Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma

BACKGROUND: Several genome scans have reported linkage of markers on chromosome 7p with asthma and related phenotypes in different populations. A fine mapping in Finnish and French-Canadian populations has associated the GPR154 gene (also known as G-protein-coupled receptor for asthma susceptibility, GPRA) with elevated IgE or asthma. OBJECTIVE: To confirm chromosome 7p linkage and candidate gene association in Italian families with atopic asthma. METHODS: In a two-phase approach, we first performed a linkage analysis of chromosome 7, and then a family-based association study on the GPR154 gene for allergic asthma phenotypes in the Italian population. RESULTS: The screening of 117 families with 19 microsatellite markers showed potential linkage for elevated IgE (P<0.002 at 22 cM from p-ter), asthma (P<0.005 at 44 cM), or atopy (P<0.005 at 54 cM). In the second phase of the present study, candidate gene GPR154, which is located in the phase one-linked region, was investigated in 211 families with seven single nucleotide polymorphisms (SNPs) that tag most haplotype variability, by the pedigree disequilibrium test. Elevated IgE levels were associated with two GPR154 gene SNPs (SNP 546333, P=0.0046; rs740 347, P=0.006), and with haplotypes in the global test (P=0.013). Haplotype analysis performed in nuclear families having at least 1 asthmatic parent showed a significant association with asthma (P=0.0173), atopy (P=0.0058), SPT (P=0.0025), and bronchial hyper reactivity (P=0.0163). CONCLUSION: These results support a susceptibility locus for asthma and related phenotypes on chromosome 7, and are in agreement with recent reports suggesting that a common susceptibility factor for atopic manifestations in asthma is likely conferred by the locus containing the GPR154 gene.     

Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates

BACKGROUND: Polymorphism at the pi class glutathione-S-transferase locus (GSTP1) is associated with allergen-induced asthma and related phenotypes. OBJECTIVE: We sought to determine whether GSTP1 polymorphism influences susceptibility to asthma induced by toluene diisocyanate (TDI). METHODS: The role of GSTP1 was assessed in 131 workers exposed to TDI, 92 with TDI-induced asthma and 39 asymptomatic subjects. The phenotype of the disease was characterized by using detailed clinical history, lung volumes, airway responsiveness to methacholine, and airway responsiveness to TDI. GST genotypes were determined by using PCR-based assays. RESULTS: In patients exposed to TDI for 10 or more years, the frequency of the GSTP1 Val/Val genotype was lower in subjects who had asthma (odds ratio, 0.23; 95% confidence interval, 0.05-1.13; P =.074). Similarly, the frequency of this genotype was significantly lower in subjects with evidence of moderate-to-severe airway hyperresponsiveness to methacholine compared with the frequency in subjects with normal or mild hyperresponsiveness (P =.033). CONCLUSION: These data suggest that homozygosity for the GSTP1*Val allele confers protection against TDI-induced asthma and airway hyperresponsiveness. This view is supported by the finding that the protective effect increases in proportion to the duration of exposure to TDI.     

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case-control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV₁ and MMEF) and a methacholine provocation test (PC₂₀) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower log ECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher log PC₂₀. In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC₂₀ ? 16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness.     

Genetic variation in S-nitrosoglutathione reductase (GSNOR) and childhood asthma

BACKGROUND: S-nitrosothiols are potent endogenous bronchodilators depleted in asthmatic airway lining fluid. S-nitrosoglutathione reductase (GSNOR; also known as alcohol dehydrogenase 5 or formaldehyde dehydrogenase) catalyzes the metabolism of S-nitrosoglutathione (GSNO) and controls intracellular levels of S-nitrosothiols. GSNOR knockout mice have increased lung S-nitrosothiol levels and are therefore protected from airway hyperresponsiveness after methacholine or allergen challenge. OBJECTIVE: We sought to investigate whether genetic variation in GSNOR is associated with childhood asthma and atopy. METHODS: We genotyped 5 tagging and 2 additional single nucleotide polymorphisms (SNPs) in GSNOR in 532 nuclear families consisting of asthmatic children aged 4 to 17 years and both parents in Mexico City. Atopy was determined by means of skin prick testing. RESULTS: Carrying 1 or 2 copies of the minor allele of SNP rs1,154,404 was associated with decreased risk of asthma (relative risk [RR], 0.77; 95% CI, 0.61-0.97; P = .028 for 1 copy and RR, 0.66; 95% CI, 0.44-0.99; P = .046 for 2 copies). Homozygosity for the minor allele of SNP rs28,730,619 was associated with increased risk of asthma (RR, 1.60; 95% CI, 1.13-2.26; P = .0077). Haplotype analyses supported the single SNP findings. GSNOR SNPs were not associated with the degree of atopy. CONCLUSION: This is the first study of genetic polymorphisms in GSNOR and asthma. These data suggest that genetic variation in GSNOR might play a role in asthma susceptibility. CLINICAL IMPLICATIONS: The association of GSNOR polymorphisms with asthma suggests a potential therapeutic target.     

