. It still appears to be very worthwhile to continue to aggressively search for cytokine gene polymorphisms in order to predict the development of such disease.     

Scanning of genetic effects of alcohol metabolism gene (ADH1B and ADH1C) polymorphisms on the risk of alcoholism

Alcoholism is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Alcohol metabolism is one of the biological determinants that could significantly be influenced by genetic polymorphisms in alcohol-metabolism genes. These genetic polymorphisms are believed to influence drinking behavior and development of alcoholism. Direct DNA sequencing of whole ADH1B and ADH1C genes revealed 36 sequence variants, including six nonsynonymous and 14 novel polymorphisms. Seventeen polymorphisms among them were selected for genotyping in a larger study (n = 352) based on linkage disequilibria (LDs) among SNPs, locations, and frequencies. Hardy-Weinberg equilibrium (HWE) analyses of polymorphisms revealed severe deviations only in alcoholics, which strongly suggest that a selection bias (or pressure) may be involved. The analyses of genotype distribution in alcoholics (n = 106) and normal controls (n = 246) showed dramatic associations with the risk of alcoholism. Fourteen polymorphisms in ADH1C and ADH1B showed a series of different strengths of association and magnitudes of risk. Based on referent and subgroup analysis, it was strongly suggested that the genetic effects come from the ADH1B*47Arg/*47Arg genotype, and that the positive signals from other sites are just tracking the genetic effect of ADH1B His47Arg. In this article we present summaries of previous studies and of the present study, to give an overview of the worldwide effects of ADH1B His47Arg on the risk of alcoholism. The information derived from this study could be valuable for understanding the genetic factors involved in the risk of alcoholism and facilitate further investigation in other ethnic groups.     

Interleukin (IL)-12, IL-2, and IL-6 gene polymorphisms in Takayasu's arteritis from Turkey

Takayasu's arteritis (TA) is a chronic arterial inflammation of unknown etiology involving mainly the aorta and its major branches. Genetic polymorphisms of cytokines are screened as susceptibility factors for TA in Turkey. A total of 94 patients with TA were investigated for the genetic polymorphisms of the interleukin genes IL12, IL2,and IL6 and were compared with 108 healthy control subjects using polymerase chain reaction-sequence-specific primer method. The frequencies of IL12B 1188 C allele (p = 0.03, OR = 1.7) and CC genotype (p = 0.007, OR = 3.7) were both higher in TA patients than in control subjects. TT genotype at IL2-330 (p = 0.006, OR = 2.4) and GG genotype at IL6-174 (p = 0.04, OR = 1.9) were more frequent in TA patients. Lower prevalence of GT genotype at IL2-330 (p = 0.005, OR = 0.4), CG genotype at IL6-174 (p = 0.001, OR = 0.4), and AG genotypes at IL6-598 (p = 0.01, OR = 0.4) were also detected. The polymorphism of IL-12 as well as IL-6 and IL-2 genes may contribute to susceptibility and pathogenesis of TA by altering cytokine production and inducing inflammation.     

IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterised by bone marrow infiltration and the presence of a monoclonal protein in serum and/or urine. Interleukin-6 (IL-6) has been identified as one of the most important cytokines that contributes to myeloma cell survival and proliferation. Recent investigations suggest involvement of another cytokine, IL-10, in the activation of MM cells. The present study aimed to determine whether there is an association between the polymorphic features located within the promoter regions of IL-6 and IL-10 genes and progression the disease. IL-6 (-174 G/C) and IL-10 (-1082 A/G, -819 C/T, -592 A/C) promoter single nucleotide polymorphisms (SNPs) were determined by PCR-SSP technique using commercial primers. Our single centre results were compared with the data from literature and combined in cumulative analysis employing the Mantel-Haenszel method. In univariate analysis, only IL-10 ACC genotype tended to prevail in our (Polish) group of patients. None of IL-6 genotypes or IL-10 (-1082) alleles was found to associate with MM disease either in our single centre or in cumulative study. Among patients who died within 36 months of diagnosis, a significant prevalence (P < 0.05) of IL-6 heterozygous cases as opposed to IL-6 homozygotes was observed. IL-6 and IL-10 promoter gene polymorphisms were not found to associate with the susceptibility to the development of MM. However, the IL-6 polymorphic features appeared as factors that might affect the survival of MM patients. The latter observation warrants further study.     

Identification of novel single nucleotide polymorphisms in intron 1B and exon 1C of the human interleukin-1 receptor type I (IL-1RI) gene

We have identified two novel single nucleotide polymorphisms in the 5' region of the human IL-1RI gene: (1) A-->G at position 52 in intron 1B (GenBank accession number AF146426), which creates an Mspl restriction endonuclease site. Allele frequencies in a Caucasian population were 0.1 (A allele) and 0.9 (G allele). (2) A-->T at position 140 in exon 1C (GenBank accession number AF146427). Allele frequencies in a Caucasian population were 0.27 (A allele) and 0.73 (T allele).     

