Combined effect of tumour necrosis factor-α and interleukin-13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma

Background TNF‐α and IL‐13, two pivotal pro‐inflammatory cytokines, are increased in asthmatic airways and may be linked to asthma susceptibility and/or bronchial hyperresponsiveness (BHR). Objective We investigated the association between the TNF‐α?308G/A polymorphism and asthma susceptibility or asthma‐related phenotypes in Korean children with asthma, and tested for a combined effect with IL‐13 polymorphisms. Methods Asthmatic children (n=719) and non‐atopic healthy control children (n=243) were evaluated for asthma phenotypes including total serum IgE and BHR to methacholine. Genotypes were determined by PCR‐restriction fragment length polymorphism analysis. Results The allele frequency of TNF‐α?308A in asthmatics (14.1%) was higher than that in control children [8.7%, odds ratio (OR) 1.72, 95% confidence interval (CI) 1.05–2.82]. Significantly lower PC₂₀ values were found in asthmatic children carrying one or two copies of the TNF‐α risk allele (?308A) vs. those homozygous for the common allele (P=0.026). Combined analysis revealed that atopic asthmatic children co‐inherited the risk alleles of TNF‐α?308G/A and IL‐13 +2044G/A more frequently than control children (aOR 1.91, 95% CI 1.00–3.65), and asthmatic children co‐inheriting both risk alleles had significantly lower PC₂₀ values vs. asthmatic children homozygous for the common alleles (P=0.024). Conclusion The TNF‐α promoter polymorphism (?308G/A) may be associated with asthma susceptibility and BHR in Korean children with asthma. In addition, there appears to be a synergistic effect between the TNF‐α promoter polymorphism and an IL‐13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.     

Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children

Many studies have shown the implication of CD14 and toll-like receptors (TLRs) 2, 4 and 9 in the pathogenesis of asthma or atopy. To evaluate the association of CD14 and TLRs gene polymorphisms with asthma or atopy, 210 asthmatic children, 224 controls and 80 families were enrolled in this study. Six single nucleotide polymorphisms TLR2 (+2408 G-->A), TLR4 (+1196 C-->T), TLR4 (+896 A-->G), TLR9 (-1237 T-->C), TLR9 (-1486 T-->C) and CD14 (-159 C-->T) were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism in the case-control and family study. The -1237C allele in TLR9 gene polymorphisms was associated with increased risk of asthma [odds ratio 1.53, 95% confidence interval (1.03-2.27)], although no statistically significant differences in allele or genotype frequencies of four other TLRs polymorphisms were evident between the asthmatic and control groups. The CD14 -159 C allele was found to be significantly higher in the asthmatic group when compared with controls (P=0.0006<0.05). Transmission disequilibrium test of 80 asthmatic families showed significant transmission of the -159 C allele in the CD14 gene to asthma-affected offspring. It was concluded that TLR9 and CD14 gene polymorphisms may contribute to an inherited predisposition to asthma in Tunisian children.     

Meta-analysis of TNF-alpha promoter -308 A/G polymorphism and SLE susceptibility

Alleles of tumor necrosis factor-alpha (TNF-alpha) gene have been inconsistently associated with systemic lupus erythematosus (SLE), particularly the 308-A/G functional promoter polymorphism. To generate large-scale evidence on whether 308-A/G promoter polymorphism is associated with SLE susceptibility we have conducted a meta-analysis. We have identified 21 studies of this polymorphism and SLE using MEDLINE search. Meta-analysis was performed for genotypes A/A (recessive effect), A/A+A/G (dominant effect), and A allele in fixed or random effects models. All control samples were in Hardy-Weinberg proportion. The overall odds ratio (OR) of the A/A genotype was 3.2 (95% CI=2.0-5.3, P<0.001). Stratification by ethnicity indicated that the A/A genotype was associated with SLE in European-derived population (OR=4.0, CI=2.5-6.4, P<0.001). No association was detected in Asian-derived population (OR, 1.3, CI=0.3-6.3, P=0.76). The overall OR for the risk genotypes (A/A and A/G) was 2.0 (CI=1.3-3.1, P<0.001). Similar results were found between the risk allele A and SLE where a significant association was found in European population (OR=2.1, CI=1.6-2.7, P<0.001), but not in Asian (OR=1.4, CI=0.8-2.3, P=0.2) or African (OR=1.2, CI=0.6-2.5, P=0.59) populations. In summary, this meta-analysis demonstrates that the TNF-alpha promoter -308 A/G polymorphism may confer susceptibility to SLE, especially in European-derived population.     

