IL-10 Promoter Polymorphisms Research Articles

The Influence of Human Leukocyte Antigen and IL-10 Gene Polymorphisms on Hepatitis B Virus Outcome

The clinical outcome of hepatitis B virus (HBV) infection is variable, ranging from spontaneous recovery to an inactive carrier state, chronic hepatitis, occult HBV infection, liver cirrhosis, or hepatocellular carcinoma. This variable pattern and clinical outcomes of the infection were mainly determined by virological and host genetic factors. Since the most of host genetic factors associated with HBV infection have currently focused on human leukocyte antigen (HLA) associations and interleukin (IL)-10 gene polymorphisms, this review focuses on the recent progresses in these issues to provide prognostic markers for the outcome of HBV infection. A study on serum levels of IL-10 in occult HBV infected patients reported that the higher level of IL-10 production may suppress function of the immune system against HBV in patients with occult HBV infection. IL-10 promoter polymorphism at position -592 is associated with susceptibility to occult HBV infection. Findings of this study suggest that the host HLA polymorphism is an important factor in determining outcome of HBV infection but regarding IL-10 gene promoter polymorphisms, we are still have a long way to achieve a definite conclusion.

An Interleukin-10 Gene Promoter Polymorphism (−592A/C) Associated with Type 2 Diabetes: A North Indian Study

In this first report on the association of an IL-10 promoter polymorphism with type 2 diabetes mellitus in a North Indian population, the -592A/C SNP (rs1800872) was genotyped by PCR-RFLP and the IL-10 level measured using ELISA. Although no significant difference was observed in the genotypic frequencies (P = 0.657), diabetes patients carried a significantly higher number of A alleles at the -592 position, 25.6% (P < 0.001, odds ratio 0.887, 95% CI 0.670-1.184). Significant correlations were detected in postprandial glucose levels of CC-genotype patients and controls (P = 0.025), age and waist-hip ratio of CA patients and controls (P ≤ 0.001), and fasting glucose (P = 0.045) and low-density lipoprotein (P = 0.049) in all patients and controls. The serum IL-10 level was significantly higher in patients than in controls (P = 0.033). The polymorphism was significantly associated with disease incidence and its biochemical manifestations.

520 Involvement of Il-10 Gene Promoter Polymorphisms in the Susceptibility for Childhood Asthma

BackgroundAsthma and atopy have a complex background which may result from the interaction of genes and environments. Interleukin (IL)-10 is known to play various roles in immune-regulating and anti-inflammatory responses. The aim of this study was to evaluate the possible effect of the IL-10 promoter polymorphisms on susceptibility to childhood asthma.MethodsWe recruited 333 patients with atopic asthma, 55 with non-atopic asthma, and 248 normal controls. We performed a genetic association study of 3 genetic polymorphisms (IL-10–1082A>G, IL-10 –819T>C, –592A>C) of the IL-10 promoter.ResultsThere was no difference between atopic asthma, non-atopic asthma and normal controls in allele, genotype or haplotype frequencies of these IL-10 polymorphisms. However, the –1082A>G polymorphism and ATA haplotype in the IL-10 promoter gene were associated with airway hyperresponsiveness (AHR) and the –819T>C, –592A>C, and ATA and ACC haplotypes were also shown to be related with serum eosinophil cationic protein (ECP).ConclusionsOur results suggest that the polymorphisms within the IL-10 promoter may have a disease-modifying effect in asthmatic airway.

