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BACKGROUND: Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations. METHODS: We performed family-based genome-wide association analyses of childhood-onset asthma based on whole-genome sequencing (WGS) data for the 'The Genetic Epidemiology of Asthma in Costa Rica' study (GACRS) and the Childhood Asthma Management Program (CAMP). Based on parent-child trios with children diagnosed with asthma, we performed a single variant analysis using an additive and a recessive genetic model and a region-based association analysis of low-frequency and rare variants. RESULTS: Based on 1180 asthmatic trios (894 GACRS trios and 286 CAMP trios, a total of 3540 samples with WGS data), we identified three novel genetic loci associated with childhood-onset asthma: rs4832738 on 4p14 ($P=1.72\ast{10}^{-9}$, recessive model), rs1581479 on 8p22 ($P=1.47\ast{10}^{-8}$, additive model) and rs73367537 on 10q26 ($P=1.21\ast{10}^{-8}$, additive model in GACRS only). Integrative analyses suggested potential novel candidate genes underlying these associations: PGM2 on 4p14 and FGF20 on 8p22. CONCLUSION: Our family-based whole-genome sequencing analysis identified three novel genetic loci for childhood-onset asthma. Gene expression data and integrative analyses point to PGM2 on 4p14 and FGF20 on 8p22 as linked genes. Furthermore, region-based analyses suggest independent potential low-frequency/rare variant associations on 8p22. Follow-up analyses are needed to understand the functional mechanisms and generalizability of these associations.
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Asma , Estudio de Asociación del Genoma Completo , Humanos , Predisposición Genética a la Enfermedad , Asma/genética , Sitios Genéticos , Secuenciación Completa del Genoma , Polimorfismo de Nucleótido Simple/genética , Factores de Crecimiento de Fibroblastos/genéticaRESUMEN
BACKGROUND: Infection with rhinovirus (RV) is a major risk factor for disease exacerbations in patients with allergic asthma. This study analysed a broad set of cytokines in the noses of children and adults with asthma during RV infection in order to identify immunophenotypes that may link to virus-induced episodes. METHODS: Nasal wash specimens were analysed in children (n = 279 [healthy, n = 125; stable asthma, n = 64; wheeze, n = 90], ages 2-12) who presented to a hospital emergency department, and in adults (n = 44 [healthy, n = 13; asthma, n = 31], ages 18-38) who were experimentally infected with RV, including a subset who received anti-IgE. Cytokines were measured by multiplex bead assay and data analysed by univariate and multivariate methods to test relationships to viral load, allergic status, airway inflammation, and clinical outcomes. RESULTS: Analysis of a core set of 7 cytokines (IL-6, CXCL8/IL-8, IL-15, EGF, G-CSF, CXCL10/IP-10 and CCL22/MDC) revealed higher levels in children with acute wheeze versus those with stable asthma or controls. Multivariate analysis identified two clusters that were enriched for acutely wheezing children; one displaying high viral load ("RV-high") with robust secretion of CXCL10, and the other displaying high IgE with elevated EGF, CXCL8 and both eosinophil- and neutrophil-derived mediators. Broader assessment of 39 cytokines confirmed that children with acute wheeze were not deficient in type 1 anti-viral responses. Analysis of 18 nasal cytokines in adults with asthma who received RV challenge identified two clusters; one that was "RV-high" and linked to robust induction of anti-viral cytokines and anti-IgE; and the other associated with more severe symptoms and a higher inflammatory state featuring eosinophil and neutrophil factors. CONCLUSIONS: The results confirm the presence of different immunophenotypes linked to parameters of airway disease in both children and adults with asthma who are infected with RV. Such discrepancies may reflect the ability to regulate anti-viral responses.
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Asma , Infecciones por Enterovirus , Infecciones por Picornaviridae , Adolescente , Adulto , Quimiocina CXCL10 , Niño , Preescolar , Análisis por Conglomerados , Citocinas , Infecciones por Enterovirus/complicaciones , Factor de Crecimiento Epidérmico , Factor Estimulante de Colonias de Granulocitos , Humanos , Interleucina-15 , Interleucina-6 , Interleucina-8 , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/diagnóstico , Ruidos Respiratorios , Rhinovirus , Adulto JovenRESUMEN
Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34-1.79, p=6.3×10-9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (ß=0.10, p=2.18×10-7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).