The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma

BACKGROUND: Endotoxin, with its potential to enhance type 1 immunity, is a significant player in the hygiene hypothesis. The combined effects of the genetic variants of various molecules in the endotoxin response pathway on asthma related phenotypes are largely unknown. OBJECTIVE: To investigate the effects of the genetic variants of CD14 and TLR4 genes on asthma phenotypes in a large number of asthmatic children. METHODS: 613 asthmatic children were genotyped at the CD14-C159T, TLR4-A896G and TLR4-C1196T loci. IgE, eosinophil numbers and FEV1 were compared in 327 children who were not on any controller medications and were symptom free. Multivariate logistic regression was used to determine the factors associated with total IgE. RESULTS: Among children with atopic asthma, total IgE levels were significantly different among the three genotypes in the co-dominant model [CC: 435 kU/l (interquartile range: 146-820); CT: 361 (140-710); TT 204 (98-435), P = 0.035]. TT genotype was significantly and independently associated with lower IgE levels (OR: 0.5 95%; CI = 0.28-0.90, P = 0.021). Both TLR4-A896G and TLR4-C1196T polymorphisms were more frequent in the mild asthma group with atopy (P = 0.032, 0.018, respectively). The combined effects of the genetic variants in CD14 and TLR4 genes did not improve the observed associations. CONCLUSION: Our study demonstrates that the CD14-C159T promoter variant influences total IgE levels and also indicates that the T allele has a more profound effect on total IgE in children with atopic asthma. Polymorphisms in the TLR4 gene may be associated with milder forms of disease in atopic asthmatics in the population studied.     

Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity.

BACKGROUND: Chemokines play an important role in the pathophysiology of asthma and allergy. Recently, polymorphisms in the gene regulatory region of monocyte chemoattractant protein 1 (MCP-1) and in the promoter region of RANTES have been found; these polymorphisms increase the expression of the chemokines. OBJECTIVE: We investigated whether the presence of the polymorphisms was associated with atopy or asthma and whether these alleles influenced the severity of asthma in affected individuals. METHODS: Three groups of subjects-160 children with asthma (disease severity being classified according to the Global Initiative for Asthma guidelines, modified for children), 151 children with nonasthmatic but allergic phenotype, and 303 children without allergic or asthmatic disorders-were screened with a PCR-based assay for genotyping. RESULTS: The frequency of the -2518G polymorphism in the gene regulatory region of MCP-1 was significantly higher in asthmatic children than in controls (P <.001; odds ratio [OR] = 2.0 [1.4-2.6]) and nonasthmatic atopic children (P <.001; OR = 2.0 [1.4-2.9]). The MCP-1 G/G genotype correlated with asthma severity. In asthmatic children, the MCP-1 -2518G allele was also associated with an increased blood eosinophil level. The promoter polymorphisms in the RANTES gene did not have a detectable effect on the susceptibility to asthma or allergy or on the blood eosinophil count. CONCLUSION: In this cohort of children, there are associations between carrying G at -2518 of the MCP-1 gene regulatory region and the presence of asthma as well as between asthma severity and homozygosity for the G allele. In asthmatic children, the MCP-1 -2518G polymorphism correlated with increased eosinophil levels. This variant of MCP-1 might belong to the predictor gene set for asthma.     

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.     