Associations between TNF-α, IL-6 and IL-10 Promoter Polymorphisms and Mortality in Severe Sepsis

Aims: To determine whether an association exists between TNF-α 308 A/G, IL-6 174 G/C, and IL-10-1082 A/G promoter polymorphisms and the corresponding systemic cytokine concentrations and outcome in patients suffering from sepsis. Place and Duration of Study: The study was performed in the Intensive Care Unit (ICU)

Diverse H. pylori strains, IL-10 promoter polymorphisms with high morbidity of gastric cancer in Hexi area of Gansu Province, China

In Hexi area of Gansu Province, people have a higher susceptibility of gastric cancer than people in the rest area of China. There is substantial geographic variation in the incidence of gastric cancer. In this article, the present author explored the roles of H. pylori infection and IL-10 promoter polymorphisms in development of gastric cancer in this area. A total of 304 participants were admitted to our study, and they were divided into two groups: control group and case group. Blood samples from all subjects were collected for gene extraction using DNA extraction kits. IL-10 polymorphisms were determined by SNaPshot Multiplex. To test H. pylori infection and its typing H. pylori antibody Immunoblotting Kits were used. This research suggested that environmental factor played an important role in the pathogenesis of gastric carcinoma in the area, H. pylori infection increased the risk of gastric cancer (OR = 2.612, 95% CI 1.636-4.170) and subject with H. pylori I-type positive was at significantly higher risk for progression to gastric cancer (OR = 4.712, 95% CI 2.656-8.537). For subjects with the ATA/GCC or GCC/GCC haplotype of the IL-10-1082/-819/-592 polymorphism relative to the ATA/ATA haplotype group, the risk of gastric cancer development was significantly increased. It has been demonstrated that the presence of IL-10-819 C alleles and IL-10-592 C alleles was associated with an increased risk for gastric cancer development in H. pylori-infected patients and IL-10 promoter polymorphisms and H. pylori have a synergistic effect on gastric cancer in Hexi population.

A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria

Urticaria is the commonest cutaneous reaction caused by aspirin or other nonsteroidal anti-inflammatory drugs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration. To investigate the genetic contribution of interleukin (IL)-18, which can amplify acute inflammation by promoting mast cell activation, neutrophil migration and cytokine production, to the pathogenesis of AIU. A case-control association study was performed using 275 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL18 gene (-607A/C and -137G/C) were genotyped using the primer extension method. The functional effect of the IL18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter assay and electrophoretic mobility shift assays (EMSAs) and ex vivo studies involving neutrophil chemotaxis assays. A significant association was detected between both AIU in general and the aspirin-intolerant acute urticaria (AIAU) phenotype and the IL18 promoter polymorphism -607A/C. Patients with AIAU showed higher frequencies of the C(-607) G(-137) haplotype, ht1 [CG], compared with controls (P=0·02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSAs identified a -607C allele-specific DNA-binding protein as CREB2. Neutrophil chemotactic activity was highest in subjects with AIU exhibiting the high transcript haplotype, ht1 [CG] (P=0·019). The high transcript haplotype ht1 [CG] of the IL18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU.

Targeting IL-6 promoter polymorphism −174G/C should be dependent on ethnicity

Targeting IL-6 promoter polymorphism −174G/C should be dependent on ethnicity

116-P Association of IL-10 promoter polymorphisms with prostate cancer risk in African- Americans

116-P Association of IL-10 promoter polymorphisms with prostate cancer risk in African- Americans

The IL-10 Promoter Polymorphism at Position −592 is Correlated with Susceptibility to Occult HBV Infection

Occult hepatitis B infection (OBI) is characterized as a form of hepatitis in which detectable amounts of HBV-DNA can be monitored in the peripheral blood of patients whereas the hepatitis B surface antigen is undetectable. The main aim of this study was to investigate whether there is a relationship between OBI and single nucleotide polymorphisms in the -592 region of the IL-10 gene. In this study, the polymorphism at position -592 of the IL-10 promoter of 57 OBI cases was compared and correlated to that of 100 healthy controls by PCR-RFLP techniques. Our results showed that patient and control groups had significant differences regarding genotypes and alleles of the -592 polymorphism in the IL-10 gene. Based on our results, it can be concluded that the -592 polymorphism within the promoter of the IL-10 gene is associated with OBI.

Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression

Chronic non-bacterial osteomyelitis (CNO) is an auto-inflammatory disorder that affects the skeletal system. Interleukin (IL-)10 is an immune-modulatory cytokine that controls inflammation, and limits inflammatory cytokine responses. Dysregulation of IL-10 expression has been shown to result in autoimmune and infectious diseases. We investigated IL-10 expression by monocytic cells from CNO patients and controls. In response to stimulation with LPS, IL-10 expression from CNO monocytes was reduced (p<0.001). This was independent of IL10 promoter polymorphisms. Thus, we investigated Sp1 recruitment to the IL10 promoter and saw markedly reduced binding in CNO monocytes. This was accompanied with reduced phosphorylation of histone H3 serine 10 (H3S10), an activating epigenetic mark. Impaired recruitment of Sp1 to the IL10 promoter, and reduced H3S10 phosphorylation, may be a reflection of deficient MAPK signaling in CNO monocytes in response to LPS stimulation. Thus, we have discovered a mechanism that may be central in the pathophysiology of CNO.

Involvement of IL-10 Gene Promoter Polymorphisms in the Susceptibility for Childhood Asthma

Asthma and atopy have a complex background that may result from the interaction of genes and the environment. Interleukin (IL)-10 is known to play various roles in immune-regulating and anti-inflammatory responses. The aim of this study was to evaluate the possible effect of the IL-10 promoter polymorphisms on susceptibility to childhood asthma. We recruited 333 patients with atopic asthma, 55 with nonatopic asthma, and 248 normal controls. We performed a genetic association study of three genetic polymorphisms (IL-10 -1082A>G, IL-10 -819T>C, and IL-10 -592A>C) of the IL-10 promoter. There was no difference between atopic asthma, nonatopic asthma, and normal controls with respect to allele, genotype, or haplotype frequencies of these IL-10 polymorphisms. However, the -1082A>G polymorphism and ATA haplotype in the IL-10 promoter gene were associated with airway hyper responsiveness (AHR) and the -819T>C, -592A>C, and ATA and ACC haplotypes were also shown to be related to serum eosinophil cationic protein (ECP). Our results suggest that the polymorphisms within the IL-10 promoter may have a disease-modifying effect in the asthmatic airway.

Functional variants of IL4 and IL6 genes and risk of tobacco‐related oral carcinoma in high‐risk Asian Indians

Tobacco-related oral squamous cell carcinoma (OSCC) is one of the most common cancers involving Indian males. We assessed the association of IL4 promoter -589 T>C, -33 T>C, and IL6-174 G>C functional genetic polymorphisms with tobacco-related OSCC in Asian Indians. The IL4 and IL6 promoter polymorphisms were assessed in 140 patients with OSCC and 120 normal subjects by PCR-RFLP technique, and significance of the data was determined using chi-square test. The frequency of TC, CC genotype, and C allele at IL4 promoter sites -589 and -33 were higher in patients when compared with controls. Consequently, TC/CC genotypes and C allele at both sites appeared as susceptible. However, IL6-174 G>C single-nucleotide polymorphisms (SNP) appeared to be protective in patients with OSCC. Of eight haplotypes, five were associated with two- to seven-fold increased risk of tobacco-related OSCC. These SNPs further showed heterogeneity among different ethnic population, but their distribution in Asian Indians stand closer to other Asian populations. In this study, IL4-589 CC, -33 CC genotype, and *C allele at both sites appeared to be susceptible, while IL6-174 CC genotype and *C allele appeared to be protective in patients with OSCC; hence, these SNPs may be a potential prognostic markers for tobacco-related OSCC in Asian Indians.