Integrated effect of EGFR and PAR-1 signaling crosstalk on airway hyperresponsiveness

Among previous genetic studies for asthma, inconsistent findings were often reported. We used a new approach to examine an integrated effect of haplotype blocks, newly termed 'haplotype cluster' over two different types of receptors which share common intracellular pathways on airway hyperresponsiveness (AHR). We recruited 165 young atopic adults without respiratory symptoms and measured airway responsiveness to methacholine and classified them into two groups, those with AHR (PC20?<8.0?mg/ml) and without AHR. In addition, we identified haplotype blocks or cluster tagging single nucleotide polymorphisms (SNPs) through two genes, epidermal growth factor receptor (EGFR) and protease activated receptor (PAR)-1, in all subjects, and compared the frequencies of haplotype block or cluster between subject groups. Significant differences in the frequencies were observed in the haplotype blocks within the EGFR gene (rs4947972, rs12718945 and rs2072454; rs4947972, rs12718945 and rs2227983; and rs4947972, rs12718945 and rs2293347) and the PAR-1 gene (rs37243 and rs253072). An integrated effect was also observed in one haplotype cluster consisting of both regions of the EGFR gene (rs2293347) and the PAR-1 gene (rs253072) (P=0.0426). Our results suggest the possibility that the integrated effect of functionally-related EGFR and PAR-1 genes (haplotype cluster) is associated with susceptibility to AHR.     

Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population

BACKGROUND: Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T(H)2 inflammation. OBJECTIVE: We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. METHODS: A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. RESULTS: The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance (P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 (P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients (P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). CONCLUSIONS: The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.     

Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families

BACKGROUND: Genome and chromosome screens reported DNA markers on chromosome 14 linked to allergic asthma or intermediate phenotypes in several populations. OBJECTIVE: We sought to perform a linkage study on chromosome 14 and a further association study on candidate genes mapped in the region found to be linked to allergic asthma or intermediate phenotypes. METHODS: The study consisted of a sample of 189 families (847 genotyped individuals) from a restricted geographic area in northeastern Italy. The subjects were characterized for the following phenotypes: allergic asthma, total serum IgE levels, skin prick test responses, and bronchial hyperresponsiveness (BHR) to methacholine. Genotyping was done with 14 DNA markers and 4 polymorphisms in the genes encoding alpha(1)-anti-trypsin and alpha(1)-antichymotrypsin (ACT). RESULTS: Multipoint analysis indicated a potential linkage of BHR with marker D14S617 (nonparametric linkage z score = 2.32, P =.01). Transmission disequilibrium of Thr -15Ala in the gene encoding ACT was observed with all the phenotypes investigated: allergic asthma, BHR, total IgE levels, or skin prick test responses (P =.041,.02,.0053, or.026, respectively). CONCLUSION: Chromosome 14 screening and transmission disequilibrium testing on the gene encoding ACT suggest that it or a closely located gene may be involved in susceptibility to allergic asthma in the Italian population.     

The Association of Lung Function,Bronchial Hyperresponsiveness,and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children

Purpose

Although many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA.

Methods

One hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5''-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured.

Results

The AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only.

Conclusions

These findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR.     