白介素-10-627基因多态性和儿童哮喘的相关性研究

目的探讨白介素-10(IL-10)基因-627位点多态性与昆明地区儿童哮喘的相关性。方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析方法,检测50例哮喘儿童和36例健康儿童IL-10基因-627位点基因型,比较两组IL-10基因-627位点的基因型和等位基因分布频率。结果哮喘组和健康组3种基因型CC、CA、AA分别为:12.0%、48.0%、40.0%;8.3%、50.0%、41.7%。两组基因型分布差异无显著性(P>0.05)。哮喘组和健康组C和A的等位基因分布频率分别为:36.0%、64.0%;31.9%、68.1%。两组等位基因分布频率差异无显著性(P>0.05)。结论本研究表明IL-10基因-627位点多态性可能与昆明地区儿童哮喘易感性无关。     

Preferential transmission and association of the -403 G --> A promoter RANTES polymorphism with atopic asthma

Asthma is a complex inherited disease. The study was undertaken to identify the association of RANTES promoter polymorphisms with atopy and asthma using family-based association tests (FBATs) and generation-specific case-control analyses. We identified 154 nuclear families (453 individuals) in whom we established RANTES promoter status using the RFLP-PCR method. Of the two known promoter polymorphisms -403G/A and -28C/G, only the former appeared with a clinically relevant frequency. A total of 61 families were eligible for assessment of transmission of the allele with asthma and atopy by the pedigree disequilibrium test (PDT). Overall, allele frequency for -403A was 38.3% and 84 of 89 (94.3%) alleles were transmitted with physician diagnosed asthma (PDA) (P=0.001). All 89 children with atopy received the mutant allele, which was more than expected following Mendelian Laws of transmission (P=0.0001). In 303 unrelated parents, significant associations of the mutant allele were for atopy with or without asthma (P=0.001). In 150 unrelated children, significant associations were for atopy alone (P=0.001) and asthma (P=0.001). No associations were found for bronchial hyper-responsiveness (BHR). The -403 G --> A is transmitted with atopy and atopic asthma, although its contribution appears to relate more to atopy than asthma and BHR.     

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 of TNF-α genetic polymorphism with HLA DPB1*0301

BACKGROUND: We speculated TNF-alpha can be one of candidate gene for aspirin-intolerant asthma (AIA) because TNF-alpha is pro-inflammatory cytokine and known to be increased level in asthmatic airways. In addition, genetic interaction between TNF-alpha and human antigen leucocyte (HLA) DPB1*0301, which is a strong genetic marker for AIA, was examined for its close location within chromosome 6. METHOD: To investigate genetic association of TNF-alpha with an AIA phenotype, three study groups (163 patients with AIA, 197 patients with aspirin-tolerant asthma (ATA), 257 normal control subjects) were enrolled. Single nucleotide polymorphisms (SNPs) were genotyped using a single-base extension method and HLA DPB1 genotyping was determined by high-throughput sequencing method. RESULTS: All five SNPs of TNF-alpha were tested; there were no significant differences in allele and genotype frequencies among the three groups. However, significant association between TNF-alpha-308G>A polymorphism and atopy status was noted (P<0.05). Gene to gene interaction between TNF-alpha-1031T>C (or -863C>A or -857C>A) and HLA DPB1*0301could synergistically increase the susceptibility to AIA with odds ratio (OR) to 7.738 (or OR=8.184 for -863C>A, OR=7.500 for -857C>T, P<0.001, respectively). CONCLUSION: TNF-alpha promoter polymorphism may significantly increase susceptibility to AIA by gene-to-gene interaction with HLA DPB1*0301.     