Association of IL10 promoter polymorphisms with idiopathic achalasia

Idiopathic achalasia is an esophageal motor disorder of unknown etiology. A wealth of evidence supports the concept that achalasia is an immune-mediated disease. According to this evidence, achalasia has been significantly associated with specific alleles of the human leukocyte antigen class II, PTPN22 and IL23R. Several studies have demonstrated association of the IL10 gene with different inflammatory disorders. Our aim was to evaluate the role of functional IL10 promoter polymorphisms in susceptibility to idiopathic achalasia. A case–control study was performed with the -1082, -819, and -592 IL10 promoter polymorphisms in 282 patients and 529 controls and in an independent replication set of 75 patients and 575 controls. The GCC haplotype of the IL10 promoter was reported to be associated with a lower risk of achalasia in the discovery sample (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64–0.98, p = 0.029). This association was validated in a replication set (OR = 0.69, 95% CI = 0.48–1.00, p = 0.04). In the combined analysis no heterogeneity was observed between the 2 sample sets and the GCC haplotype was significantly associated with the disease (OR MH = 0.76, 95% CI = 0.63–0.91, p = 0.003). Our results provide the first evidence for an association between IL10 promoter polymorphisms and idiopathic achalasia, suggesting that the interleukin-10 cytokine may contribute to the pathogenesis of this disease.

Contribution of functional IL-18 promoter polymorphisms to the risk of idiopathic recurrent spontaneous miscarriage (117.29)

Abstract Interleukin (IL)-18 is a proinflammatory cytokine, which modulates Th1 differentiation and CTL effector activity, both of which were implicated in the pathogenesis of recurrent spontaneous miscarriage (RSM). We evaluate the association of single nucleotide polymorphisms (SNPs) in the IL18 gene promoter at -656G/T (rs1946519),-137G/C (rs187238), -119T/G (rs360718), and -105T/C (rs360717), were detected by TaqMan assays in analysis in 277 RSM cases and 283 control women matched for age and ethnic background; serum IL-18 level was measured by ELISA. Association of IL-18 alleles, genotypes, and haplotypes with RSM were evaluated by Fisher's exact test and regression analysis. The -656T (P&amp;lt;0.001; OR, 1.87; 95% CI, 1.44-2.42) and -105C (P&amp;lt;0.001; OR, 2.00, 95% CI, 1.54-2.59) alleles, significantly increased RSM risk. Significant differences in the distribution of -656G/T and -105T/C genotypes were seen between RSM cases and controls; no association was found between -137G/C or -119T/G and RSM. Haploview analysis revealed linkage disequilibrium between VEGF SNPs analyzed SNPs. Four-locus (rs1946519/rs187238/rs360718/rs360717) haplotype analysis identified two RSM-protective (1111 and 1222) and two RSM-susceptible (1112 and 2112) haplotypes. Multivariate analysis confirmed the positive association of 2112 haplotype with RSM, after controlling for a number of covariates. These results demonstrate that the VEGF polymorphisms are significantly associated with idiopathic RSM.

Association of G-137C Interleukin-18 Promoter Polymorphism With Early Renal Glomerulus Injury in Liver Transplantation Recipients

