The role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos

Background Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of arachidonate 5‐lipoxygenase‐activating protein (ALOX5AP) and leukotriene A₄ hydrolase (LTA4H) in asthma have been inconclusive. Objective To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans. Methods The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single‐nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analysed for associations with asthma and asthma‐related phenotypes in 687 parent–child trios of Mexican and Puerto Rican origin. Results In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P=0.007 and 0.05, respectively). Among the Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (odds ratio=0.78, P=0.02) and baseline lung function (P=0.018) in Puerto Ricans. A gene–gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P=0.003, in the combined sample). Conclusion Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations. Cite this as: M. Via, A. De Giacomo, H. Corvol, C. Eng, M. A. Seibold, C. Gillett, J. Galanter, S. Sen, H. Tcheurekdjian, R. Chapela, J. R. Rodríguez‐Santana, W. Rodríguez‐Cintrón, S. Thyne, P. C. Avila, S. Choudhry and E. González Burchard on behalf of the Genetics of Asthma in Latino Americans (GALA) Study, Clinical & Experimental Allergy, 2010 (40) 582–589.     

The role of the bone marrow in allergy and asthma

The above studies have begun to address the fundamental question of the mechanisms of bone marrow involvement and response to allergen challenge in allergic asthmatics. Further studies in this area should complement our investigations in human asthma — which suggest that a particular bias toward differentiation of Eo-Baso progenitors characterizes the atopic state — as well as our findings in the dog model of allergen-induced airway hyperresponsiveness, which indicate that the bone marrow responds to inhalation of allergen or corticosteroids. Taken in the context of previous indications that IgE and bronchial responsiveness may both be transferrable through bone marrow transplantation (log), these findings indicate a physiologic role for the bone marrow in allergic inflammation. Likewise, these concepts provide a basis for making certain predictions regarding management and novel therapeutic interventions in atopy and asthma.     

Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males

BACKGROUND: Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA). METHODS: To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC). RESULTS: Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04). CONCLUSION: These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.     

The cysteinyl-leukotriene type 1 receptor polymorphism 927T/C is associated with atopy severity but not with asthma

BACKGROUND: The cysteinyl-leukotriene receptor type 1 (CysLT1) mediates the bronchoconstrictor and pro-inflammatory actions of cysteinyl-leukotrienes (LTC4, LTD4, LTE4) in asthma and is the molecular target of the lukast class of oral anti-leukotriene drugs. We screened the CYSLTR1 gene on chromosome Xq13-21 for coding region polymorphisms, and investigated their associations with allergy and asthma. METHODS: Solid-phase chemical cleavage was used to screen polymorphisms in the coding region of CYSLTR1. A TaqMan allelic discrimination assay was used to genotype a 927T/C SNP and oligonucleotide ligation assays were used to genotype the previously reported 617T/C and 898G/A SNPs of CYSLTR1 in 341 asthmatic families from the UK. Associations with asthma diagnosis, atopic status, serum-specific IgE and severity of allergy and asthma were examined. RESULTS: Family-based association tests showed that the 927 T allele was associated with atopy severity, especially in female subjects, but not with asthma diagnosis or severity, atopic status, bronchial hyper-responsiveness to methacholine or forced expiratory volume in 1 s. CONCLUSION: Mutation screening identified only one polymorphism, 927T/C, in the coding region of the CysLT1 receptor. This polymorphsim is predictive of atopy severity, but not associated with asthma.     

The regulation of allergy and asthma

Summary: Allergic diseases and asthma are caused by exaggerated T‐helper 2 (Th2)‐biased immune responses in genetically susceptible individuals. Tolerance to allergens is a mechanism that normally prevents such responses, but the specific immunological events that mediate tolerance in this setting are poorly understood. A number of recent studies indicate that regulatory T cells (Tregs) play an important role in controlling such Th2‐biased responses. Tregs involved in regulating allergy and asthma consist of a family of related types of T cells, including natural CD25⁺ Tregs as well as inducible forms of antigen‐specific adaptive Tregs. Impaired expansion of natural and/or adaptive Tregs is hypothesized to lead to the development of allergy and asthma, and treatment to induce allergen‐specific Tregs could provide curative therapies for these problems.     