Association study using combination analysis of SNP and STRP markers: CD14 promoter polymorphism and IgE level in Taiwanese asthma children

Chromosome 5, especially the 5q31-33 region, may contain one or more loci to control total serum IgE as well as asthma and bronchial hyperresponsiveness. To investigate the regions related with IgE level in chromosome 5, we performed a case-control association study on 105 high-IgE-level and 85 normal-IgE-level asthmatic children using 43 microsatellite markers that span the whole chromosome 5 with 5 cM intervals. One of microsatellite marker, D5S2011, had significantly different allele frequency between the two asthmatic groups. E allele (143 bp) of the D5S2011 marker was more frequent in high-IgE asthmatics. CD14 is the candidate gene of atopy and asthma and is distant from D5S2011 by about 1 Mb. We analyzed the SNP genotypes in the CD14 gene region alone and in combination with microsatellite marker D5S2011. The CD14/–2984 polymorphism but not the CD14/–159 is associated with IgE level in Taiwanese asthmatic children. The CD14/–159 allele was observed only to be associated with IgE level when –159T was part of a haplotype containing a D5S2011 E allele. The combination analysis using SNP and STRP markers provided a novel method for increasing detection power in candidate gene association studies.     

The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy

BACKGROUND: CD14, the receptor for LPS, plays an important role in innate immunity. A polymorphism in the promotor for CD14, -159 C-->T, has been implicated in atopy. OBJECTIVE: We explored the relationship of this polymorphism with both atopic and nonatopic asthma, as well as with food allergy. METHODS: Patients with asthma and food allergy were recruited along with nonatopic, nonasthmatic control subjects. The -159 C-->T polymorphism was genotyped by using the PCR-based RFLP assay. RESULTS: The -159 T allele was more common among patients with nonatopic asthma and food allergy than among control subjects (chi(2) = 6.03, P =.01 and chi(2) = 4.94; P =.03, respectively). Patients with food allergy had a 4-fold increased odds of having the TT genotype versus carriers of the C allele compared with control subjects (odds ratio [OR] = 3.9, 95% CI = 1.5-10.3), whereas patients with nonatopic asthma had a 3-fold increased odds of having the TT genotype (OR = 3.1 [95% CI = 1.1-9.1]). Controlling for sex differences between groups did not alter this relationship, which remained significant for patients with food allergy (OR = 3.7 [95% CI = 1.4-10.1]) or nonatopic asthma (OR = 2.7 [95% CI = 0.9-8.0]). We performed a stratified analysis, limited to white patients, to reduce population stratification. The relationship with the TT genotype was stronger in white patients with nonatopic asthma (OR = 4.4 [95% CI = 1.3-14.8]) and patients with food allergy (OR = 5.1 [95% CI = 1.6-16.2]), even adjusting for sex differences (OR = 3.9 [95% CI = 1.1-13.5] and OR = 4.6 [95% CI = 1.4-14.8], respectively). CONCLUSIONS: The TT genotype of -159 C-->T CD14 is associated with nonatopic asthma and food allergy, particularly in white subjects. Thus CD14 is a candidate gene specifically for nonatopic asthma and not for asthma in general. This indicates that atopic and nonatopic asthma might be distinct conditions in their genetic predisposition, despite the fact that they are very similar once they have been established.     

Genetic susceptibility to SLE is associated with TNF-alpha gene polymorphism -863, but not -308 and -238, in Thai population

The production of cytokine varies among individuals and correlates with the polymorphism of cytokine genes. Three functional single nucleotide polymorphisms (SNPs) at position -863, -308, and -238 in the tumour necrosis factor alpha (TNF-alpha) gene promoter were analysed for association with systemic lupus erythematosus (SLE) (n = 154), and clinical manifestations in a Thai population were compared with 154 ethnically matched controls. The genotyping was determined by polymerase chain reaction-restriction fragment length polymorphism method. The association between these SNPs and SLE was analysed using chi-squared test. The -863A allele and -863A, -308G, -238G haplotype were found to be significantly increased in SLE patients (25%) compared with healthy controls (15.3%) (Pc = 0.009, OR = 1.85, 95% CI = 1.21-2.83). In addition -863A allele was found to be significantly increased in the SLE group with Raynaud's phenomenon compared to SLE without Raynaud's phenomenon (35% vs. 19.4%) (Pc = 0.048, OR = 2.23, 95% CI = 1.21-4.10). The -863A allele of TNF-alpha gene and the extended haplotype of -863A, -308G, -238G can be used as a genetic marker for SLE susceptibility in Thai populations. In addition, the -863A genotype could produce high TNF levels and potentially induce the occurrence of Raynaud's phenomenon.     

