1,720,966 research outputs found
Interleukin-10 polymorphisms, cancer susceptibility and prognosis
No full textInterleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions and may have both tumour-promoting and -inhibiting properties. A large number of polymorphisms (primarily single nucleotide polymorphisms (SNPs)) have been identified in the IL-10 gene promoter. Convincing evidence that certain of these polymorphisms are associated with differential expression of IL-10 in vitro and in some cases in vivo has been obtained and a number of studies have investigated associations between IL-10 polymorphisms and cancer susceptibility/prognosis. The results from 22 studies in 13 different malignancies are reviewed. In 17 of these studies, positive associations between IL-10 genotype or haplotype and disease susceptibility and/or progression were reported. In some of these cancers genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, while in others genotypes associated with high IL-10 expression were a risk factor. Published findings in breast cancer are as yet conflicting. Most, but not all of the studies reviewed are based on small sample sizes and a limited number of IL-10 polymorphisms. However, the preliminary data obtained thus far indicate that larger studies are required in a number of cancers, in order to confirm initial results, extend studies to include more detailed genotype/haplotype analysis and combine genotype and gene expression studies in the same subjects. Such studies will contribute significantly to our understanding of the biological role of IL-10 in cancer development
ICAM-1 polymorphisms and development of cutaneous malignant melanoma
No full textTumour growth in cutaneous malignant melanoma (CMM) is mediated by cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). ICAM-1 expression is associated with increasing Breslow thickness of vertical growth-phase tumours and, in patients with stage 1 disease, may be associated with disease free and patient survival. In this study we have investigated whether two single nucleotide polymorphisms (SNPs) in the ICAM-1 gene encoding amino acid substitutions in codons 241 and 469 of the expressed ICAM-1 molecule are associated with susceptibility to and markers of prognosis (including tumour Breslow thickness) in CMM. A total of 164 CMM patients and 264 cancer-free controls were genotyped for these SNPs by the 5' nuclease assay for allelic discrimination (TaqMan). No genotypes showed any significant associations with CMM susceptibility, although there was a non-significant increase in frequency of the ICAM-1 469 AA genotype among CMM patients vs. controls (38.4% vs. 29.9%; P = 0.11). However, the ICAM-1 241 GG genotype was significantly decreased in frequency among patients with primary invasive tumours of greater Breslow thickness (72.5% vs. 91.2%; P = 0.013; OR = 0.25 (0.072-0.85)). These results provide no evidence for a role for the ICAM-1 codon 241 and 469 SNPs in determining susceptibility to CMM, but provide preliminary evidence that the role of ICAM-1 polymorphism in modulating tumour growth in CMM requires further investigation in a larger study group
VEGF polymorphisms and severity of atherosclerosis
No full textIntroduction: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, and neovascularisation has been shown to be important in atherosclerotic plaque development. There is some disagreement as to whether VEGF acts as a pro-atherosclerotic or anti-atherosclerotic factor. In the present study we have sought to clarify this by determining genotypes and haplotypes for three reportedly functional VEGF SNPs in a large series of well documented coronary atherosclerosis patients.Methods: VEGF –2578, –1154, and –634 single nucleotide polymorphisms were genotyped in 984 subjects from the Southampton Atherosclerosis Study, using the 5' nuclease assay for allelic discrimination (TaqMan).Results: VEGF –2578 genotypes showed a significantly different distribution in patients without myocardial infarction when stratified according to number of diseased arteries. VEGF –2578 was also associated with mean number of stenotic segments in the same patient group. The AA genotype was a risk factor and CC was protective. These associations were significant before and after adjustment for classic risk factors, and were reflected in associations between VEGF haplotypes and the number of diseased arteries and stenotic segments. As VEGF –2578 CC has been provisionally shown to be associated with higher VEGF expression than the AA genotype, these results are consistent with a protective effect for VEGF in atherosclerosis development. Some changes in VEGF –1154 genotype frequencies were also detected, but no significant associations were detected for any one particular genotype.Conclusions: This study provides preliminary evidence that VEGF polymorphism is associated with development of atherosclerosis, possibly via regulation of VEGF expression, supporting a protective effect for VEGF in atherosclerosis. These results require replication in an independent study group, combined with study of additional candidate polymorphisms in the VEGF gene
Copy-number variation genotyping of GSTT1 and GSTM1 gene deletions by real-time PCR
Full text linkBackground: Structural variation in the human genome is increasingly recognized as being highly prevalent and having relevance to common human diseases. Array-based comparative genome-hybridization technology can be used to determine copy-number variation (CNV) across entire genomes, and quantitative PCR (qPCR) can be used to validate de novo variation or assays of common CNV in disease-association studies. Analysis of large qPCR data sets can be complicated and time-consuming, however.Methods: We describe qPCR assays for GSTM1 (glutathione S-transferase mu 1) and GSTT1 (glutathione S-transferase theta 1) gene deletions that can genotype up to 192 samples in duplicate 5-µL reaction volumes in <2 h on the ABI Prism 7900HT Sequence Detection System. To streamline data handling and analysis of these CNVs by qPCR, we developed a novel interactive, macro-driven Microsoft Excel® spreadsheet. As proof of principle, we used our software to analyze CNV data for 1478 DNA samples from a family-based cohort.Results: With only 8 ng of DNA template, we assigned CNV genotypes (i.e., 2, 1, or 0 copies) to either 96% (GSTM1) or 91% (GSTT1) of all DNA samples in a single round of PCR amplification. Genotyping accuracy, as ascertained by familial inheritance, was >99.5%, and independent genotype assignments with replicate real-time PCR runs were 100% concordant.Conclusions: The genotyping assay for GSTM1 and GSTT1 gene deletion is suitable for large genetic epidemiologic studies and is a highly effective analysis system that is readily adaptable to analysis of other CNV