Corticosteroid allergy in asthma

BACKGROUND: Glucocorticosteroids form the basis of therapy for asthma and other allergic diseases. However, they frequently cause delayed contact allergy and occasionally immediate allergy. The purpose of this study was to investigate the occurrence of corticosteroid allergy among patients with asthma and with some complaints caused by inhaled corticosteroids. METHODS: Patch tests with corticosteroids were performed in 51 asthma patients with side-effects from inhalant corticosteroids and in 50 symptom-free asthma patients using the Finn Chamber system. The corticosteroids and their vehicles were: betamethasone-17-valerate 1% in petrolatum, hydrocortisone-17-butyrate (Hc-17-B) 1% in ethanol, tixocortol-21-pivalate 1% in petrolatum, budesonide 0.1% in petrolatum, beclomethasone dipropionate 0.1 and 0.5% in petrolatum and as inhalant powder 200 microg, and fluticasone propionate 0.1 and 0.5% in petrolatum and as inhalant powder 250 microg. The results were read twice, on D4-5 and again on D10. RESULTS: Two patients in the symptomatic group reacted to corticosteroids in patch tests, one to betamethasone-17-valerate, Hc-17-B and budesonide, and the other to budesonide and Hc-17-B. The first patient suffered from widespread eczematous dermatitis when using beclomethasone. Fluticasone caused oropharyngeal irritation, hoarseness and shortness of breath. The second patient experienced a severe rash after the fourth budesonide inhalation. She had used various topical corticosteroids for her atopic dermatitis without any side-effects. None of the symptom-free patients showed positive results. CONCLUSIONS: Delayed allergy to corticosteroids occurs occasionally in asthma, perhaps in the same frequency as in dermatitis. A positive patch test reaction usually means clinical allergy, i.e. the patient cannot use that particular steroid. Cross allergy between corticosteroids is common. However, such patients usually tolerate some other common corticosteroids.     

TIM-1, a novel allergy and asthma susceptibility gene

Atopic diseases, including asthma, allergic rhinitis, and atopic dermatitis, are caused by environmental factors in genetically predisposed individuals. Although the prevalence of these diseases has risen dramatically over the past two decades, it has been difficult to identify the underlying causes of these diseases due to the complex interplay between the genetic and environmental factors involved. Using a congenic mouse model of asthma, we simplified this complex trait and identified the novel T cell immunoglobulin domain, mucin-like domain (TIM) gene family, that encodes transmembrane proteins expressed by CD4 T cells. Recent studies demonstrate that the TIM family, particularly TIM-1, plays a critical role in immune responses that regulate the development of atopic diseases. In humans, certain polymorphic variants of TIM-1 are strongly associated with protection against atopy, and this association occurs only in individuals who have had past infection with hepatitis A virus (HAV). Since TIM-1 functions as the cellular receptor for HAV, activation of T cells through TIM-1 by HAV or by its natural ligand may affect T cell differentiation and the development of Th2-driven allergic inflammatory responses. Epidemiologically, HAV infection is associated with a reduced risk of developing atopy, and because the incidence of HAV infection has been significantly reduced in industrialized countries over the past 30 years, the discovery of a genetic interaction between HAV and TIM-1 provides the first molecular genetic evidence for the hygiene hypothesis.     

TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma

Background Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma‐related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma‐related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise‐induced bronchoconstriction (EIB). Methods Asthmatic children (n=695) and control children (n=159) were evaluated for asthma‐related phenotypes including total IgE, pulmonary function test, and bronchial hyperresponsiveness to methacholine or exercise. Genotypes were detected by PCR‐RFLP. In the montelukast study, exercise challenge was performed before and after an 8‐week montelukast treatment. Results The TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma. However, asthmatic children with combinations of the TBXA2R+795T>C and +924T>C risk alleles had significantly higher total IgE levels (P=0.01), total eosinophil counts (P<0.01) and lower forced expiratory volume in 1 s (FEV₁) (P=0.02) and forced expiratory rates at 25–75% of vital capacity (P=0.02) than those carrying the common alleles. When compared with individuals with the common alleles, patients with the TBXA2R+924T>C TT homozygote and TBXA2R+795T>C hetero‐ or homozygote (CT or CC) had a 3.67‐fold poor response to 8‐week montelukast treatment with respect to maximum percent fall in FEV₁ after exercise (odds ratio, 3.67; 95% confidence interval, 1.15–11.15). Conclusions A combined effect of TBXA2R+795T>C and +924T>C risk alleles may be linked to IgE production, eosinophilic inflammation, and severity of asthma. In addition, the TBXA2R+795T>C genotype may be a predictive marker of a clinical response to the LTRA in Korean asthmatic children with EIB.     

Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma

BACKGROUND: Toluene diisocyanate (TDI)-induced asthma is a common cause of occupational asthma and it affects 5-15% of the exposed population suggesting an underlying genetic susceptibility. METHODS: To investigate the role of genetic factors in the development of TDI-induced asthma, we analyzed the distribution of human leukocyte antigen (HLA) class I genes and of tumor necrosis factor (TNF)-alpha A-308G polymorphism in 142 patients with TDI-induced asthma and in 50 asymptomatic exposed subjects. RESULTS: Neither the distribution of HLA class I antigens nor the distribution of TNF-alpha A-308G polymorphism was different between patients with TDI-induced asthma and asymptomatic exposed subjects. CONCLUSIONS: These results suggest that HLA class I antigens and TNF-alpha A-308G are not associated with susceptibility or resistance to the development of TDI-induced asthma.     

Genetic susceptibility to severe asthma with fungal sensitization

Severe asthma is problematic and its pathogenesis poorly understood. Fungal sensitization is common, and many patients with severe asthma with fungal sensitization (SAFS), used to denote this subgroup of asthma, respond to antifungal therapy. We have investigated 325 haplotype‐tagging SNPs in 22 candidate genes previously associated with aspergillosis in patients with SAFS, with comparisons in atopic asthmatics and healthy control patients, of whom 47 SAFS, 279 healthy and 152 atopic asthmatic subjects were genotyped successfully. Significant associations with SAFS compared with atopic asthma included Toll‐like receptor 3 (TLR3) (p = .009), TLR9 (p = .025), C‐type lectin domain family seven member A (dectin‐1) (p = .043), interleukin‐10 (IL‐10) (p = .0010), mannose‐binding lectin (MBL2) (p = .007), CC‐chemokine ligand 2 (CCL2) (2 SNPs, p = .025 and .041), CCL17 (p = .002), plasminogen (p = .049) and adenosine A2a receptor (p = .024). These associations differ from those found in ABPA in asthma, indicative of contrasting disease processes. Additional and broader genetic association studies in SAFS, combined with experimental work, are likely to contribute to our understanding of different phenotypes of problematic asthma.     

The role of breast-feeding in the development of allergies and asthma

Breast-feeding is the preferred method of infant nutrition for numerous reasons. However, its role in the prevention of allergic disease remains controversial. Reasons for this controversy include methodological differences and flaws in the studies performed to date, the immunologic complexity of breast milk itself and, possibly, genetic differences among patients that would affect whether breast-feeding is protective against the development of allergies or is in fact sensitizing. The preponderance of evidence does suggest, however, that there would be much to lose by not recommending breast-feeding. In general, studies reveal that infants fed formulas of intact cow's milk or soy protein compared with breast milk have a higher incidence of atopic dermatitis and wheezing illnesses in early childhood. Consistent with these findings, exclusive breast-feeding should be encouraged for at least 4 to 6 months in infants at both high and low risk of atopy and irrespective of a history of maternal asthma.     

ALOX5AP基因SG13S114A/T多态性与颈动脉粥样硬化斑块稳定性的相关性

目的 探讨花生四烯酸5-脂氧合酶激活蛋白(arachidonate 5-lipoxygenase acttvating protein,ALOX5AP)基因SG13S114 A/T的多态性与颈动脉粥样硬化斑块稳定程度的关系.方法 应用聚合酶链反应-限制性片段长度多态性分析法检测132例颈动脉易损斑块及152例稳定斑块的急性脑梗死者ALOX5AP基因SG13S114 A/T基因型,比较两组间该位点多态性的差异.结果 易损斑块组ALOX5AP基因SG13S114 AA基因型和A等位基因频率高于稳定斑块组,两组差异有统计学意义(P＜0.01),其中男性和女性上述基因型和等位基因频率的比较,易损斑块组均高于稳定斑块组,两组差异有统计学意义(P＜0.01).结论 ALOX5AP基因SG13S114 A/T多态性可能与动脉粥样斑块的稳定性有关,其中SG13S114 A等位基因可能是易损斑块的风险因素.     

