Association between an interleukin-13 promoter polymorphism and atopy.

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)-13 has been mapped to the cytokine cluster on chromosome 5q31-33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL-13 gene (C to T exchange) at position -1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case-control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position -1111. In the present study, we established that this polymorphism is located at position -1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL-13 -1024TT genoype and inhalation allergy (P = 2.4E-02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E-05) between the IL-13 -1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E-02). No association with MS was found.     

Association of interleukin‐10 promoter region polymorphisms with risk factors of Atherosclerosis

Atherosclerosis is considered as an inflammatory disease, and carotid artery intima‐media thickness (IMT) and carotid plaque are generally used as intermediated phenotype of atherosclerosis. The aim of this study was to investigate whether carotid IMT and plaque are associated with promoter region polymorphisms of interleukin 10 (IL‐10) gene. We recruited 135 subjects from a rural area of south‐eastern part of South Korea. Three polymorphisms in the promoter region of IL‐10 (?1082 A/G, ?819 T/C and ?592 A/C) were genotyped by pyrosequencing. Carotid IMT was measured at common carotid arteries, and carotid bulbs and cardiovascular risk factors such as cholesterol, blood pressure, uric acid and homocysteine were measured using blood samples. Subjects with the minor allele (C) of ?819 T/C or the minor allele (C) of ?592A/C showed lower values in carotid IMT than those with major allele homozygote of each polymorphism (P = 0.018 and P = 0.031, respectively). Subjects with carotid plaque were significantly older and showed higher values in carotid IMT, uric acid and homocysteine than those without plaque (P < 0.01, respectively). In conclusion, the promoter region polymorphisms of IL‐10 gene associate with carotid IMT and plaque. Further studies with larger samples are needed to provide stronger evidence to justify anti‐atheromatous properties of IL‐10.     

Association of interleukin‐18 promoter polymorphisms with chronic obstructive pulmonary disease in male smokers

Chronic obstructive pulmonary disease (COPD) is considered a complex genetic disorder and it is expected that many genes play a role in the pathogenesis of this disease. Previous studies have reported that several variations within the interleukin (IL)‐18 gene promoter region have been associated with different inflammatory diseases such as asthma. However, the association of IL‐18 promoter polymorphisms with COPD has not been studied yet. We then performed a prospective case–control study to explore this association in male smokers of Chinese Han people. Our study recruited 112 COPD cases and 105 healthy controls matched for age. The genotyping of IL‐18 promoter polymorphisms (‐607 C/A and ‐137 G/C) was performed using TaqMan single nucleotide polymorphism genotyping assays. The frequencies of the alleles and genotypes in patients and controls were compared. We found that the frequency of IL‐18 ‐607 C allele was significantly increased in patients with COPD (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 1.01–2.15, P = 0.04). The frequency of IL‐18 ‐607 C allele was significantly higher in the GOLD (Global initiative for Obstructive Lung Disease) 3–4 group compared with the GOLD 1–2 group (OR=2.06, 95% CI = 1.21–3.51, P = 0.01). There were no significant differences in the frequencies of the alleles and genotypes of IL‐18 ‐137 G/C polymorphism between the patients and healthy smokers or between GOLD 3–4 group and GOLD 1–2 group. Our study revealed that the IL‐18 ‐607 C/A polymorphism was associated with COPD susceptibility and severity of airflow limitation in male smokers of Chinese Han people.     

Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy.

The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study.     

Association between interleukin‐21 gene polymorphisms (rs12508721) and HBV‐related hepatocellular carcinoma

Interleukin‐21 (IL‐21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases. We aimed to investigate the relationship between polymorphisms of IL‐21 gene and susceptibility of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) in a Chinese population. Studied subjects were divided into three groups: 100 patients with HBV‐related HCC, 115 patients with chronic HBV infection and 127 healthy controls. Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction–ligase detection reaction (PCR‐LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL‐21 gene. Our results showed that IL‐21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls. The rs2221903A/G AG genotype was associated with a higher risk of chronic HBV infection when compared with healthy controls [AG versus AA + GG, P = 0.036, OR = 1.898, 95%CI = 1.038–3.471]. The rs12508721C/T TT genotype was related with a lower risk of chronic HBV infection and HBV‐related HCC than in healthy controls [TT versus CT + CC, P = 0.026, OR = 0.451, 95%CI = 0.221–0.920; P = 0.049, OR = 0.482, 95%CI = 0.231–1.005]. No significant difference in the genotype and allele distrubutions of rs907715G/A SNP was observed in the HBV‐related HCC group, chronic HBV‐infected group and the healthy control group when compared to each other. Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL‐21 gene are associated with the susceptibility of HBV‐related HCC and chronic HBV infection. The genetic variant may in fact cause protection against the HBV‐related HCC. However, the function in these SNPs of IL‐21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV‐related HCC further.     