Association of IFN-gamma and IFN regulatory factor 1 polymorphisms with childhood atopic asthma

BACKGROUND: IFN-gamma and related molecules play important roles in the differentiation and function of TH2 cells. OBJECTIVE: We sought to determine whether IFNG and related genes contribute to any susceptibility to atopic asthma, a representative TH2-dominant disorder. METHODS: We investigated the association of IFNG (CA repeat polymorphism within the first intron), IRF1 (GT repeat polymorphism within the intron 7), IFNGR1 (Val 14 Met), and IFNGR2 (Gln 64 Arg) gene polymorphisms with atopic asthma in the Japanese child population. RESULTS: A significant association (P =.0018) was observed between IFNG gene polymorphism and atopic asthma. The tendency was more prominent in patients with age of onset of 3 years or younger (P =.0004) or patients with a family history of allergic diseases (P =.0038). Furthermore, there was a significant association between IRF1 gene whole-allele distribution and atopic asthma (P =.044). The tendency was more prominent in patients with onset at 3 years of age or less (P =.0058). On the other hand, IFNGR1 and IFNGR2 gene polymorphisms showed no association with atopic asthma. CONCLUSION: These results suggested that among IFNG and related genes, IFNG and IRF1 genes confer genetic susceptibility to atopic asthma in Japanese children.     

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.     

Relationship between neurokinin 2 receptor gene polymorphisms and serum vascular endothelial growth factor levels in patients with toluene diisocyanate-induced asthma

BACKGROUND: Among the various pathogenic mechanisms of toluene diisocyanate (TDI)-induced asthma, a contribution from neurogenic inflammation has been suggested. OBJECTIVE: To evaluate neurokinin 2 receptor (NK2R) gene polymorphisms in association with the clinical phenotype of TDI-induced asthma, 70 TDI-induced occupational asthma (TDI-OA)patients, 59 asymptomatic exposed controls (AEC), and 93 unexposed healthy controls (NC) were enrolled in the study. METHODS: Two single-nucleotide polymorphisms (SNPs) of NK2R, 7853G>A (Gly231Glu) and 11 424G>A (Arg375His), were genotyped using a single base extension method. The levels of PC20 methacholine, specific IgE and IgG to TDI-human serum albumin conjugate, and serum vascular endothelial growth factor (VEGF), matrix metalloproteinase-9, and TGF-beta1 were compared according to the NK2R genotypes of the subjects with TDI-OA and AEC. RESULTS: No significant differences in allele, genotype, or haplotype frequencies of these two SNPs were noted among the three groups (P>0.05, respectively). Moreover, subjects with the NK2R 7853GG genotype had higher serum VEGF levels than those with GA or AA among the TDI-exposed workers (P=0.040). CONCLUSION: The NK2R 7853GG genotype may contribute to increased serum VEGF levels, which result in airway inflammation after TDI exposure.     

Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children

BACKGROUND. Although asthma diagnosed by a physician is known to be related to serum IgE levels, it is not known whether there is a relation between the level of IgE and airway hyperresponsiveness to a methacholine challenge. The characteristics of asymptomatic persons that predispose them to airway hyperresponsiveness are also unknown. METHODS. We studied the relation between the serum total IgE level and airway hyperresponsiveness in the presence or absence of asthma and other atopic diseases in a birth cohort of children. Data from a questionnaire regarding respiratory symptoms, plus measurements of the serum total IgE level and airway responsiveness to inhaled methacholine, were obtained for 562 11-year-olds in New Zealand. RESULTS. The boys had a higher prevalence than the girls of current diagnosed asthma (13 percent vs. 6 percent), current symptoms of wheezing (22 percent vs. 15 percent), and airflow obstruction at base line (6 percent vs. 1 percent) and had a wider distribution of IgE levels, although mean IgE levels (120.8 IU per milliliter in the boys and 98.1 IU per milliliter in the girls) did not differ significantly between the sexes. The prevalence of diagnosed asthma was strongly related to the serum IgE level (P for trend less than 0.0001). No asthma was reported in children with IgE levels less than 32 IU per milliliter, whereas 36 percent of those with IgE levels greater than or equal to 1000 IU per milliliter were reported to have asthma. This relation with the serum IgE level was not explained by a concomitant diagnosis of allergic rhinitis or eczema. Airway hyperresponsiveness to a methacholine challenge also correlated very highly (P less than 0.0001) with the serum IgE level. This relation remained significant even after the exclusion of children with diagnosed asthma (P less than 0.0001) and of all children with a history of wheezing, allergic rhinitis, or eczema (P less than 0.0001). CONCLUSIONS. Even in children who have been asymptomatic throughout their lives and have no history of atopic disease, airway hyperresponsiveness appears to be closely linked to an allergic diathesis, as reflected by the serum total IgE level.     