Fine mapping of an IgE-controlling gene on chromosome 2q: Analysis of CTLA4 and CD28

BACKGROUND: Several genomic regions have been identified that might contain genes contributing to the development of asthma and atopy. These include chromosome 2q33, where we have observed evidence for linkage for variation in total serum IgE levels in a Dutch asthma population. Two candidate genes, CTLA4 and CD28, important homeostatic regulators of T-cell activation and subsequent IgE production, map within this candidate region. OBJECTIVE: We sought to fine-map the chromosome 2q33 region and evaluate CTLA4 and CD28 as candidate genes for the regulation of total serum IgE levels and related phenotypes. METHODS: The coding regions of CTLA4 and CD28 were resequenced in 96 individuals; 4 novel SNPs in CTLA4 and 10 in CD28 were identified. Polymorphisms in both genes were analyzed in 200 asthmatic probands and their spouses (n = 201). RESULTS: Subsequent fine- mapping in this region has resulted in an increased log of the odds (lod) score (1.96 to 3.16) for total serum IgE levels. For CTLA4, the +49 A/G single nucleotide polymorphism (SNP) in exon 1 and the 3 ' untranslated region microsatellite were significantly associated with total serum IgE levels (P =.0005 and.006, respectively). For the combined +49 A/G and 3 'untranslated region genotypes, individuals homozygous for the risk allele for both polymorphisms (AA and 86/86) had the highest total serum IgE values (87.1 IU/mL), whereas those individuals with the GG and XX/XX genotypes (anything but the 86-bp allele) had the lowest IgE values (29.3 IU/mL). Significant association was also observed for the CTLA4 -1147 C/T SNP with bronchial hyperresponsiveness (BHR) and asthma (P =.008 and.012, respectively), but not for allergy-related phenotypes. Promoter luciferase assays examining the -1147 polymorphism suggested that the T allele, which was associated with increased BHR susceptibility, was expressed at half the level of the C allele. Individuals with the risk genotypes for both BHR (-1147 CT or TT) and elevated IgE levels (+49 AA) were 4.5 times more likely to have asthma than individuals with both nonrisk genotypes (P =.0009). No significant associations were observed for SNPs in CD28. CONCLUSION: These data suggest that the costimulatory pathway, specifically CTLA4, is important in the development of atopy and asthma.     

Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection

The mechanisms underlying the resolution of hepatitis B virus (HBV) infection remain undetermined. Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in host immune response to HBV, and the capacity for cytokine production in individuals has a major genetic component. The aim of this study was to examine whether TNF-alpha promotor polymorphisms are associated with the clearance of HBV infection. A total of 1400 Korean subjects were enrolled in two different groups: 'chronic carrier group' (CC; n=1109), who were repeatedly hepatitis B surface antigen (HBsAg)-positive, and 'subjects who spontaneously recovered' (SR; n=291), who were HBsAg-negative with antibodies to HBsAg and hepatitis B core antigen. TNF-alpha promoter polymorphisms at positions -1031T>C, -863C>A, -857C>T, -376G>A, -308G>A, -238G>A and -163G>A were determined and the genotype distributions of the CC and SR groups were compared. The TNF-alpha promoter alleles that were previously reported to be associated with higher plasma levels, i.e. the presence of the -308A allele (TNF-alpha-308A/G or A/A) or the absence of the -863A (TNF-alpha-863C/C) variant, were strongly associated with the resolution of HBV infection in three alternative analyzing models, i.e. TNF-alpha-308G>A (P=0.01) and TNF-alpha-863C>A (P=0.003-0.14), respectively. Haplotype analysis also revealed that TNF-alpha haplotype 1 [-1031T; -863C; -857C; -308G; -238G; -163G] and haplotype 2 [-1031C; -863A; -857C; -308G; -238G; -163G] were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P=0.003-0.02). Our findings imply that variations in the genes governing the levels of constitutive and inducible TNF-alpha might be an important factor, which might explain the variable outcome of HBV infection.     

