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Background: Asthma is a chronic inflammatory disease of the airways that is heterogeneous and multifactorial, making its accurate characterization a complex process. Therefore, identifying the genetic variations associated with asthma and discovering the molecular interactions between the omics that confer risk of developing this disease will help us to unravel the biological pathways involved in its pathogenesis. Objective: We sought to develop a predictive genetic panel for asthma using machine learning methods. Methods: We tested 3 variable selection methods: Boruta's algorithm, the top 200 genome-wide association study markers according to their respective P values, and an elastic net regression. Ten different algorithms were chosen for the classification tests. A predictive panel was built on the basis of joint scores between the classification algorithms. Results: Two variable selection methods, Boruta and genome-wide association studies, were statistically similar in terms of the average accuracies generated, whereas elastic net had the worst overall performance. The predictive genetic panel was completed with 155 single-nucleotide variants, with 91.18% accuracy, 92.75% sensitivity, and 89.55% specificity using the support vector machine algorithm. The markers used range from known single-nucleotide variants to those not previously described in the literature. Our study shows potential in creating genetic prediction panels with tailored penalties per marker, aiding in the identification of optimal machine learning methods for intricate results. Conclusions: This method is able to classify asthma and nonasthma effectively, proving its potential utility in clinical prediction and diagnosis.
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Congenital Zika virus syndrome (CZS) is associated with damage to neural progenitor cells by ZIKA virus infection. There are no accurate statistics on the percentage of pregnant mothers who have had babies affected by the syndrome. Few cases of discordant twins have been described in the literature and, therefore, we hypothesize that the genetic background of the progeny and/or mother may play a role in the fate of the syndrome. We performed a complete exome sequencing in a set of dizygotic individuals and their parents. After that, we selected discordant variants on the MTOR gene between the affected and unaffected twin and we observed a mutation (rs2295079), placed in a region restricted to proximal 5'-UTR, as a strong possible causal variant. In addition, in most brain tissues (including fetal brain) evaluated for expression quantitative trait loci (eQTL), this locus is strongly correlated with post-translational modifications of histones (promoter and enhancer marks) and hypersensitivity to DNAse I (open chromatin mark). Taken together, our data suggest that changes in the MTOR gene may be related to CZS. Additional functional studies should be carried out to prove how and why a MTOR mutation can predispose the fetus to the syndrome.
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BACKGROUND: Genetic ancestry plays a role in asthma health disparities. OBJECTIVE: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. METHODS: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. RESULTS: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV1 percent predicted values (P < .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10-10) and was independent of an association with the haplotype HLA-DQA1â¼HLA-DQB1:04.01â¼04.02 (P = 1.55 × 10-05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005). CONCLUSION: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.
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Asma/genética , Genotipo , Inmunoglobulina E/metabolismo , Pueblos Indígenas , Pulmón/metabolismo , Adolescente , Américas , Asma/epidemiología , Niño , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA-DQ/metabolismo , Humanos , Pulmón/inmunología , Masculino , Perú/epidemiología , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética , España , Adulto JovenRESUMEN
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.
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Asma/etiología , Etnicidad , Predisposición Genética a la Enfermedad , Helmintiasis/etiología , Polimorfismo Genético , Factor de Crecimiento Transformador beta1/genética , Alelos , Asma/epidemiología , Brasil/epidemiología , Brasil/etnología , Niño , Preescolar , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Helmintiasis/epidemiología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Interleucina-10/metabolismo , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Pruebas CutáneasRESUMEN
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.
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Enfermedades Endémicas , Proteína 1 Similar al Receptor de Interleucina-1/genética , Cirrosis Hepática/genética , Hígado/patología , Schistosoma japonicum/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis/genética , Adulto , Animales , Brasil/epidemiología , China/epidemiología , Enfermedad Crónica , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Fibrosis , Genotipo , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Interleucina-33/metabolismo , Hígado/parasitología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Esquistosomiasis/complicaciones , Esquistosomiasis/epidemiologíaRESUMEN
Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (ß = 1.3, P = 0.04), Barbadians (ß = 3.8, P = 0.03), and Brazilians (ß = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.