A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.     

Enhanced production of leukotrienes by peripheral leukocytes and specific IgE antibodies in patients with chronic obstructive pulmonary disease

BACKGROUND: How leukotrienes (LTs) and IgE-mediated allergy reflect clinical features in patients with chronic obstructive pulmonary disease (COPD) remains unclear. OBJECTIVE: Our goal was to determine whether LTB4 and LTC4 would correlate with airway obstruction and whether IgE-mediated allergy would influence the generation of LTs and bronchial hyperresponsiveness in patients with COPD. METHODS: We measured the pulmonary function, methacholine bronchial hyperresponsiveness, and generation of LTB4 and LTC4 from peripheral leukocytes stimulated with calcium ionophore A23187 in relation to the presence of specific IgE antibodies against inhalant allergens. RESULTS: The leukocytes of patients with COPD generated significantly more LTB4 (with allergy, P <.001; without allergy, P <.001) and LTC4 (with allergy, P <.001; without allergy, P <.01) than the leukocytes of the control subjects. LTC4 production was significantly higher in the allergic COPD subjects than in the nonallergic COPD patients (P <.01), but the amount of LTB4 generated was not significantly different. FEV(1) significantly correlated with the level of both LTB4 (with allergy, r = -0.556, P =.0375; without allergy, r = -0.731, P =.0046) and LTC4 (with allergy, r = -0.764, P =.0043; without allergy, r = -0.526, P =.0414) generation in COPD. The log(10) of the minimum dose of methacholine was significantly higher in COPD patients without allergy than in those with allergy (P <.05). CONCLUSION: Enhanced LT generation from peripheral leukocytes is observed in patients with COPD, and the presence of specific IgE antibodies against inhalant allergens enhances LTC4 generation, bronchial hyperresponsiveness, and the relationship between LTC4 generation and airway obstruction.     

Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial

BACKGROUND: Grass pollen immunotherapy significantly reduces hay fever symptoms and medication requirements. Effects on seasonal asthma are less clear, and concerns over safety persist. OBJECTIVE: The goal of this study was to assess the effects of grass pollen immunotherapy on symptoms, bronchial hyperresponsiveness, and quality of life in seasonal rhinitis and asthma. METHODS: Forty-four patients with severe summer hay fever (of whom 36 reported seasonal chest symptoms and 28 had seasonal bronchial hyperresponsiveness) participated in a randomized, double-blind, placebo-controlled, parallel group study. After symptom monitoring for one summer, participants received injections of a depot grass pollen vaccine (n = 22) or matched placebo injections (n = 22) in a rapid updosing cluster regimen for 4 weeks, followed by monthly injections for 2 years. Outcome measures included hay fever symptoms and medication use, health-related quality of life, and measurements of nonspecific bronchial responsiveness. RESULTS: Significant reductions were observed in the immunotherapy group compared with the placebo group in hay fever symptoms (49%, 15%; P =.01), medication scores (80%, 18%; P =.007), and seasonal chest symptoms (90%, 11%; P <.05). Impairment of overall quality of life (mean score of 7 domains) during the pollen season was less in the immunotherapy group than in the placebo group (median difference [95% CI], 0.8 [0.18-1.5]; P =.02). During the pollen season there was no change in airway methacholine PC(20) (provocation concentration producing a 20% fall in FEV(1)) in the immunotherapy-treated group (P =.5), compared with an almost 3 doubling-dose decrease in the placebo-treated group (P =.01, between-group difference). There were no significant local or systemic side effects during the study. CONCLUSION: Grass pollen immunotherapy improves quality of life in seasonal allergic rhinitis and reduces seasonal asthma symptoms and bronchial hyperresponsiveness.     