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Asma , Estudio de Asociación del Genoma Completo , Adolescente , Asma/genética , Brasil , Niño , Hispánicos o Latinos/genética , Humanos , Puerto RicoRESUMEN
Our aim is to review current asthma epidemiology, achievements from the last 10 years, and persistent challenges of asthma management and control in low-middle income countries (LMICs). Despite global efforts, asthma continues to be an important public health problem worldwide, particularly in poorly resourced settings. Several epidemiological studies in the last decades have shown significant variability in the prevalence of asthma globally, but generally a marked increase in LMICs resulting in significant morbidity and mortality. Poverty, air pollution, climate change, exposure to indoor allergens, urbanization and diet are some of the factors that contribute to inadequate control and poor outcomes in developing countries. Although asthma guidelines have been developed to raise awareness and improve asthma diagnosis and treatment, problems with underdiagnosis and undertreatment are still common. In addition, important social, financial, cultural and healthcare barriers are common obstacles in LMICs in achieving control. Given the high burden of asthma in these countries, adaptation and implementation of national asthma guidelines tailored to local needs should be a public health priority. Governmental commitment, education, better health system infrastructure, access to care and effective asthma medications are the cornerstone of achieving success. CONCLUSION: Asthma poses significant challenges to LMICs. Whilst there are ongoing efforts in improving asthma diagnosis and decreasing asthma burden in LMICs; reasons for inadequate asthma control are also common and difficult to tackle. Improving asthma diagnosis, access to appropriate treatment and decreasing risk factors should be key goals to reduce asthma morbidity and mortality worldwide.
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Asma/epidemiología , Países en Desarrollo , Contaminación del Aire/estadística & datos numéricos , Contaminación del Aire Interior/estadística & datos numéricos , Alérgenos , Asma/diagnóstico , Asma/terapia , Niño , Cambio Climático/estadística & datos numéricos , Errores Diagnósticos , Dieta/estadística & datos numéricos , Humanos , Pobreza/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Salud Pública , Política Pública , Factores de Riesgo , Urbanización/tendenciasRESUMEN
De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of CâA and TâC mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
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Amish/genética , Genoma Humano , Adulto , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Genética de Población , Heterocigoto , Humanos , Masculino , Mutación , Linaje , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
The role of metabolism in modifying age-related differential responses to asthma medications is insufficiently understood. The objective of this study was to determine the role of the metabolome in modifying the effect of age on bronchodilator response (BDR) in individuals with asthma. We used longitudinal measures of BDR and plasma metabolomic profiling in 565 children with asthma from the Childhood Asthma Management Program (CAMP) to identify age by metabolite interactions on BDR. The mean ages at the three studied time-points across 16 years of follow-up in CAMP were 8.8, 12.8, and 16.8 years; the mean BDRs were 11%, 9% and 8%, respectively. Of 501 identified metabolites, 39 (7.8%) demonstrated a significant interaction with age on BDR (p-value < 0.05). We were able to validate two significant interactions in 320 children with asthma from the Genetics of Asthma in Costa Rica Study; 2-hydroxyglutarate, a compound involved in butanoate metabolism (interaction; CAMP: ß = -0.004, p = 1.8 × 10-4; GACRS: ß = -0.015, p = 0.018), and a cholesterol ester; CE C18:1 (CAMP: ß = 0.005, p = 0.006; GACRS: ß = 0.023, p = 0.041) Five additional metabolites had a p-value < 0.1 in GACRS, including Gammaminobutyric acid (GABA), C16:0 CE, C20:4 CE, C18.0 CE and ribothymidine. These findings suggest Cholesterol esters and GABA may modify the estimated effect of age on bronchodilator response.
