RESUMEN
We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.
Asunto(s)
Negro o Afroamericano , Hispánicos o Latinos , Americanos Mexicanos , Humanos , Negro o Afroamericano/genética , Estudio de Asociación del Genoma Completo , Hispánicos o Latinos/genética , Americanos Mexicanos/genética , Fenotipo , Polimorfismo de Nucleótido Simple , TranscriptomaRESUMEN
BACKGROUND: Little is known about the genetic determinants of severe asthma exacerbations. OBJECTIVES: We aimed to identify genetic variants associated with asthma hospitalizations. METHODS: We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. RESULTS: At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10-8); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10-6. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. CONCLUSIONS: We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data-based mendelian randomization analyses.
Asunto(s)
Asma/genética , Genotipo , Cadenas beta de HLA-DQ/genética , Hospitalización/estadística & datos numéricos , Adulto , Asma/epidemiología , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA-D/genética , Antígenos HLA-DQ/genética , Cadenas beta de HLA-DR/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Reino Unido/epidemiologíaRESUMEN
Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain.Objectives: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island (n = 836).Methods: We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data.Measurements and Main Results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; P = 6.62 × 10-8) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; P = 5.03 × 10-6). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function.Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.
Asunto(s)
Asma/genética , Población Negra/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 5/genética , Volumen Espiratorio Forzado/genética , Indígenas Norteamericanos/genética , Pulmón/fisiopatología , Adolescente , Asma/fisiopatología , Bronquios/citología , Estudios de Casos y Controles , Línea Celular , Niño , Inmunoprecipitación de Cromatina , Mapeo Cromosómico , Mucosa Esofágica/metabolismo , Femenino , Expresión Génica , Humanos , Desequilibrio de Ligamiento , Pulmón/fisiología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Miocitos del Músculo Liso , Mucosa Nasal/metabolismo , Polimorfismo de Nucleótido Simple , Puerto Rico , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ARN , Población Blanca/genética , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
BACKGROUND: In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico. METHODS: CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than ââââ60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools. RESULTS: Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del. CONCLUSIONS: In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Adolescente , Secuencia de Bases , Población Negra , Fibrosis Quística/epidemiología , República Dominicana/epidemiología , Femenino , Hispánicos o Latinos , Humanos , Masculino , Puerto Rico/epidemiología , Población BlancaRESUMEN
American Thoracic Society guidelines recommend inhaled corticosteroid (ICS) therapy, plus a short-acting bronchodilator, in patients with persistent asthma. However, few prior studies have examined the efficacy of this combination in children of all racial/ethnic groups. We evaluated the association between ICS use and bronchodilator response (BDR) in three pediatric populations with persistent asthma (656 African American, 916 Puerto Rican, and 398 Mexican American children). The association was assessed using multivariable quantile regression. After adjusting for baseline forced expiratory volume in one second and use of controller medications, ICS use was significantly associated with increased BDR only among Mexican Americans (1.56%, P = 0.028) but not African Americans (0.49%, P = 0.426) or Puerto Ricans (0.16%, P = 0.813). Our results demonstrate that ICS augmentation is disproportionate across racial/ethnic groups, where improved BDR is observed in Mexican Americans only. This study highlights the complexities of treating asthma in children, and reinforces the importance of investigating the influence of race/ethnicity on pharmacological response.
Asunto(s)
Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/etnología , Broncodilatadores/uso terapéutico , Grupos Raciales/estadística & datos numéricos , Administración por Inhalación , Adolescente , Corticoesteroides/administración & dosificación , Negro o Afroamericano/estadística & datos numéricos , Broncodilatadores/farmacología , Niño , Femenino , Volumen Espiratorio Forzado , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Americanos Mexicanos/estadística & datos numéricos , Puerto Rico/etnología , Estados Unidos/epidemiologíaRESUMEN
RATIONALE: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. OBJECTIVES: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. METHODS: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 µm and ≤2.5 µm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. MEASUREMENTS AND MAIN RESULTS: A 5 µg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 µm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. CONCLUSIONS: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.