As renal injury after transplantation is associated with increased cardiovascular events, mortality, and hepatic allograft dysfunction, early recognition of renal injury and implementing changes may improve the long-term outcome of transplantation. A common cause of renal failure after allo-liver transplantation is calcineurin inhibitor toxicity. However, several other potential causes may also contribute to renal injury after liver transplantation. Recently, interleukin (IL)-18 has been found to have an early and important role in renal injury after transplantation (1). Two single-nucleotide polymorphisms (A-607 C and G-137C) in the promoter region of the IL-18 gene have been repeatedly found to be associated with the IL-18 promoter transcription activity (2). We investigated whether the A-607C and G-137 C IL-18 promoter polymorphism were associated with early renal injury in liver transplantation recipients. Reliance on serum creatinine typically leads to an overestimation of renal function in patients after transplantation. Microproteinuria as a hallmark of reflecting early changes in the glomeruli and proximal tubular function can be used as an accurate predictor to monitor early changes in renal function. We included 152 liver transplantation patients. The recipients were all in a stable stage with normal serum creatinine. The patient with hepatitis C virus and hepatitis B virus infection and diabetes mellitus after transplantation were excluded. When the urine immunoglobulin elevated, we defined this patient had an early renal glomerulus injury (ERGI) and divided the patients into ERGI group (n=37) and no ERGI group (n=115). When the urine α1-microglobulin elevated, we define this patient had an early renal tubular injury (ERTI) and divided the patients into ERTI group (n=106) and no ERTI group (n=46). There is no difference of drug used in those groups (see Table, Supplemental Digital Content 1, https://links.lww.com/TP/A350). We found significant differences in the genotype frequency (P=0.027) and allele frequency (P=0.034) between the ERGI and no ERGI in G-137C IL-18 promoter polymorphism. The GG genotype was significantly more frequent in ERGI compared with no ERGI (Table 1). The genotype and allele frequencies of the G-607C IL-18 promoter polymorphism were not significantly different between the early renal injury groups (see Table, Supplemental Digital Content 2, https://links.lww.com/TP/A351). We can see the tendency that the ERGI and ERTI recipients had higher IL-18 serum levels. However, there was no significant difference (see Figure, Supplemental Digital Content 3, https://links.lww.com/TP/A352).TABLE 1: Analysis on allele and genotype frequencies (%) of IL-18 polymorphism G–137C in alloliver recipients with or without early renal injuryIn conclusion, our study investigated the influence of the G-137C IL-18 promoter polymorphism on early renal injury after liver transplantation. We found that the polymorphism in the IL-18 promoter at position G-137C is associated with an increased risk of ERGI after liver transplantation. The −137GG homozygote was significantly more frequent in ERGI in liver transplantation. As we know that this is the first time to find the relationship between IL-18 gene polymorphism and early renal injury after liver transplantation. The earlier diagnosis of renal injury could lead to more timely intervention, and potentially, to better patient outcomes. This genotype may be a useful marker of ERGI after liver transplantation. Yi Li1 Bin Yang1 Bei Cai1 Lanlan Wang1 Department of Clinical Immunological Laboratory West China Hospital, Sichuan University Chengdu, Sichuan, People's Republic of China Binwu Ying2 Department of Clinical Molecular Laboratory West China Hospital, Sichuan University Chengdu, Sichuan, People's Republic of China Yunying Shi3 Department of Nephrology West China Hospital, Sichuan University Chengdu, Sichuan, People's Republic of China

IL-6 promoter polymorphism (−174G/C) and systemic lupus erythematosus

We investigated the possible association between susceptibility to systemic lupus erythematosus (SLE) and single-nucleotide polymorphisms located in the promoter region of the interleukin-6 gene (−174 G/C) in a sample of the Egyptian population and the contribution of this polymorphism in the clinical or immunological manifestation of the disease. Forty-two Egyptian patients with SLE and 40 unrelated healthy control volunteers were genotyped by polymerase chain reaction followed by visualization on 4% agarose gel electrophoresis on ultraviolet transilluminator to detect the genotype distribution and allelic frequencies of the polymorphisms. The homozygous GG genotypes was significantly increased in SLE patients compared to control group (p value = 0.04). On the other hand, the heterozygous G/C genotype was significantly elevated in the controls compared to SLE patients (p value = 0.01). The odds ratio value for G/G was 2.6 with a 95% CI from 1.1 to 6.7. As regard the association of clinical manifestations to the genotype frequency, we found a statistical significant increase in the frequency of GG genotype with chest disease, nephritis, and arthritis. From this study, we suggest that G carrier is more susceptible to develop SLE and that SNP may have a role in the pathogenesis of the disease and may be associated with some of its clinical manifestations.

Pilot study: possible association of IL10 promoter polymorphisms with CRMO

Pilot study: possible association of IL10 promoter polymorphisms with CRMO

Interleukin 18 gene promoter polymorphisms in Latvian patients with rheumatoid arthritis