Influence of cytokine and ICAM-1 gene polymorphisms on susceptibility to chronic pancreatitis
No full textAims:
To test the hypothesis that single nucleotide polymorphisms (SNPs) within genes (or their promoter regions) encoding cytokines, growth factors, and intercellular adhesion molecules modulate the risk of development of chronic pancreatitis (CP). Methods:
DNA was extracted from peripheral blood leucocytes or formalin fixed, paraffin wax embedded tissue from 53 patients with CP and 266 healthy controls. SNPs within the interleukin 1ß (IL-1ß), IL-6, IL-8, tumour necrosis factor (TNF) and vascular endothelial growth factor (VEGF) gene promoter regions and the transforming growth factor ß1 (TGFß1) and intercellular cell adhesion molecule 1 (ICAM-1) genes were genotyped by the amplification refractory mutation system polymerase chain reaction or 5' nuclease (Taqman®) techniques. Patient–control comparisons were made using 2 x 2 contingency tables and 2 analyses. Results:
A non-significant decrease in the frequency of the IL-8 –251 AA genotype and a non-significant increase in the frequency of the ICAM-1 +469 GA genotype was seen in patients compared with controls. No associations were identified between SNPs in the promoter regions of the IL-1ß, IL-6, or TNF proinflammatory cytokines genes or the TGFß1 and VEGF genes and susceptibility to CP. Conclusions:
This preliminary study suggests that genetic polymorphism within several cytokine genes is unlikely to influence susceptibility to CP, but the possible role of IL-8 and ICAM-1 polymorphisms in the development of this disease requires further investigation
The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility.
No full textLeukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI). Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Methods: Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test. Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32). Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis
Level of ex vivo interleukin 6 expression in human peripheral fat compared with other tissues
No full textObjectives: Adipose tissue is able to secrete a variety of active mediators into the circulation. One of these is Interleukin 6 (IL6). IL6 may play a causal role in the development of atherosclerosis. It has therefore been suggested that IL6 may form part of the link between obesity and vascular disease. The aim of this study was to quantify the relative IL6 expression in adipose tissue compared to other tissues.Methods: Tissue (vein, fat, muscle, blood) was collected from 32 patients undergoing varicose vein surgery. RNA was extracted and mRNA measured using RT-PCR relative quantification. The mean relative IL6 mRNA levels were compared between tissues using the Mann Whitney U test and the independent t-test. Tissue levels were compared for individuals using the Wilcoxon signed rank test.Results: Mean relative IL6 mRNA levels (mean ± SEM) were significantly greater in adipose tissue 44.8 ± 16.1 than in other tissues (leukocytes 1.1 ± 0.3, vein 2.0 ± 0.8, muscle 0.06 ± 0.03: p < 0.001). mRNA expression levels were also significantly higher in fat than in all other tissue types in individuals (p < 0.001).Conclusions: IL6 mRNA expression is significantly higher in adipose than in many other tissues known to express IL6
Alpha-tryptase gene variation is associated with levels of circulating IgE and lung function in asthma
No full textBackgroundTryptase, a major secretory product of human mast cells has been implicated as a key mediator of allergic inflammation. Genetic variation in the tryptases is extensive, and ?-tryptase, an allelic variant of the more extensively studied ?-tryptase, is absent in substantial numbers of the general population. The degree to which ?-tryptase expression may be associated with asthma has not been studied. We have investigated the ?-tryptase gene copy number variation and its potential associations with phenotypes of asthma.ObjectivesCaucasian families (n=341) with at least two asthmatic siblings (n=1350) were genotyped for the ?-tryptase alleles, using high resolution melting assays. Standards for the possible ?-/?-tryptase ratios were constructed by cloning ?-and ?-tryptase PCR products to generate artificial templates. Association analysis of asthma affection status and related phenotypes (total and allergen-specific serum IgE, bronchial hyperresponsiveness to methacholine, FEV1, and atopy and asthma severity scores) were undertaken using family based association tests (FBAT).ResultsFour consistent melting patterns for the ?-tryptase genotype were identified with alleles carrying null, one or two copies of the ?-tryptase allele. Possessing one copy of ?-tryptase was significantly associated with lower serum levels of total and dust mite-specific IgE levels and higher FEV1 measurements, while two copies were related to higher serum concentrations of total and dust mite-specific IgE and greater atopy severity scores.Conclusions and Clinical RelevanceAssociations of ?-tryptase copy number with serum IgE levels, atopy scores and bronchial function may reflect roles for tryptases in regulating IgE production and other processes in asthma
The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms
No full textObjective: Food additives can exacerbate ADHD symptoms and cause non-immunoglobulin E-dependent histamine release from circulating basophils. However, children vary in the extent to which their ADHD symptoms are exacerbated by the ingestion of food additives. The authors hypothesized that genetic polymorphisms affecting histamine degradation would explain the diversity of responses to additives.Method: In a double-blind, placebo-controlled crossover trial, challenges involving two food color additive and sodium benzoate (preservative) mixtures in a fruit drink were administered to a general community sample of 3-year-old children (N = 153) and 8/9-year-old children (N = 144). An aggregate ADHD symptom measure (based on teacher and parent blind ratings of behavior, blind direct observation of behavior in the classroom, and—for 8/9-year-old children only—a computerized measure of attention) was the main outcome variable.Results: The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105Ile in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. There was no evidence that polymorphisms in catecholamine genes COMT Val108Met, ADRA2A C1291G, and DRD4-rs7403703 moderated the effect on ADHD symptoms.Conclusions: Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms.<br/
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