Asunto(s)
Contaminación del Aire/efectos adversos , Asma/epidemiología , Negro o Afroamericano/estadística & datos numéricos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Pulmón/fisiopatología , Grupos Minoritarios/estadística & datos numéricos , Adolescente , Contaminantes Atmosféricos/efectos adversos , Asma/fisiopatología , Niño , Femenino , Humanos , Masculino , Puerto Rico/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.
Asunto(s)
Variación Genética , Indígenas Norteamericanos/genética , Americanos Mexicanos/genética , Población/genética , Población Negra/genética , Genoma Humano , Humanos , México , Población Blanca/genéticaRESUMEN
RATIONALE: Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications. OBJECTIVES: To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions. METHODS: This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO2), sulfur dioxide, particulate matter not greater than 10 µm in diameter, and particulate matter not greater than 2.5 µm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant. MEASUREMENTS AND MAIN RESULTS: After adjustment for confounders, a 5-ppb increase in average NO2 during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31). CONCLUSIONS: Early-life NO2 exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Asma/etnología , Negro o Afroamericano , Hispánicos o Latinos , Grupos Minoritarios , Material Particulado/efectos adversos , Adolescente , Factores de Edad , Contaminación del Aire , Asma/etiología , Niño , Intervalos de Confianza , Monitoreo del Ambiente/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Oportunidad Relativa , Puerto Rico/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Estados Unidos/epidemiología , Población Urbana , Adulto JovenRESUMEN
BACKGROUND: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. OBJECTIVE: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. METHODS: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. RESULTS: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[ß] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[ß] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. CONCLUSIONS: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.
Asunto(s)
Asma/complicaciones , Asma/etnología , Emigración e Inmigración , Interacción Gen-Ambiente , Hispánicos o Latinos/estadística & datos numéricos , Hipersensibilidad Inmediata/etnología , Hipersensibilidad Inmediata/genética , Adolescente , Alérgenos/inmunología , Asma/genética , Asma/inmunología , Población Negra , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Hipersensibilidad Inmediata/diagnóstico , Hipersensibilidad Inmediata/inmunología , Masculino , Prevalencia , Puerto Rico , Factores de Riesgo , Pruebas Cutáneas , Estados Unidos/epidemiologíaRESUMEN
MOTIVATION: Local ancestry analysis of genotype data from recently admixed populations (e.g. Latinos, African Americans) provides key insights into population history and disease genetics. Although methods for local ancestry inference have been extensively validated in simulations (under many unrealistic assumptions), no empirical study of local ancestry accuracy in Latinos exists to date. Hence, interpreting findings that rely on local ancestry in Latinos is challenging. RESULTS: Here, we use 489 nuclear families from the mainland USA, Puerto Rico and Mexico in conjunction with 3204 unrelated Latinos from the Multiethnic Cohort study to provide the first empirical characterization of local ancestry inference accuracy in Latinos. Our approach for identifying errors does not rely on simulations but on the observation that local ancestry in families follows Mendelian inheritance. We measure the rate of local ancestry assignments that lead to Mendelian inconsistencies in local ancestry in trios (MILANC), which provides a lower bound on errors in the local ancestry estimates. We show that MILANC rates observed in simulations underestimate the rate observed in real data, and that MILANC varies substantially across the genome. Second, across a wide range of methods, we observe that loci with large deviations in local ancestry also show enrichment in MILANC rates. Therefore, local ancestry estimates at such loci should be interpreted with caution. Finally, we reconstruct ancestral haplotype panels to be used as reference panels in local ancestry inference and show that ancestry inference is significantly improved by incoroprating these reference panels. AVAILABILITY AND IMPLEMENTATION: We provide the reconstructed reference panels together with the maps of MILANC rates as a public resource for researchers analyzing local ancestry in Latinos at http://bogdanlab.pathology.ucla.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Asunto(s)
