RESUMO
BACKGROUND: Environmental pollutants, which coexist with allergens, have been associated with the exacerbation of asthma. However, the underlying molecular mechanisms remain elusive. We sought to determine whether benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced asthma and its underlying mechanisms. METHODS: The effect of BaP was investigated in Der f 1-induced mouse model of asthma, including airway hyper-responsiveness, allergic inflammation, and epithelial-derived cytokines. The impact of BaP on Der f 1-induced airway epithelial cell oxidative stress (ROS) and cytokine release was further analyzed. The role of aryl hydrocarbon receptor (AhR) signaling in BaP-promoted Der f 1-induced ROS, cytokine production, and allergic inflammation was also investigated. RESULTS: Compared with Der f 1, BaP co-exposure with Der f 1 led to airway hyper-responsiveness and increased lung inflammation in mouse model of asthma. Increased expression of TSLP, IL-33, and IL-25 was also found in the airways of these mice. Moreover, BaP co-exposure with Der f 1 activated AhR signaling with increased expression of AhR and CYP1A1 and promoted airway epithelial ROS generation and TSLP and IL-33, but not IL-25, expression. Interestingly, AhR antagonist CH223191 or cells with AhR knockdown abrogated the increased expression of ROS, TSLP, and IL-33. Furthermore, ROS inhibitor N-acetyl-L-cysteine (NAC) also suppressed BaP co-exposure-induced expression of epithelial TSLP, IL-33, and IL-25. Finally, AhR antagonist CH223191 and NAC inhibited BaP co-exposure with Der f 1-induced lung inflammation. CONCLUSIONS: Our findings suggest that BaP facilitates Der f 1-induced epithelial cytokine release through the AhR-ROS axis.
Assuntos
Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Asma/etiologia , Asma/metabolismo , Benzo(a)pireno/efeitos adversos , Cisteína Endopeptidases/imunologia , Citocinas/biossíntese , Receptores de Hidrocarboneto Arílico/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Alérgenos/imunologia , Animais , Modelos Animais de Doenças , Poluentes Ambientais/efeitos adversos , Células Epiteliais/metabolismo , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: The innate pattern recognition C-type-lectin receptors (CLRs), including mannose receptor (MRC1; CD206), have been suggested to functionally interact with allergens and are critical in controlling immune response. Fibrocytes have been considered to play a role in allergic asthma. Here we sought to investigate the functional interaction of cockroach allergens with CD206 in fibrocytes. METHODS: Profiling of N-linked glycans from natural purified cockroach allergen Bla g 2 was accomplished by MALDI-MS. The binding activity of cockroach allergens to CD206 was determined by solid-phase binding assays. Levels of CD206 expression on human fibrocytes and CD206 mediated signaling and cytokine production in Bla g 2 treated fibrocytes were determined. RESULTS: Profiling of N-linked glycans from Bla g 2 revealed a predominance of small, mannose-terminated glycans with and without fucose. Significant binding of Bla g 2 to CD206 was observed, which was inhibited by yeast mannan (a known CD206 ligand), free mannose, and a blocking antibody (anti-hMR). Flow cytometric analyses of human fibrocytes (CD45(+) and collagen-1(+)) showed selective expression of CD206 on fibrocytes. Functionally, a concentration-dependent uptake of FITC labeled Bla g 2 by fibrocytes was observed, but was significantly inhibited by anti-hMR. Bla g 2 can stimulate up-regulation of inflammatory cytokines including TNF-alpha and IL-6 and activation of nuclear factor kappa B (NF-kB/p65), p38 mitogen-activated protein kinase (p38), ERK, and JNK in cultured fibrocytes. This increased secretion of TNF-alpha and IL-6 and activation of NF-kB, ERK, and JNK was significantly inhibited by the addition of either mannan or mannose. Furthermore, Bla g 2 induced increase in TNF-alpha and IL-6 production was also inhibited by the use of NF-kB, ERK, and JNK inhibitors. CONCLUSION: These results provide evidence supporting the existence of a functional cockroach allergen-CD206 axis in human fibrocytes, suggesting a role for CD206 in regulating allergen induced allergic responses in asthma.