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BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10-8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10-3), postbronchodilator (PB) FEV1 (7.3 × 10-3), and PB FEV1/FVC ratio (P = 2.7 × 10-3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
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Asma/genética , Asma/fisiopatología , Moléculas de Adhesión Celular/genética , Volumen Espiratorio Forzado/genética , Factores Reguladores del Interferón/genética , Capacidad Vital/genética , Secuenciación Completa del Genoma , Adolescente , Adulto , Niño , Preescolar , Costa Rica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenómenos Fisiológicos Respiratorios/genética , Adulto JovenRESUMEN
BACKGROUND: Rhinovirus (RV) infections exacerbate asthma in part by enhancing an allergic state, and these exacerbations can be mitigated via administration of anti-IgE. OBJECTIVE: We investigated the presence of local IgE production in the nose of allergic and non-allergic subjects and assessed whether this was enhanced by RV. METHODS: Local production of specific IgE was determined by comparing ratios of specific to total IgE concentrations between nasal and serum samples. Our initial studies were performed in subjects presenting to the emergency department for allergic and non-allergic respiratory complaints. Subsequently, we investigated influences of experimental RV infection on nasal sIgE production in an allergic cohort. RESULTS: We found evidence of local sIgE production to Dermatophagoides pteronyssinus in 30.3% and to Blomia tropicalis in 14.6% of allergic subjects. None of the non-allergic subjects demonstrated local IgE. Subjects with active RV infection were more than twice as likely to have local sIgE (45% vs 14%), and subjects with local sIgE being produced were ~3 times more likely to be having an asthma exacerbation. Experimental RV infection was able to induce local sIgE production. CONCLUSION: These studies confirm local IgE production in a large subset of allergic subjects and demonstrate that allergic asthmatics with local IgE are more likely to develop an asthma exacerbation when infected with RV. Our RV challenge studies demonstrate that at least some allergic asthmatics can be induced to secrete locally generated IgE in their nasal airway after RV infection.
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Inmunoglobulina E/inmunología , Mucosa Nasal/inmunología , Infecciones por Picornaviridae/inmunología , Rinitis Alérgica/inmunología , Rhinovirus/inmunología , Animales , Niño , Dermatophagoides pteronyssinus/inmunología , Femenino , Humanos , Masculino , Rinitis Alérgica/virologíaRESUMEN
RATIONALE: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry. OBJECTIVES: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations. METHODS: GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies. MEASUREMENTS AND MAIN RESULTS: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV1 in ZSWIM7 (rs4791658; P = 4.99 × 10-9) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV1/FVC (P = 9.59 × 10-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV1, which replicated. A novel locus for FEV1 identified among ever smokers (rs291231; P = 1.92 × 10-8) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10-8) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level. CONCLUSIONS: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Población Blanca/genética , Adolescente , Adulto , Anciano , Estudios de Cohortes , Europa (Continente) , Femenino , Frecuencia de los Genes , Sitios Genéticos , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función Respiratoria , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes. OBJECTIVE: We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure. METHODS: A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study. RESULTS: Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10-8), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10-9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/forced vital capacity replicated in the independent cohorts. CONCLUSIONS: Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions.
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Antígenos Dermatofagoides/inmunología , Asma/inmunología , Interacción Gen-Ambiente , Pulmón/fisiología , Polimorfismo de Nucleótido Simple , Adolescente , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-17/metabolismo , Masculino , Unión Proteica , Puerto Rico , Pruebas de Función RespiratoriaAsunto(s)
Asma/genética , Hispánicos o Latinos/genética , Capacidad Vital/genética , Adolescente , Adulto , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Asma/fisiopatología , Broncodilatadores/uso terapéutico , Proteínas Portadoras/genética , Niño , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Femenino , Factores de Crecimiento de Fibroblastos/genética , Volumen Espiratorio Forzado/genética , Estudio de Asociación del Genoma Completo , Humanos , Hipoxantina Fosforribosiltransferasa/genética , Péptidos y Proteínas de Señalización Intracelular , Modelos Lineales , Masculino , Polimorfismo de Nucleótido Simple , Proteínas/genética , Puerto Rico/etnología , Resultado del Tratamiento , Adulto JovenRESUMEN
Consistent with the diversity of Latin America, there is profound variability in asthma burden among and within countries in this region. Regional variation in asthma prevalence is likely multifactorial and due to genetics, perinatal exposures, diet, obesity, tobacco use, indoor and outdoor pollutants, psychosocial stress and microbial or parasitic infections. Similarly, non-uniform progress in asthma management leads to regional variability in disease morbidity. Future studies of distinct asthma phenotypes should follow-up well-characterised Latin American subgroups and examine risk factors that are unique or common in Latin America (eg, stress and violence, parasitic infections and use of biomass fuels for cooking). Because most Latin American countries share the same barriers to asthma management, concerted and multifaceted public health and research efforts are needed, including approaches to curtail tobacco use, campaigns to improve asthma treatment, broadening access to care and clinical trials of non-pharmacological interventions (eg, replacing biomass fuels with gas or electric stoves).