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Asma/etnología , Asma/genética , Población Negra/genética , Inmunoglobulina E/genética , Negro o Afroamericano/genética , Algoritmos , Asma/epidemiología , Barbados , Brasil , Estudios de Casos y Controles , Colombia , District of Columbia , Predisposición Genética a la Enfermedad , Humanos , Inmunoglobulina E/sangre , Jamaica , Modelos Estadísticos , Epidemiología Molecular , New York , Factores de Riesgo , Población Blanca/genéticaRESUMEN
BACKGROUND: Helminth infections are associated with protection against allergies. It is postulated that IL-10 production after helminth infection suppresses skin hypersensitivity and increases IgG4 production, protecting against allergies. OBJECTIVE: We aimed to determine whether IL10 polymorphisms are associated with helminth infection and the risk of wheeze and allergy. METHODS: Twelve IL10 single nucleotide polymorphisms were genotyped in 1353 children aged 4 to 11 years living in a poor urban area in Salvador, Brazil. Wheezing status, Ascaris lumbricoides and Trichuris trichiura infection, IL-10 production by peripheral blood leukocytes stimulated with A lumbricoides extract, serum total IgE levels, specific IgE levels, skin prick test responses to common aeroallergens, and IgG4 and IgE anti-A lumbricoides antibody levels were measured in all children. Association tests were performed by using logistic or linear regression when appropriate, including sex, age, helminth infection, and principal components for ancestry informative markers as covariates by using PLINK. RESULTS: Allele G of marker rs3024496 was associated with the decreased production of IL-10 by peripheral blood leukocytes in response to A lumbricoides stimulation. Allele C of marker rs3024498 was negatively associated with helminth infection or its markers. Marker rs3024492 was positively associated with the risk of atopic wheeze, total IgE levels, and skin prick test responses to cockroach. CONCLUSIONS: Our findings suggest that IL10 polymorphisms might play a role in the production of IL-10, helminth infection, and allergy. We hypothesize that polymorphisms related to protection against helminths, which would offer an evolutionary advantage to subjects in the past, might be associated with increased risk of allergic diseases.
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Asma/epidemiología , Asma/etiología , Helmintiasis/complicaciones , Interleucina-10/biosíntesis , Interleucina-10/genética , Polimorfismo Genético , Ruidos Respiratorios/etiología , Adolescente , Alelos , Brasil/epidemiología , Niño , Preescolar , Femenino , Orden Génico , Ligamiento Genético , Genotipo , Humanos , Lactante , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Población UrbanaRESUMEN
BACKGROUND: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.
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Asma/genética , Población Negra/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Adulto , Negro o Afroamericano/genética , Barbados , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
African descended populations exhibit an increased prevalence of asthma and allergies compared to Europeans. One approach to distinguish between environmental and genetic explanations for this difference is to study relationships of asthma risk to individual admixture. We aimed to determine the admixture proportions of a case-control sample from the Caribbean Coast of Colombia currently participating in genetic studies for asthma, and to test for population stratification and association between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 368 asthmatics and 365 non-asthmatics for 52 autosomal ancestry informative markers, six mtDNA haplogroups and nine haplogroups and five microsatellites in Y chromosome. Autosomal admixture proportions, population stratification, and associations between ancestry and the phenotypes were estimated by ADMIXMAP. The average admixture proportions among asthmatics were 42.8% European, 39.9% African and 17.2% Native American and among non-asthmatics they were 44.2% (P = 0.068), 37.6% (P = 0.007) and 18.1% (P = 0.050), respectively. In the total sample, the paternal contributions were 71% European, 25% African and 4.0% Native American and the maternal lineages were 56.8% Native American, and 20.2% African; 22.9% of the individuals carried other non-Native American mtDNA haplogroups. African ancestry was significantly associated with asthma (OR: 2.97; 95% CI: 1.08-8.08), high tIgE (OR: 1.9; 95% CI: 1.17-3.12) and socioeconomic status (OR = 0.64; 95% CI: 0.47-0.87). Significant population stratification was observed in this sample. Our findings indicate that genetic factors can explain the association between asthma and African ancestry and suggest that this sample is a useful resource for performing admixture mapping for asthma.
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Asma/genética , Población Negra/genética , Genética de Población , Inmunoglobulina E/sangre , Adolescente , Adulto , Asma/epidemiología , Estudios de Casos y Controles , Cromosomas Humanos Y/genética , Colombia/epidemiología , ADN Mitocondrial/genética , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunoglobulina E/genética , Indígenas Norteamericanos/genética , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Factores de Riesgo , Análisis de Secuencia de ADN , Clase Social , Población Blanca/genética , Adulto JovenRESUMEN
RATIONALE: Asthma prevalence and severity are high among underserved minorities, including those of African descent. The Duffy antigen/receptor for chemokines is the receptor for Plasmodium vivax on erythrocytes and functions as a chemokine-clearing receptor. Unlike European populations, decreased expression of the receptor on erythrocytes is common among populations of African descent, and results from a functional T-46C polymorphism (rs2814778) in the promoter. This variant provides an evolutionary advantage in malaria-endemic regions, because Duffy antigen/receptor for chemokines-negative erythrocytes are more resistant to infection by P. vivax. OBJECTIVES: To determine the role of the rs2814778 polymorphism in asthma and atopy as measured by total serum IgE levels among four populations of African descent (African Caribbean, African American, Brazilian, and Colombian) and a European American population. METHODS: Family-based association tests were performed in each of the five populations to test for association between the rs2814778 polymorphism and asthma or total IgE concentration. MEASUREMENTS AND MAIN RESULTS: Asthma was significantly associated with the rs2814778 polymorphism in the African Caribbean, Colombian, and Brazilian families (P < 0.05). High total IgE levels were associated with this variant in African Caribbean and Colombian families (P < 0.05). The variant allele was not polymorphic among European Americans. CONCLUSIONS: Susceptibility to asthma and atopy among certain populations of African descent is influenced by a functional polymorphism in the gene encoding Duffy antigen/receptor for chemokines. This genetic variant, which confers resistance to malarial parasitic infection, may also partially explain ethnic differences in morbidity of asthma.