Association of serum interleukin‐33 level and the interleukin‐33 genetic variant with Japanese cedar pollinosis

Background IL‐33, an IL‐1‐like cytokine, is a ligand for IL1RL1, which is an important effector molecule of type 2 T helper responses. Although IL‐33/IL1RL1 interaction has been suggested to be important in induction of allergic airway inflammation, serum levels of IL‐33 and the genetic influences of the polymorphisms of IL‐33 in human allergic diseases are unclear. Objective The aim of this study was to examine whether the serum IL‐33 level and polymorphisms in IL‐33 are associated with Japanese cedar (JC) pollinosis, the most common form of allergic rhinitis, and a major public health problem, in Japan. Methods We performed linkage disequilibrium (LD) mapping of the gene using the HapMap database, and two selected tag single nucleotide polymorphisms were genotyped. We conducted an association study of IL‐33 (JC pollinosis, n=170; normal controls, n=100) and measured the IL‐33 levels in sera of the 270 subjects by ELISA. Results Serum levels of IL‐33 were significantly higher in patients with JC pollinosis (P=0.0018) than in controls. In genetic association analysis, we found a positive association between the polymorphism and JC pollinosis (P=0.048). Conclusion Our results support a role for IL‐33 in the pathogenesis of JC pollinosis.     

Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection

AIMS: To assess the importance of tumour necrosis factor alpha (TNF-alpha) promoter polymorphism in relation to infection with the cytotoxin associated gene A (cagA) subtype of Helicobacter pylori within a dyspeptic Korean population. METHODS: Eighty three patients with gastric disease and 113 healthy controls were studied. The DNA from gastric biopsy specimens was analysed by H pylori specific and cagA specific polymerase chain reaction (PCR). To characterise TNF-alpha polymorphism at positions -308 and -238, PCR based restriction fragment length polymorphism analysis was performed. RESULTS: Helicobacter pylori infection was closely correlated with G to A transition at position -308 of the TNF-alpha promoter when compared with healthy controls (odds ratio (OR), 2.912; 95% confidence interval (CI), 1.082 to 7.836; p = 0.034). Although TNF-alpha -308 polymorphism in patients with H pylori was not significantly different from that in patients without H pylori, the -308A polymorphism was strongly associated with H pylori cagA subtype infection when compared with the polymorphism in cagA negative H pylori infection (OR, 8.757; 95% CI, 1.413 to 54.262; p = 0.019) and healthy controls (OR, 3.683; 95% CI, 1.343 to 10.101; p = 0.011). G to A genetic change at position -238 of the TNF-alpha gene was not significantly associated with H pylori cagA subtype infection. In addition, genetic polymorphisms at both sites of the TNF-alpha promoter in patients with H pylori infection did not correlate with the severity of disease. CONCLUSION: TNF-alpha -308A polymorphism was significantly related to infection with the H pylori cagA subtype in Korean patients with gastric disease.     

Association between atopy and recurrent vaginal candidiasis

To determine whether there is an association between atopy and recurrent vaginal candidiasis (RVC) and to evaluate the type-2 immune response in patients with RVC. Evaluation of immediate hypersensitivity skin tests to aeroallergens, measurement of total IgE and Candida albicans specific IgE and levels of IL-5 in 44 women with RVC and 26 with sporadic vaginal candidiasis (SVC). Statistical analyses were performed by Mann-Whitney test and chi(2) test with Yates correction. History of atopy (68%) and positive skin test (42%) were higher (P < 0.05) in RVC than in patients with SVC. No significant difference was found in total IgE, C. albicans specific IgE and IL-5 levels. There was a strong association between atopy and RVC, but type-2 immune response to C. albicans antigen was absent or similar in the two groups of patients.     