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Asma/epidemiología , Asma/etiología , Humanos , América Latina/epidemiología , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: Gene-environment interaction studies using genome-wide association study data are often underpowered after adjustment for multiple comparisons. Differential gene expression in response to the exposure of interest can capture the most biologically relevant genes at the genome-wide level. OBJECTIVE: We used differential genome-wide expression profiles from the Epidemiology of Home Allergens and Asthma birth cohort in response to Der f 1 allergen (sensitized vs nonsensitized) to inform a gene-environment study of dust mite exposure and asthma severity. METHODS: Polymorphisms in differentially expressed genes were identified in genome-wide association study data from the Childhood Asthma Management Program, a clinical trial in childhood asthmatic patients. Home dust mite allergen levels (<10 or ≥10 µg/g dust) were assessed at baseline, and (≥1) severe asthma exacerbation (emergency department visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica Study and a Puerto Rico/Connecticut asthma cohort were used for replication. RESULTS: IL9, IL5, and proteoglycan 2 expression (PRG2) was upregulated in Der f 1-stimulated PBMCs from dust mite-sensitized patients (adjusted P < .04). IL9 polymorphisms (rs11741137, rs2069885, and rs1859430) showed evidence for interaction with dust mite in the Childhood Asthma Management Program (P = .02 to .03), with replication in the Genetics of Asthma in Costa Rica Study (P = .04). Subjects with the dominant genotype for these IL9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to increased dust mite levels. CONCLUSIONS: Genome-wide differential gene expression in response to dust mite allergen identified IL9, a biologically plausible gene target that might interact with environmental dust mite to increase severe asthma exacerbations in children.
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Antígenos Dermatofagoides/inmunología , Proteínas de Artrópodos/inmunología , Asma/genética , Asma/inmunología , Cisteína Endopeptidasas/inmunología , Dermatophagoides farinae/inmunología , Interacción Gen-Ambiente , Interleucina-9/genética , Leucocitos Mononucleares/fisiología , Animales , Células Cultivadas , Niño , Preescolar , Estudios de Cohortes , Costa Rica , Progresión de la Enfermedad , Servicios Médicos de Urgencia , Exposición a Riesgos Ambientales/efectos adversos , Proteína Mayor Básica del Eosinófilo/genética , Proteína Mayor Básica del Eosinófilo/metabolismo , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Interleucina-5/genética , Interleucina-5/metabolismo , Masculino , Polimorfismo de Nucleótido Simple , Proteoglicanos/genética , Proteoglicanos/metabolismo , Puerto Rico , Transcriptoma , Estados Unidos , Regulación hacia ArribaRESUMEN
RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.