Atopy in childhood. II. Relationship to airway responsiveness, hay fever and asthma

While airway hyperresponsiveness is usually associated with a diagnosis of asthma or symptoms of wheezing, some individuals with rhinitis show airway hyperresponsiveness as do some with no symptoms whatsoever. We have studied the correlations between symptoms, airway hyperresponsiveness and atopy as determined by skin-prick tests in a cohort of New Zealand children. A total of 662 members of a birth cohort were studied at age 13 years using a respiratory questionnaire, skin-prick tests to 11 common allergens, and an abbreviated validated methacholine challenge test to determine airway responsiveness. Airway hyperresponsiveness (methacholine PC20 FEV1 < or = 8 mg/ml) was strongly correlated with reported asthma and current wheezing (P<0.0001) and also with atopy, especially to house dust mite and cat (P<0.0001). As weal size for both house dust mite and cat increased, so did the proportion of children with airway hyperresponsiveness. All children with diagnosed asthma and airway hyperresponsiveness were atopic. Skin-test reactions to house dust mite and cat were strongly correlated with any degree of measurable airway responsiveness (PC20 FEV1 < or = 25 mg/ml) in children with rhinitis (P<0.00001), and remained significantly correlated even in children without current asthma, without asthma ever and without rhinitis (P<0.001). Atopy is a major determinant of airway hyperresponsiveness in children, not only in those with reported histories of asthma and wheezing, but also in the absence of any history suggesting asthma and rhinitis.     

血管内皮生长因子基因多态性与克罗恩病的相关性CSCD

目的探讨血管内皮生长因子（vascular endothelial growth factor,VEGF）基因多态性与克罗恩病（Crohn’S disease,CD）易感性的关系。方法收集275例CD患者和495名性别、年龄相匹配的健康对照者,采用SNaPshot技术检测VEGF基因rs699947和rs3025039位点的等位基因和基因型频率。结果CD组与对照组之间整体比较,VEGF基因rs699947和rs3025039位点的变异等位基因和基因型频率差异无统计学意义（P均〉o．05）。分层分析发现,结肠型CD患者中rs699947的变异等位基因（A）和基因型（CA＋AA）频率显著高于对照组（P=0．006,95％CI：1．143～2．234;P=0．005,95％CI：1．203～2．900）。与对照组相比,回肠受累（回肠末段型＋回结肠型）的CD患者中,rs699947的变异等位基因（A）和基因型（CA4-AA）频率偏低（P=0．033,95％CI：0．524～0．974;P=0．043,95％CI：0．481～0．989）。此外,非狭窄非穿透型CD患者中rs3025039纯合子变异基因型（TT）频率低于对照组（0．62％vs．4．85％,P=0．036,95％CI：0．016～O．870）。结论VEGF基因rs699947位点基因变异可能增加结肠型CD的发病风险,但在回肠受累的CD患者中可能发挥保护作用。VEGF基因rs3025039位点的纯合子变异基因型（TT）携带者中非狭窄非穿透型CD的发病风险可能降低。     

Age-dependent relationship between bronchial hyperresponsiveness to methacholine and total serum IgE level in asthmatic children.

BACKGROUND: A relationship between nonspecific bronchial hyperresponsiveness and allergic airway inflammation has been reported in children and in adults with asthma, but the relationship in infants with asthma is still unclear. OBJECTIVE: To evaluate the relationship between bronchial hyperresponsiveness and total serum IgE level throughout childhood. Bronchial reactivity to methacholine from the age of 1 to 16 years was studied by methacholine inhalation challenge using transcutaneous oxygen pressure (tcPO2) monitoring. METHODS: Two hundred one asthmatic children (boys:girls = 132:69; 7.3+/-4.0 years of age, mean +/- SD) were enrolled in this study. The tcPO2 was measured using a tcPO2 monitor. Serial doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO2 was considered to represent the bronchial reactivity to methacholine. RESULTS: There was no relationship between the cumulative dose of methacholine at the inflection point of tcPO2 and total serum IgE level in the group of children aged 1 to 4 years (P = 0.212), but significant correlations were found in the groups aged 5 to 10 years and 11 to 16 years (P = 0.044 and P = 0.014, respectively). CONCLUSIONS: We conclude that there is an age-dependent relationship between bronchial reactivity to methacholine and the total serum IgE level and that inhaled allergens, which were more common allergens in older children, may have some effects on the degree of bronchial reactivity to methacholine in children with asthma.     

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma

BACKGROUND: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. OBJECTIVE: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. METHODS: Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. RESULTS: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. CONCLUSION: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. CLINICAL IMPLICATIONS: Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.