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.     

Association between − 308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma

BACKGROUND: Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro. OBJECTIVE: In this study we tested the hypothesis that two such polymorphisms, lymphotoxin alpha NcoI B*1 and -308 TNF2 may be components of the genetic predisposition to asthma. METHODS: Five hundred and fifty-six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTalpha NcoI locus. RESULTS: There was an association between allele two of the -308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04-4.32, P = 0.036). However, there was no association with LTalpha NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR. CONCLUSIONS: We conclude that the -308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.     

Association between farm exposure and atopy, according to the CD14 C-159T polymorphism

BACKGROUND: A higher exposure to bacterial compounds is purported to explain the lower prevalence of allergy in farm children, but responsiveness to bacterial compounds is modulated by genetic factors. OBJECTIVE: To assess whether the protective effect of farm exposure on atopy is influenced by a CD14 promoter functional polymorphism. METHODS: We administered a detailed questionnaire on farm exposure in childhood and genotyped the CD14 C-159T polymorphism in 2 French centers participating in the European Community Respiratory Health Survey (ECRHS)-II. RESULTS: Six hundred randomly selected young adults provided blood samples for IgE measurements and had CD14 C-159T genotyped. Exposure to a farming environment in early life was associated with a reduced risk of nasal allergies (odds ratio [OR], 0.54; 95% CI, 0.29-1.00) and atopic sensitization (OR, 0.47; 95% CI, 0.24-0.93) in adulthood. A lower risk of allergic rhinitis and atopy was also observed in carriers of the CD14-159TT genotype compared with -159CC subjects (OR, 0.52; 95% CI, 0.30-0.88; and OR, 0.54; 95% CI, 0.31-0.92, respectively). When farm exposure and CD14 C-159T were considered together, the risk of nasal allergies and atopy was the most reduced in the subjects who combined both an early-life exposure to a farming environment and the -159TT genotype (OR, 0.26; 95% CI, 0.07-0.94; and OR, 0.21; 95% CI, 0.05-0.93, respectively, vs nonexposed -159CC+CT subjects). The results were consistent in the 2 centers, supporting the validity of the results. CONCLUSION: A gene-by-environment interaction between CD14 C-159T and environmental exposure in childhood may modify the development of atopy. CLINICAL IMPLICATIONS: This polymorphism should be considered in interventions studies that use microbial stimuli to reduce sensitization.     

Association between survivin -31G > C promoter polymorphism and cancer risk: a meta-analysis

Survivin is an inhibitor of apoptosis protein and has a crucial role in the development of cancer. The survivin -31G>C (rs9904341) promoter polymorphism influences survivin expression and has been implicated in cancer risk. However, conflicting results have been published from studies on the association between survivin -31G>C polymorphism and the risk of cancer. To clarify the role of this polymorphism in cancer, we performed a meta-analysis of all available and relevant published studies, involving a total of 3485 cancer patients and 3964 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant genotypes were associated with a significantly increased cancer risk (CC vs GG: OR=1.58, 95% CI=1.20-2.10; CC/GC vs GG: OR=1.23, 95% CI=1.00-1.51; CC vs GG/GC: OR=1.51, 95% CI=1.23-1.85). In the stratified analyses, significantly increased risk was associated with the Asian populations (CC vs GG: OR=1.67, 95% CI=1.16-2.40; CC vs GG/GC: OR=1.50, 95% CI=1.17-1.91). We also performed the analyses by cancer type, and no statistical association was observed. The results suggest that the survivin -31G>C promoter polymorphism might be associated with an increased risk of cancer, especially in the Asian populations.     

Association of a lymphotoxin alpha gene polymorphism and atopy in Italian families

Tumour necrosis factor (TNF) is a proinflammatory cytokine that increases human airway tissue responsiveness and is considered a candidate gene for asthma. Two common polymorphisms (LTalphaNcoI and TNFalpha-308) in the TNF gene complex were studied in 600 subjects from 131 Italian families with atopic asthmatic children. Skin prick test (SPT), total IgE levels, atopy (defined as increased IgE levels or SPT positivity or both), bronchial hyperresponsiveness, and clinical asthma were investigated. The observed distribution of the identical by descent alleles at the LTalphaNcoI locus was different from expected for SPT and atopy (p=0.015). The LTalphaNcoI genotype distribution for increased IgE levels was different between males and females (p=0.0011), and an association of the 2.2 genotype with increased IgE levels was observed in females (p=0.0032). The results indicate that the LTalpha gene, or a closely linked locus, is associated with atopy, and suggest a sex difference in the effect of the gene.     