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Ansiedad/complicaciones , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/genética , Estrés Psicológico/complicaciones , Adolescente , Ansiedad/diagnóstico , Ansiedad/etnología , Ansiedad/genética , Asma/complicaciones , Asma/etnología , Asma/genética , Estudios de Casos y Controles , Niño , Estudios Transversales , Regulación hacia Abajo , Femenino , Marcadores Genéticos , Genotipo , Humanos , Modelos Lineales , Masculino , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Puerto Rico , Receptores Adrenérgicos beta 2/genética , Rhode Island , Factores de Riesgo , Estrés Psicológico/diagnóstico , Estrés Psicológico/etnología , Resultado del TratamientoRESUMEN
RATIONALE: Genome-wide association studies (GWAS) of chronic obstructive pulmonary disease (COPD) have identified disease-susceptibility loci, mostly in subjects of European descent. OBJECTIVES: We hypothesized that by studying Hispanic populations we would be able to identify unique loci that contribute to COPD pathogenesis in Hispanics but remain undetected in GWAS of non-Hispanic populations. METHODS: We conducted a metaanalysis of two GWAS of COPD in independent cohorts of Hispanics in Costa Rica and the United States (Multi-Ethnic Study of Atherosclerosis [MESA]). We performed a replication study of the top single-nucleotide polymorphisms in an independent Hispanic cohort in New Mexico (the Lovelace Smokers Cohort). We also attempted to replicate prior findings from genome-wide studies in non-Hispanic populations in Hispanic cohorts. MEASUREMENTS AND MAIN RESULTS: We found no genome-wide significant association with COPD in our metaanalysis of Costa Rica and MESA. After combining the top results from this metaanalysis with those from our replication study in the Lovelace Smokers Cohort, we identified two single-nucleotide polymorphisms approaching genome-wide significance for an association with COPD. The first (rs858249, combined P value = 6.1 × 10(-8)) is near the genes KLHL7 and NUPL2 on chromosome 7. The second (rs286499, combined P value = 8.4 × 10(-8)) is located in an intron of DLG2. The two most significant single-nucleotide polymorphisms in FAM13A from a previous genome-wide study in non-Hispanics were associated with COPD in Hispanics. CONCLUSIONS: We have identified two novel loci (in or near the genes KLHL7/NUPL2 and DLG2) that may play a role in COPD pathogenesis in Hispanic populations.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Hispánicos o Latinos , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/etnología , Adolescente , Adulto , Anciano , Niño , Femenino , Volumen Espiratorio Forzado/fisiología , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estudios Retrospectivos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. OBJECTIVE: We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma. METHODS: eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. RESULTS: Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. CONCLUSIONS: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.
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Asma , Linfocitos T CD4-Positivos/inmunología , Ácido Graso Desaturasas , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , alfa-N-Acetilgalactosaminidasa , Asma/epidemiología , Asma/genética , Asma/inmunología , Asma/patología , Linfocitos T CD4-Positivos/patología , Niño , Preescolar , Costa Rica , Método Doble Ciego , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/inmunología , Femenino , Humanos , Masculino , alfa-N-Acetilgalactosaminidasa/genética , alfa-N-Acetilgalactosaminidasa/inmunologíaRESUMEN
BACKGROUND: Little is known about trends in morbidity and/or mortality due to asthma in Latin America. OBJECTIVE: To examine trends in hospitalizations and mortality due to asthma from 1997-2000 to 2011 in Costa Rica. METHODS: The rates of hospitalization due to asthma were calculated for each sex in 3 age groups from 1997 to 2011. The number of deaths due to asthma was first calculated for all groups and then for each sex in 3 age groups from 2000 to 2011. All analyses were conducted over the entire period and separately for the periods before and after a National Asthma Program (NAP) in 2003. Data also were available for prescriptions for beclomethasone since 2004. All analyses were conducted by using Epi Info. RESULTS: Substantial reductions were found in hospitalizations and deaths due to asthma in Costa Ricans (eg, from 25 deaths in 2000 to 5 deaths in 2011). Although, the percentage decrement in the rates of hospitalization for asthma in subjects <20 years old was similar before and after the NAP, the reduction in both deaths due to asthma and rates of asthma hospitalizations in older subjects were more pronounced after the NAP, when prescriptions for beclomethasone were also increased by approximately 129%. CONCLUSION: In Costa Rica, there was a marked decrement in hospitalizations and mortality due to asthma from 1997-2000 to 2011. In younger subjects, this is likely due to guidelines that, since 1988, recommend inhaled corticosteroids for persistent asthma. In older adults, the NAP probably enhanced reductions in hospitalizations and deaths due to asthma through inhaled corticosteroid use.