The role of leukotriene receptor antagonists in the treatment of chronic asthma in childhood

A considerable increase in the prevalence of childhood asthma over the last few decades has been mirrored by a dramatic increase in usage of anti-asthma drugs; however, there has been no reduction in the numbers of patients dying of asthma. Concern has been expressed about the development of tolerance with continuous use of inhaled β-agonist bronchodilators and about the potential adverse systemic effects of high-dose inhaled corticosteroids in children. Moreover, patient compliance with inhaled therapy tends to be poor. The leukotriene receptor antagonists, including montelukast, pranlukast and zafirlukast, are orally administered agents with proven benefits in asthma. In a large, placebo-controlled pediatric trial, montelukast significantly ( P <0.02) reduced requirements for rescue β-agonist bronchodilators, improved quality of life, reduced the circulating level of blood eosinophils and produced improvements in lung function. In adult studies, montelukast reduced sputum eosinophils and attenuated early and late phase allergen-induced reactions. Montelukast has also demonstrated protective effects against exercise-induced bronchospasm in both adults and children, and this protection was maintained during the trough period at the end of the once-daily administration interval (namely, 20–24 h post-dose). Several studies have demonstrated that the formation of cysteinyl leukotrienes in the airways of asthmatic patients is not suppressed by corticosteroids; thus, it is not surprising that montelukast demonstrates complementary effects when given with inhaled corticosteroids. Currently, the most compelling evidence from published trials suggests that leukotriene receptor antagonists can be used as add-on therapy to inhaled corticosteroids to allow tapering of corticosteroid dose and reduction in β-agonist use. Recent clinical trial results suggest there may also be a role for these agents as first-line therapy in children with mild asthma.     

HLA Dr-Dq haplotypes and the TNFA-308 polymorphism: associations with asthma and allergy

BACKGROUND: The HLA (human leukocyte antigen) class II genes DQB1 and DRB1 and the Tumor Necrosis Factor alpha gene (TNFA) within the HLA complex (chromosome 6p21) have been associated with asthma and allergy. Due to the strong linkage disequilibrium characterizing this complex and the multiple asthma/allergy expressions, we aimed to determine which of these genes were primarily involved in specific asthma/allergy traits. METHODS: The DRB1-DQB1 alleles and TNFA-308 polymorphism were genotyped in 959 children from the Environment and Childhood Asthma study and analyzed for possible associations with allergic and non-allergic asthma (with/without at least one positive skin prick test for allergens) and specific allergic sensitization, as well as bronchial hyperresponsiveness and total IgE, using both allele and extended haplotype analyses. RESULTS: Different genes within the HLA complex were associated with separate asthma and allergy traits. Nonallergic asthma was associated with both the TNFA-308A allele [Odds ratio (OR) 1.7 (1.3-2.3)] and DRB1 03 allele [OR 1.6(1-2.6)], but extended DRB1 03-TNFA-308 haplotype analysis suggested that the DRB1-DQB1 association was secondary to linkage disequilibrium with the TNFA-308 polymorphism. Allergies were associated with HLA class II alleles only; birch sensitization with DQB1 0603-DRB1 13 [OR 2.3 (1.4-4.0)] and mugwort sensitization with DQB1 0609-DRB1 13 [OR 7.1 (1.9-27.0)] and DQB1 0501-DRB1 01 [OR 2.0 (1.0-4.0)]. CONCLUSIONS: Our data suggests that asthma is not associated with DRB1 or DQB1 but rather TNFA or a gene(s) in linkage disequilibrium, while sensitization to specific allergens is associated with particular alleles at the DQ and/or DR loci. A novel association between DQB1 0603-DRB1 13 and birch allergy is identified.