Correlation between polymorphisms at interleukin‐6 but not at interleukin‐10 promoter and the risk of human T lymphotropic virus type I‐associated myelopathy/tropical spastic paraparesis in Brazilian individuals

HTLV‐1 is the etiologic agent of ATL and HAM/TSP. The majority of HTLV‐1‐infected individuals remain asymptomatic, indicating that the infection alone is not sufficient to cause the diseases. It has been reported that cytokine gene polymorphisms, including polymorphisms at IL‐6 and IL‐10 gene, might be important. We analyzed SNP in the promoter region of the IL‐6: ?174, ?572, ?597, and ?634 positions, and IL‐10: ?592 position to evaluate the role of these polymorphisms in the HAM/TSP pathogenesis in 133 HTLV‐1 infected individuals and in 100 healthy individuals from Salvador, Bahia, Brazil. The ?634C allele frequencies were higher among HAM/TSP patients (21.2%) than among oligosymptomatic (6.5%; P = 0.038) and asymptomatic (9.5%; P = 0.025) subjects. Similarly, the ?174G allele frequencies were higher in HAM/TSP patients than in oligosymptomatic patients (P = 0.02). Moreover, the ?634GC/?174GG genotype combination was identified at a higher frequency (38.5%) in the HAM/TSP patients than in subjects with other clinical status (8.7%; P = 0.016 for oligosymptomatic and 15.5%, P = 0.012 for asymptomatic patients). However, the multivariate logistic regression including the genotypes of the three studied loci showed that only ?634 C IL‐6 carriers remain as significant and independent TSP/HAM predictor (odds ratio [OR] = 5.31; 95% [CI] = 1.60–17.56; P = 0.006). We suggest that ?634 G C in IL‐6 could contribute to HAM/TSP development and that identification of the collective influence of several cytokine polymorphisms, their prevalence, and their interaction could help to better understand this disease. J. Med. Virol. 80:2141–2146, 2008. © 2008 Wiley‐Liss, Inc.     

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.     

哮喘患者IL-13基因多态性与IL-13、TIgE水平相关性研究

目的:探讨白细胞介素13(IL-13)基因内含子区+1923C/T多态性与哮喘患者外周血单个核细胞(PBMC)产IL-13、血浆总IgE(TIgE)水平及其相关性。方法:用聚合酶链反应和限制性片段长度多态性(PCR/RFLP)方法检测哮喘组与对照组+1923C/T位点多态性。IL-13、血浆总IgE采用ELISA法。结果:+1923位点等位基因C、T频率在两组间分布的差异具有显著性(X2=9.30,P<0.01);等位基因T与哮喘关联,OR(T/C)=1.87,95%CI=1.25-2.80,P<0.01。两组基因型(TT、CT、CC)频率的分布差异亦有显著意义(X2=9.92,P<0.01)。其优势比:OR(TT/CC)=3.76,95%CI=1.52-9.29,P<0.01;OR(CT/CC)=2.10,95%CI=1.11-3.95,P<0.05;OR(TT/CT)=1.79,95%CI=0.77-4.19,P>0.05。哮喘组中TT、TC基因型人群PBMC产IL-13及TIgE水平与同组及对照组CC基因相比较差异均有显著性(P<0.01)。结论:IL-13基因+1923位点多态性是影响哮喘的重要候选基因,T等位基因与哮喘关联。     

Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes

BACKGROUND: Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility alleles for one disease provide protection for the other. OBJECTIVE: Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (CTLA4, PTPN22, IL2RA). METHODS: As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling. RESULTS: We obtained evidence of association between IL13 variants and total serum IgE levels (P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes CTLA4 and PTPN22 and the candidate gene IL2RA with IgE levels. CONCLUSION: Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes. CLINICAL IMPLICATIONS: Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.