Assuntos
Alérgenos/imunologia , Baratas/imunologia , Lectinas Tipo C/imunologia , Lectinas de Ligação a Manose/imunologia , Células-Tronco Mesenquimais/imunologia , Receptores de Superfície Celular/imunologia , Alérgenos/metabolismo , Alérgenos/farmacologia , Animais , Ácido Aspártico Endopeptidases/imunologia , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/farmacologia , Western Blotting , Células Cultivadas , Baratas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Lectinas Tipo C/metabolismo , Mananas/metabolismo , Mananas/farmacologia , Manose/metabolismo , Manose/farmacologia , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Receptores de Superfície Celular/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismoRESUMO
OBJECTIVE: The gene (SCGB1A1) encoding Clara cell 10-kDa protein (CC10), a steroid-inducible immune modulator, is a candidate gene for asthma, but the evidence is equivocal. The potential influence of a common variant on asthma severity and serum CC10 levels during acute exacerbation and after corticosteroid treatment in Chinese case-control children and its functional relevance was investigated. METHODS: Genotyping of a non-coding variant G+38A was performed in 489 children, of whom 277 had asthma with varying severity, and 212 healthy controls. Associations were tested for asthma, asthma severity, and responsiveness to steroid treatment. The transcriptional activity of this variant was examined in a Clara-like cell line (H358) using transient transfection assays. RESULTS: Significant association was observed for the combined GA and AA genotypes of the CC10 G+38A variant and an increased risk of asthma [odds ratio (OR), 2.62, p < .001]. This association was correlated with asthma severity (moderate: OR, 2.85, p < .001; near-fatal: OR, 4.81, p < .001). Also, patients with the GA and AA genotypes showed significantly lower serum CC10 (p < .01) and provocation concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1)) (p < .0001) when compared with those with the GG. After glucocorticoid treatment, the CC10 levels were significantly increased in asthmatic patients with GG (p < .0001), but not those with the GA and AA genotypes. Moreover, a lower dexamethasone-induced reporter (luciferase) activity was observed for H358 cells transiently transfected with the G38A risk allele (A) compared with wild-type allele (G). CONCLUSIONS: These findings suggest that the CC10 G+38A variant may contribute to the severity of asthma and lower level of steroid responsiveness.
Assuntos
Corticosteroides/uso terapêutico , Povo Asiático/genética , Asma/genética , Polimorfismo Genético , Uteroglobina/genética , Asma/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Regiões Promotoras Genéticas , Uteroglobina/sangueRESUMO
Interferon regulatory factor 2 (IRF2) is a member of a family of transcriptional factors involved in the modulation of IFN-induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of atopic dermatitis (AD) and ADEH (atopic dermatitis complicated by eczema herpeticum), we genotyped 78 IRF2 tagging single-nucleotide polymorphisms (SNPs) in both European-American (n = 435) and African-American (n = 339) populations. Significant associations were observed between AD and two SNPs (rs793814, P = 0.007, odds ratio (OR) = 0.52; rs3756094, P = 0.037, OR = 0.66) among European Americans and one SNP (rs3775572, P = 0.016, OR = 0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs (P = 0.049-0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a five-SNP (CAGGA) haplotype showed the strongest association with ADEH (P = 0.0008). Eight IRF2 SNPs were significantly associated with IFN-γ production after herpes simplex virus (HSV) stimulation (P = 0.048-0.0008), including an AD-associated SNP (rs13139310, P = 0.008). Our findings suggest that distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.