IL-1B and IL-1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels

The balance between interleukin-1 (IL-1) and its competitive antagonist IL-1 receptor antagonist (IL-1Ra) may contribute to the pathogenesis of rheumatoid arthritis (RA). We analysed the frequency of different alleles in the IL-1B gene (at -511 and at +3954) as well as in the IL-1Ra gene (at +2018) in an association study involving 297 RA patients and 112 healthy controls from the same geographic area. We tested associations with RA susceptibility or severity, and with circulating levels of IL-1Ra and IL-1beta. Carriage of the rare IL-1B (+3954) allele 2 was increased in destructive arthritis (DRA) as compared to non-destructive arthritis (NDRA) (OR 1.7, 95% CI 1.1-2.8, 49.0% vs 35.9%) and controls (OR 1.7, 95% CI 1.1-2.8, 35.8%). Patients carrying this allele had a more destructive (Larsen wrist radiological index: mean +/- s.e.m., 2.1 +/- 0.2 vs 1.6 +/- 0.1, P = 0.005; Steinbrocker functional index: 2.4 +/- 0.1 vs 1.9 +/- 0.1, P = 0.002) and active disease (Ritchie articular index: 8.1 +/- 0.8 vs 5.3 +/- 0.6, P = 0.002; erythrocyte sedimentation rate (ESR): 36.6 +/- 2.9 mm/h vs 25.3 +/- 1.8 mm/h, P = 0.002). This contribution was independent from that of HLA DR4/DR1 to severity. IL-1Ra plasma levels adjusted to ESR values were significantly lower in IL-1B2 (+3954) positive than negative RA patients (1.0 +/- 0.1 vs 1.2 +/- 0.1 ng/ml, P = 0.01). This IL-1B (+3954) gene polymorphism may be an important marker for the severity of joint destruction in RA and is associated with an imbalance in IL-1Ra production. As this genetic association was independent and additive to the risk of HLA DR4/DR1 status, it could be a useful addition to HLA-DR4/1 as a genetic prognostic marker early in the course of the disease.     

Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not involved in the risk of recurrent pregnancy loss

The etiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in four genes, human aryl hydrocarbon (Ah) receptor, cytochrome P450 (CYP) 1A1, CYP1A2 and CYP1B1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. All cases and controls were women resident in Sapporo, Japan and the surrounding area. The Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotypes were assessed in 113 Japanese women with recurrent pregnancy loss (RPL) and 203 ethnically matched women experiencing at least one live birth and no spontaneous abortion (control). No significant differences in Ah receptor, CYP1A1, CYP1A2 and CYP1B1 genotype frequencies were found between the women with RPL and the controls [Ah receptor: Arg/Arg (reference); Arg/Lys and Lys/Lys, odds ratio (OR)=0.67; 95% confidence interval (CI)=0.40-1.11, CYP1A1: m1m1 (reference); m1m2 and m2m2, OR = 0.86; 95% CI = 0.53-1.40, CYP1A2: C/C and C/A (reference); A/A, OR = 1.16; 95% CI = 0.71-1.88, CYP1B1: Leu/Leu (reference); Leu/Val and Val/Val, OR = 1.18; 95% CI = 0.68-2.02]. The present study suggests that the Ah receptor, CYP1A1, CYP1A2 and CYP1B1 gene polymorphisms are not major genetic regulators in RPL.     

Single nucleotide polymorphisms in intron 2 of the human interleukin-1 receptor antagonist (IL-1Ra) gene: further definition of the IL-1 beta and IL-1Ra polymorphisms in North American Caucasians and Taiwanese Chinese

Previous studies have suggested that a variable number tandem repeat (VNTR) polymorphism in the second intron of the interleukin-1 receptor antagonist (IL-1Ra) gene and the single nucleotide polymorphisms at positions -511 and +3954 of the IL-1beta gene might be associated with increased risks of chronic inflammatory diseases, autoimmune diseases and gastric cancer. In the present study, IL-1beta and IL-1Ra genotypes were analyzed among Asians in Taiwan and Caucasians in North America. We identified a novel polymorphism with 3 nucleotide substitutions in the IL-1Ra VNTR 2-repeat allele. One of the substitutions corresponds with the fourth 3' end nucleotide of the reverse primer that is often used for analysis of the IL-1Ra-associated VNTR locus. Mismatching between this primer and the 2-repeat allele can cause misleading amplification results when stringent conditions are used for annealing. The estimated haplotype frequencies of the variant IL-1 genes were significantly different between Taiwanese and Caucasians. The frequency of the pro-inflammatory IL-1Ra 2-repeat allele was significantly lower in Taiwanese than in Caucasians. In contrast, the frequencies of the pro-inflammatory IL-1beta -511T allele and +3954C allele were significantly higher among Taiwanese compared with Caucasians.     

Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma

Aflatoxin B1 (AFB1) is an important environmental carcinogen and can induce DNA damage and involve in the carcinogenesis of hepatocellular carcinoma (HCC). The deficiency of DNA repair capacity related to the polymorphisms of DNA repair genes might play a central role in the process of HCC tumorigenesis. However, the interaction of DNA repair gene polymorphisms and AFB1 in the risk of hepatocellular carcinoma has not been elucidated. In this study, we investigated whether six polymorphisms (including rs25487, rs861539, rs7003908, rs28383151, rs13181, and rs2228001) in DNA repair genes (XPC, XRCC4, XRCC1, XRCC4, XPD, XRCC7, and XRCC3) interacted with AFB1, and the gene-environmental interactive role in the risk of HCC using hospital-based case-control study (including 1486 HCC cases and 1996 controls). Genotypes of DNA repair genes were tested using TaqMan-PCR technique. Higher AFB1 exposure was observed among HCC patients versus the control group [odds ratio (OR) = 2.08 for medium AFB1 exposure level and OR = 6.52 for high AFB1 exposure level]. Increasing risk of HCC was also observed in these with the mutants of DNA repair genes (risk values were from 1.57 to 5.86). Furthermore, these risk roles would be more noticeable under the conditions of two variables, and positive interactive effects were proved in the followed multiplicative interaction analysis. These results suggested that DNA repair risk genotypes might interact with AFB1 in the risk of HCC.     

Interleukin 1 receptor antagonist gene polymorphisms are not risk factors for recurrent pregnancy loss: evaluation of couples

PROBLEM: The interleukin-1 system has been implicated in pregnancy outcome. Fetal carriage of interleukin-1 receptor antagonist (IL-1Ra) specific alleles has been associated with adverse pregnancy outcomes including spontaneous abortion and pre-term labor. This study was undertaken to compare the frequency of IL-1RN 2 alleles among both male and female partners of couples experiencing recurrent pregnancy loss with that of fertile control couples. METHOD OF STUDY: Buccal swabs were obtained from 42 couples experiencing recurrent pregnancy loss and from 20 fertile control couples. DNA was extracted from the buccal swabs and analyzed for the presence of IL-1RN variable number tandem repeat. RESULTS: No significant differences were found when the frequency of IL-1RN 2 polymorphisms were compared between fertile control couples and couples experiencing recurrent pregnancy loss. Similar results were also obtained when comparing women or men respectively from each group. CONCLUSION: IL-1RN 2 allele is not a risk factor for recurrent pregnancy loss.     

Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent pregnancy loss

The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We examined the relation between RPL and polymorphisms in two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the metabolism of a wide range of environmental toxins and carcinogens. A case-control study of 115 cases with RPL and 160 controls was conducted. All cases and controls were women resident in Sapporo, Japan and the surrounding area. They were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1 null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36-3.66]. On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1 null genotype (OR = 0.95; 95% CI = 0.58-1.55). The results suggest that women with GSTM1 null polymorphism may therefore have an increased risk of RPL.     

Influence of IL-1 gene cluster polymorphisms on the development of H. pylori associated gastric ulcer

BACKGROUND AND AIMS: Chronic H. pylori infection is the main cause of ulcer disease which depicts a major burden of our healthy care systems. The individual host immune response plays a pivotal role in the outcome of the infection but genetic susceptibility to develop gastric ulcer is unknown. IL-1beta and its natural receptor antagonist IL-1ra are involved in the inflammatory response to H. pylori infection. Thus, we investigated the influence of functional genetic variants in the IL-1 gene cluster on the development of gastric ulcer disease. PATIENTS AND METHODS: 390 H. pylori infected patients were genotyped for IL-1B -31 and +3954 by TaqMan technology. Alleles of IL-1RN 86VNTR were determined by gel electrophoresis after amplification. Three hundred and sixty healthy blood donors were included as healthy controls. RESULTS: Carriage of the IL-1B -31 C allele conferred a increased but not significant risk for H. pylori infection (OR: 1.3, Wald 95% CI: 0.8相似文献   

Homocysteine, vitamin B6 and the risk of recurrent venous thromboembolism

Hyperhomocysteinemia (HHC) is an independent risk factor for cardiovascular disease, and even mildly to moderately elevated homocysteine levels have been associated with a heightened risk for a first and recurrent venous thromboembolism (VTE). Within the frame of a large prospective cohort study (Austrian Study on Recurrent Venous Thromboembolism), we assessed the impact of HHC on the risk of recurrence among 602 patients with a first unprovoked VTE. HHC was an independent risk factor of recurrence conferring a relative risk of 1.5 (95th% CI 1.0-2.4). HHC is caused either by genetic defects and/or by a deficiency of the vitamins (B12, B6 and folic acid) involved in the homocysteine metabolism. Low vitamin B6 levels are associated with an increased risk of a first venous thrombosis.We currently investigate whether or not low plasma levels of PLP are associated with a heightened risk for recurrent VTE.     

Influence of interleukin 1alpha (IL-1alpha), IL-4, and IL-6 polymorphisms on genetic susceptibility to chronic osteomyelitis

The association between cytokine gene polymorphisms and chronic osteomyelitis was investigated in order to determine whether genetic variability in cytokine genes predisposes to osteomyelitis susceptibility. Significant genotypic and allelic associations were observed between interleukin 1α (IL-1α) −889-C/T, IL-4 −1098-G/T and −590-C/T, and IL-6 −174-G/C polymorphisms and osteomyelitis in the Greek population, pointing towards their potential involvement in osteomyelitis pathogenesis.