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Asma/mortalidad , Asma/terapia , Hospitalización/tendencias , Pautas de la Práctica en Medicina/tendencias , Administración por Inhalación , Adolescente , Adulto , Distribución por Edad , Antiasmáticos/administración & dosificación , Asma/diagnóstico , Beclometasona/administración & dosificación , Niño , Costa Rica , Prescripciones de Medicamentos , Revisión de la Utilización de Medicamentos/tendencias , Femenino , Glucocorticoides/administración & dosificación , Adhesión a Directriz/tendencias , Encuestas de Atención de la Salud , Humanos , Masculino , Guías de Práctica Clínica como Asunto , Distribución por Sexo , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Whether Native American ancestry (NAA) is associated with COPD or lung function in a racially admixed Hispanic population is unknown. METHODS: We recruited 578 Costa Ricans with and without COPD into a hybrid case-control/family-based cohort, including 316 members of families of index case subjects. All participants completed questionnaires and spirometry and gave a blood sample for DNA extraction. Genome-wide genotyping was conducted with the Illumina Human610-Quad and HumanOmniExpress BeadChip kits (Illumina Inc), and individual ancestral proportions were estimated from these genotypic data and reference panels. For unrelated individuals, linear or logistic regression was used for the analysis of NAA and COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage II or greater) or lung function. For extended families, linear mixed models and generalized estimating equations were used for the analysis. All models were adjusted for age, sex, educational level, and smoking behavior; models for FEV1 were also adjusted for height. RESULTS: The average proportion of European, Native American, and African ancestry among participants was 62%, 35%, and 3%, respectively. After adjustment for current smoking and other covariates, NAA was inversely associated with COPD (OR per 10% increment, 0.55; 95% CI, 0.41-0.75) but positively associated with FEV1, FVC, and FEV1/FVC. After additional adjustment for pack-years of smoking, the association between NAA and COPD or lung function measures was slightly attenuated. We found that about 31% of the estimated effect of NAA on COPD is mediated by pack-years of smoking. CONCLUSIONS: NAA is inversely associated with COPD but positively associated with FEV1 or FVC in Costa Ricans. Ancestral effects on smoking behavior partly explain the findings for COPD but not for FEV1 or FVC.
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Volumen Espiratorio Forzado , Hispánicos o Latinos/genética , Indígenas Norteamericanos/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Capacidad Vital , Adulto , Estudios de Casos y Controles , Costa Rica , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fumar/genética , Fumar/fisiopatologíaRESUMEN
BACKGROUND: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. OBJECTIVES: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. METHODS: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. RESULTS: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. CONCLUSIONS: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.
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Asma/epidemiología , Asma/genética , Cromosomas Humanos Par 19/genética , Calicreínas/genética , Antígeno Prostático Específico/genética , Negro o Afroamericano , Asma/inmunología , Análisis Mutacional de ADN , Sitios Genéticos/inmunología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos , Humanos , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Estados Unidos , Población BlancaRESUMEN
Vitamin D deficiency is becoming more apparent in many populations. Genetic factors may play a role in the maintenance of vitamin D levels. The objective of this study was to perform a genome-wide analysis (GWAS) of vitamin D levels, including replication of prior GWAS results. We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected at the time of enrollment and at year 4 in 572 Caucasian children with asthma, who were part of a multi-center clinical trial, the Childhood Asthma Management Program. Replication was performed in a second cohort of 592 asthmatics from Costa Rica and a third cohort of 516 Puerto Rican asthmatics. In addition, we attempted replication of three SNPs that were previously identified in a large GWAS of Caucasian individuals. The setting included data from a clinical trial of childhood asthmatics and two cohorts of asthmatics recruited for genetic studies of asthma. The main outcome measure was circulating 25(OH)D levels. The 25(OH)D levels at the two time-points were only modestly correlated with each other (intraclass correlation coefficient = 0.33) in the CAMP population. We identified SNPs that were nominally associated with 25(OH)D levels at two time-points in CAMP, and replicated four SNPs in the Costa Rican cohort: rs11002969, rs163221, rs1678849, and rs4864976. However, these SNPs were not significantly associated with 25(OH)D levels in a third population of Puerto Rican asthmatics. We were able to replicate the SNP with the strongest effect, previously reported in a large GWAS: rs2282679 (GC), and we were able to replicate another SNP, rs10741657 (CYP2R1), to a lesser degree. We were able to replicate two of three prior significant findings in a GWAS of 25(OH)D levels. Other SNPs may be additionally associated with 25(OH)D levels in certain populations.