Assuntos
Dermatite Atópica/genética , Variação Genética , Fator Regulador 2 de Interferon/genética , Erupção Variceliforme de Kaposi/genética , População Negra/genética , População Negra/estatística & dados numéricos , Dermatite Atópica/etnologia , Dermatite Atópica/imunologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Erupção Variceliforme de Kaposi/etnologia , Erupção Variceliforme de Kaposi/imunologia , Masculino , Polimorfismo de Nucleotídeo Único , Simplexvirus/imunologia , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: The basis for increased susceptibility of patients with atopic dermatitis (AD) to develop disseminated viral skin infections such as eczema herpeticum (AD with a history of eczema herpeticum, ADEH(+)) is poorly understood. OBJECTIVE: We sought to determine whether subjects with AD prone to disseminated viral skin infections have defects in their IFN responses. METHODS: GeneChip profiling was used to identify differences in gene expression of PBMCs from patients with ADEH(+) compared with patients with AD without a history of eczema herpeticum (ADEH(-)) and nonatopic controls. Key differences in protein expression were verified by enzyme-linked immunosorbent spot assay and/or ELISA. Clinical relevance was further demonstrated by a mouse model of disseminated viral skin infection and genetic association analysis for genetic variants in IFNG and IFNGR1 and ADEH among 435 cases and controls. RESULTS: We demonstrate by global gene expression analysis selective transcriptomic changes within the IFN superfamily of PBMCs from subjects with ADEH(+) reflecting low IFN-γ and IFN-γ receptor gene expression. IFN-γ protein production was also significantly lower in patients with ADEH(+) (n = 24) compared with patients with ADEH(-) (n = 20) and nonatopic controls (n = 20). IFN-γ receptor knockout mice developed disseminated viral skin infection after epicutaneous challenge with vaccinia virus. Genetic variants in IFNG and IFNGR1 single nucleotide polymorphisms (SNPs) were significantly associated with ADEH (112 cases, 166 controls) and IFN-γ production: a 2-SNP (A-G) IFNGR1 haplotype (rs10457655 and rs7749390) showed the strongest association with a reduced risk of ADEH+ (13.2% ADEH(+) vs 25.5% ADEH(-); P = .00057). CONCLUSION: Patients with ADEH(+) have reduced IFN-γ production, and IFNG and IFNGR1 SNPs are significantly associated with ADEH(+) and may contribute to an impaired immune response to herpes simplex virus.
Assuntos
Dermatite Atópica/complicações , Dermatite Atópica/genética , Interferon gama/genética , Erupção Variceliforme de Kaposi/complicações , Erupção Variceliforme de Kaposi/genética , Animais , Dermatite Atópica/imunologia , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Interferon gama/imunologia , Erupção Variceliforme de Kaposi/imunologia , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Receptor de Interferon gamaRESUMO
BACKGROUND: The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. OBJECTIVE: We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. METHODS: We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. RESULTS: A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. CONCLUSION: These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.
Assuntos
Citocinas/genética , Eosinofilia/genética , Esofagite/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Criança , Pré-Escolar , Citocinas/fisiologia , Eosinofilia/etiologia , Esofagite/etiologia , Feminino , Humanos , Lactente , Masculino , Receptores de Citocinas/genética , Linfopoietina do Estroma do TimoAssuntos
Citocinas/genética , Dermatite Atópica/genética , Erupção Variceliforme de Kaposi/genética , Receptores de Citocinas/genética , Receptores de Interleucina-7/genética , Citocinas/imunologia , Citocinas/metabolismo , Análise Mutacional de DNA , Dermatite Atópica/imunologia , Dermatite Atópica/fisiopatologia , Frequência do Gene , Estudos de Associação Genética , Variação Genética , Humanos , Erupção Variceliforme de Kaposi/imunologia , Erupção Variceliforme de Kaposi/fisiopatologia , Polimorfismo de Nucleotídeo Único , Grupos Raciais , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcvarepsilonRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 x 10(-5)) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6'-sulfo-sLe(x), a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.
Assuntos
Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Asma/genética , Predisposição Genética para Doença , Lectinas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Negro ou Afro-Americano/genética , Povo Asiático/genética , Asma/etnologia , Brasil , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections. OBJECTIVE: We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. METHODS: Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects. RESULTS: Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects (P = 1.46 x 10(-5), 3.87 x 10(-5), respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio [OR], 3.4; 1.7-6.8; P = .0002). Associations with ADEH were stronger with the combined null mutations (OR, 10.1; 4.7-22.1; P = 1.99 x 10(-11)). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH and rare (<1%) among healthy individuals. CONCLUSION: The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition.
Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença , Proteínas de Filamentos Intermediários/genética , Erupção Variceliforme de Kaposi/genética , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Feminino , Proteínas Filagrinas , Frequência do Gene , Haplótipos/genética , Haplótipos/imunologia , Humanos , Lactente , Proteínas de Filamentos Intermediários/imunologia , Proteínas de Filamentos Intermediários/metabolismo , Erupção Variceliforme de Kaposi/imunologia , Erupção Variceliforme de Kaposi/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Pele/imunologia , Pele/patologia , Adulto JovemRESUMO
Atopic dermatitis (AD) is a common inflammatory skin disease associated with the local infiltration of T helper type 2 (Th2) cells. The ST2 gene encodes both membrane-bound ST2L and soluble ST2 (sST2) proteins by alternative splicing. The orphan receptor ST2L is functionally indispensable for Th2 cells. We found a significant genetic association between AD and the -26999G/A single nucleotide polymorphism (SNP) (chi2-test, raw P-value=0.000007, odds ratio 1.86) in the distal promoter region of the ST2 gene (chromosome 2q12) in a study of 452 AD patients and 636 healthy controls. The -26999A allele common among AD patients positively regulates the transcriptional activity of the ST2 gene. In addition, having at least one -26999A allele correlated with high sST2 concentrations and high total IgE levels in the sera from AD patients. Thus, the -26999A allele is correlated with an increased risk for AD. We also found that the -26999G/A SNP predominantly affected the transcriptional activity of hematopoietic cells. Immunohistochemical staining of a skin biopsy specimen from an AD patient in the acute stage showed ST2 staining in the keratinocytes as well as in the infiltrating cells in the dermal layer. Our data show that functional SNPs in the ST2 distal promoter region regulate ST2 expression which induces preferential activation of the Th2 response. Our findings will contribute to the evaluation of one of the genetic risk factors for AD.
Assuntos
Dermatite Atópica/imunologia , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Alelos , Estudos de Casos e Controles , Dermatite Atópica/genética , Fibroblastos/química , Fibroblastos/metabolismo , Genes Reporter , Haplótipos , Células-Tronco Hematopoéticas/química , Células-Tronco Hematopoéticas/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Queratinócitos/química , Queratinócitos/metabolismo , Mastócitos/química , Mastócitos/metabolismo , Proteínas de Membrana/análise , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular , Células Th2/imunologia , Transcrição GênicaRESUMO
BACKGROUND: The T-cell immunoglobulin mucin ( TIM ) proteins and their genetic variants have been suggested to play a role in regulating allergic diseases. OBJECTIVE: Genetic association of the sequence variants for TIM-1 and TIM-3 genes with asthma in an African American population was investigated. METHODS: Both case-control and family-based association analyses were performed for a total of 7 polymorphisms, including 3 single nucleotide polymorphism (SNPs) and 1 insertion/deletion polymorphism in the TIM-1 and 3 SNPs in the TIM-3 genes. The exposure to hepatitis A virus as judged by seropositivity was also examined. RESULTS: In the case-control design, the frequencies of the TT genotype for SNP rs2277025 and the homozygous deletion variant (157delMTTTVP) in the fourth exon of the TIM-1 gene were higher among patients with patients with asthma compared with the controls (odds ratio [OR], 2.779, P = .016; and OR, 3.09, P = .022, respectively). This association was substantiated by haplotype analysis of these and 2 additional SNPs (OR, 2.48; P = .004), and also by family-based tests for the allele and haplotype carrying 157delMTTTVP (P = .009 and P = .048, respectively). Furthermore, this association seems to exist even in the hepatitis A virus-seronegative subjects in our data. None of the 3 variants in TIM-3 genes yielded significant association with either asthma or asthma-related phenotypes. CONCLUSION: Our findings suggest that the genetic variants of the TIM-1 but not the TIM-3 gene contribute to asthma susceptibility in this African-American population.
Assuntos
Asma/genética , Negro ou Afro-Americano/genética , Predisposição Genética para Doença , Imunoglobulinas/genética , Mucinas/genética , Linfócitos T/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Hepatite A/sangue , Anticorpos Anti-Hepatite A/sangue , Receptor Celular 1 do Vírus da Hepatite A , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Polimorfismo Genético , Receptores Virais/genética , Estudos SoroepidemiológicosRESUMO
The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.003) of SNP rs545659. Haplotype analysis yielded additional evidence of linkage disequilibrium for the 1544G-1651G haplotype (P < 0.001). Population-based case-control analyses were conducted in two independent populations, and demonstrated significant association of the 1544G-1651G haplotype with asthma in an African American population (P = 0.004), and in a population of Chinese children (P < 0.001). Moreover, in the Chinese children the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (P = 0.001) and normal controls (P < 0.001). The 1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027). Transcriptional pulsing experiments showed that the 1544G-1651G haplotype confers a significantly higher level of reporter mRNA stability, when compared with a non-transmitted haplotype (1544C-1651A), suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.