Association of TNF-beta polymorphism with disease severity among patients infected with hepatitis C virus

The pathogenesis of chronic hepatitis C virus (HCV) infection remains unclear. Tumour necrosis factor alpha (TNF-alpha) is alleged to contribute in the pathogenesis of chronic HCV infection. Single nucleotide polymorphism in TNF-alpha and -beta genes could influence the outcome of HCV infection. The aim was to study single nucleotide polymorphism in TNF-alpha promoter region and Nco I polymorphisms in the TNF-beta gene in patients with chronic hepatitis C. Fifty-two patients with histologically proven chronic hepatitis, who had raised ALT levels (>1.5 x ULN) and were HCV RNA positive, were studied. Genotyping of -308 promoter variant of TNF-alpha was performed by PCR with primers that incorporated an Nco I restriction site. For PCR typing of the TNF-beta Nco I restriction fragment length polymorphism, sequence specific primers were used. Polymorphism in the TNF-alpha G/G, G/A and A/A allele was not different between HCV patients and healthy controls. TNF-beta A/A allele was significantly more common (P = 0.02) in patients (28.8%) as compared to controls (12.8%), whereas no significant difference was observed for TNF-beta G/A and G/G alleles [corrected]. Nco I TNF-beta A/A was strongly associated with -308 TNF-alpha G/G (RR of HCV persistence = 4.9), indicating possible linkage between TNF-beta A/A and TNF-alpha G/G allele. Patients with severe hepatic fibrosis more frequently had the TNF-beta A/A allele as compared to patients with mild disease (P = 0.04). Immunogenetic factors, such as single nucleotide polymorphisms in TNF-beta (A/A allele), may affect the natural course of HCV infection, in particular, the disease progression. Larger studies including cytokine expression profiles are needed to fully understand the contribution of the polymorphisms described in the pathogenesis of chronic hepatitis C.     

Variant in promoter region of platelet-derived growth factor receptor-alpha (PDGFRalpha) gene is associated with the severity and allergic status of childhood asthma

BACKGROUND: Upregulation of the platelet-derived growth factor receptor-alpha (PDGFRalpha) in airway myofibroblast cells is one of the mechanisms of airway remodeling. The genetic association between PDGFRalpha promoter polymorphism and severity of childhood asthma was examined. METHODS: Five single nucleotide polymorphisms (SNPs) at the promoter regions of the PDGFRalpha gene were genotyped in 277 unrelated allergic and nonallergic asthmatic children and 93 age-matched controls. Promoter haplotypes were constructed using SNP genotyping data. The serum level of PDGF-AA, the ligand for PDGFRalpha, was assayed by ELISA kits. RESULTS: The genotype distribution of SNP rs1800810 (-1171G/C) in nonallergic asthma was significantly different from controls (p=0.038), as well as its allele distribution (p=0.028). Using haplotype analysis, the combination frequency of the low expression of H1 homozygous and heterozygous genotype (H1/H1+H1/H2) was significantly higher in nonallergic asthma as compared to controls (OR=1.94, CI=1.11-3.39, p<0.02). The frequency of H2/H2 homozygous was higher in persistent asthma than in intermittent asthma (p=0.008, OR=2.625). In addition, the PDGF-AA serum level in H2/H2 homozygous haplotype was significantly lower as compared to non-H2/H2 homozygous haplotype both in asthmatic (138.1+/-62.9 vs. 249.7+/-97.1 ng/ml, p<0.05) and nonallergic asthmatic children (113.8+/-38.0 vs. 256.6+/-58.3 ng/ml, p<0.05). CONCLUSIONS: The developmental deficiency due to the low expression of PDGFRalpha may be one of the susceptible factors for nonallergic asthmatic children. There was also an autocrine effect of lower PDGF-AA and higher PDGFRalpha expression that might lead to airway remodeling causing the severity of asthma.