RESUMO
BACKGROUND: Allergic asthma is a complex disorder that results from a combination of genetic and environmental factors. Studies suggest that helminth infections can activate a regulatory network characterized by the production of regulatory cytokines, such as interleukin 10 and transforming growth factor ß1 (TGF-ß1) and subsequently protect against immune-mediated diseases, such as asthma. On the other hand, TGF-ß1 is increased in the lungs of individuals with asthma and may modulate airway inflammation. The role of TGF- ß 1 single-nucleotide polymorphisms (SNPs) in allergic disease remains inconclusive. OBJECTIVE: To evaluate the effects of genetic variations in the TGF-ß1 on allergy and helminths infections in children. METHODS: We tested for association among 4 TGF-ß1 SNPs and allergic asthma, specific IgE, skin prick test result, and IL-10 production in 1,335 Brazilians. In addition, we analyzed the association with markers of helminth infection (parasite burden, anti-Ascaris IgE, and worm specific IgG4). The polymorphisms were genotyped using Taq Man probes. RESULTS: We found an association between rs1800470 (C allele) and atopic wheezing (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.37-0.95) and markers of allergy (OR, 0.41; 95% CI, 0.22-0.79). In contrast, a positive association was observed between the haplotype ACCA and Trichuris trichiura infection (OR, 1.85; P = .003) and Ascaris lumbricoides infection (OR, 2.01; P < .001). This haplotype was also associated with increased IL-10 production (ß = 50.7; P < .001). CONCLUSION: Individuals with TGF-ß1 polymorphisms have an increased susceptibility to helminth infections and a lower risk of developing allergy. These studies suggest that immune modulation of allergic disease results not only from environmental factors but also from genetic susceptibility and IL-10 production.
Assuntos
Asma/etiologia , Etnicidade , Predisposição Genética para Doença , Helmintíase/etiologia , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Alelos , Asma/epidemiologia , Brasil/epidemiologia , Brasil/etnologia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Helmintíase/epidemiologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/metabolismo , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Testes CutâneosRESUMO
BACKGROUND: Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. OBJECTIVE: We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. METHODS: We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. RESULTS: We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. CONCLUSIONS: We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.