Interleukin 18 gene promoter polymorphisms in Latvian patients with rheumatoid arthritis Interleukin 18 (IL-18) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). There are controversial reports suggesting that IL-18 promoter polymorphisms may be an independent marker of RA susceptibility. The aim of the present study was to determine whether polymorphisms of the IL-18 gene promoter in positions -607 (rs 1946519) and -656 (rs 1946518) are associated with RA, and its characteristics in the Latvian population. We examined 105 patients with RA diagnosed according to the criteria of the American College of Rheumatology. DNA and phenotypic data from a healthy control population was obtained from Genome Database of Latvian Population. Genotypes were obtained by direct sequencing. Single-nucleotide polymorphisms (SNPs) were studied and frequencies of alleles and genotypes were compared between patients and controls. A P value less than 0.05 was accepted as statistically significant. There were no significant differences in the distribution of alleles and genotypes between RA patients and the control group. The frequencies of IL-18-607C/A and -656G/T genotypes differed between patients and the control group in women (P = 0.084 and 0.097). Heterozygous genotypes -607CA and -656GT occurred more frequently in the RA group than in the control (P = 0.046, P = 0.060), and this difference was also significant for the only women groups (P = 0.041,P = 0.054). The heterozygous states -607CA and -656GT of IL-18 gene affect susceptibility to RA. On the basis of investigated IL-18 polymorphisms, female patients with RA seem to represent a separate disease subgroup.

Interleukin-10 promoter polymorphisms associated with susceptibility to lumbar disc degeneration in a Chinese cohort

We investigated a possible association between interleukin (IL)-10 single nucleotide polymorphisms (SNPs) and susceptibility to and severity of lumbar disc degeneration (LDD) in a Chinese cohort of 320 patients with LDD and 269 gender- and age-matched controls. The degree of disc degeneration was determined by magnetic resonance imaging using Schneiderman's classification. Genetic analysis of IL-10 promoter polymorphisms (at -1082 A/G, -819 T/C, and -592 A/C) was carried out by PCR-RFLP. A total of 134 herniated lumbar intervertebral discs were collected during surgery for IL-10 mRNA detection. For SNPs at -592, the A allele and AA genotype frequencies were significantly higher in LDD patients than in controls. Similarly, the AA genotype and A allele frequencies at -1082 were significantly higher in cases than in controls. Among the LDD subjects, carriers of AA at -592 and GG at -1082 had significantly lower mean IL-10 mRNA expression than the other two genotypes. The SNPs at each locus were not significantly associated with severity grade in the LDD patients. Logistic regression analyses showed that the AA at -1082, AA at -592, and IL-10 mRNA expression level were independent risk factors for LDD. We conclude that the IL-10 SNPs at -1082 A/G and -592 A/C as well as IL-10 mRNA in the herniated lumbar intervertebral discs are associated with susceptibility to LDD in this Chinese cohort, but not with disease severity.

Association of IL-6 promoter and IFN-γ gene polymorphisms with acute rejection of liver transplantation

Liver transplantation is one of the most important therapies for end-stage liver diseases and is associated with major problems including infections and acute rejection. The outcome of transplantation can be determined by immune responses as a key role in response to the graft. Inflammatory and anti-inflammatory mediators especially cytokines influence the graft microenvironment. Th1 and Th2 immune responses in contrast to regulatory responses cause acute rejection or help graft survival. In this study, we evaluated the gene polymorphisms of IL-6 G-174C, TGF-β T + 869C, IL-4 C-590T, and IFN-γ T + 874A cytokines in liver transplant patients. ARMS-PCR method was used to characterize IL-6 G-174C, TGF-β T + 869C and IFN-γ T + 874A polymorphisms and PCR-RFLP using AvaII restriction enzyme was done for IL-4 C-590T characterization in 70 liver transplant patients. Acute rejection episodes were diagnosed according to standard criteria. The analysis of the results showed that IL-6-174 GG genotype ( P = 0.009, OR = 4.333, 95% CI = 1.043-18.000), IL-6-174G allele (P = 0.011, OR = 5.273, 95% CI = 1.454-19.127) was more frequent and IFN-γ +874 TT genotype was less frequent (P = 0.043, OR = 0.143, 95% CI = 0.0118-1.190) in acute rejection than in non-rejection patients. TGF-β T + 869C and IL-4 C-590T frequencies were not significantly different (P > 0.05). According to the results, it can be conclude that IL-6 G-174C and IFN-γ T + 874A gene polymorphisms have predictive values for acute rejection after liver transplantation. High producer genotype of IL-6 is a genetic risk factor and IFN-γ is a protective factor for acute rejection development.