Hispánicos o Latinos/genética , Sesgo , Estudios de Cohortes , Familia , Sitios Genéticos , Genética de Población/métodos , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Humanos , Americanos Mexicanos , Puerto Rico/etnología , Estados Unidos/etnologíaRESUMEN
MOTIVATION: It is becoming increasingly evident that the analysis of genotype data from recently admixed populations is providing important insights into medical genetics and population history. Such analyses have been used to identify novel disease loci, to understand recombination rate variation and to detect recent selection events. The utility of such studies crucially depends on accurate and unbiased estimation of the ancestry at every genomic locus in recently admixed populations. Although various methods have been proposed and shown to be extremely accurate in two-way admixtures (e.g. African Americans), only a few approaches have been proposed and thoroughly benchmarked on multi-way admixtures (e.g. Latino populations of the Americas). RESULTS: To address these challenges we introduce here methods for local ancestry inference which leverage the structure of linkage disequilibrium in the ancestral population (LAMP-LD), and incorporate the constraint of Mendelian segregation when inferring local ancestry in nuclear family trios (LAMP-HAP). Our algorithms uniquely combine hidden Markov models (HMMs) of haplotype diversity within a novel window-based framework to achieve superior accuracy as compared with published methods. Further, unlike previous methods, the structure of our HMM does not depend on the number of reference haplotypes but on a fixed constant, and it is thereby capable of utilizing large datasets while remaining highly efficient and robust to over-fitting. Through simulations and analysis of real data from 489 nuclear trio families from the mainland US, Puerto Rico and Mexico, we demonstrate that our methods achieve superior accuracy compared with published methods for local ancestry inference in Latinos.
Asunto(s)
Algoritmos , Genética de Población , Hispánicos o Latinos/genética , Flujo Génico , Genética de Población/métodos , Haplotipos , Humanos , Indígenas Norteamericanos/genética , Desequilibrio de Ligamiento , Cadenas de Markov , México , Puerto Rico , Estados Unidos , Población Blanca/genéticaRESUMEN
BACKGROUND: The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent. OBJECTIVE: To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children. PATIENTS AND METHODS: There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression. RESULTS: Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year. CONCLUSIONS: Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
Asunto(s)
Asma/etnología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Fumar/epidemiología , Contaminación por Humo de Tabaco/estadística & datos numéricos , Adulto , Negro o Afroamericano/estadística & datos numéricos , Asma/epidemiología , Niño , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Modelos Logísticos , Bienestar Materno , Americanos Mexicanos/estadística & datos numéricos , Embarazo , Puerto Rico/etnologíaRESUMEN
BACKGROUND: Although Mexicans and Puerto Ricans are jointly classified as "Hispanic/Latino," there are significant differences in asthma prevalence, severity, and mortality between the 2 groups. We sought to examine the possibility that population-specific genetic risks contribute to this disparity. OBJECTIVES: More than 100 candidate genes have been associated with asthma and replicated in an independent population, and 7 genome-wide association studies in asthma have been performed. We compared the pattern of replication of these associations in Puerto Ricans and Mexicans. METHODS: We genotyped Mexican and Puerto Rican trios using an Affymetrix 6.0 GeneChip and used a family-based analysis to test for genetic associations in 124 genes previously associated with asthma. RESULTS: We identified 32 single nucleotide polymorphisms (SNPs) in 17 genes associated with asthma in at least 1 of the 2 populations. Twenty-two of these SNPs in 11 genes were significantly associated with asthma in the combined population and showed no significant heterogeneity of association, whereas 5 SNPs were associated in only 1 population and showed statistically significant heterogeneity. In a gene-based approach 2 additional genes were associated with asthma in the combined population, and 3 additional genes displayed ethnic-specific associations with heterogeneity. CONCLUSIONS: Our results show that only a minority of genetic association studies replicate in our population of Mexican and Puerto Rican asthmatic subjects. Among SNPs that were successfully replicated, most showed no significant heterogeneity across populations. However, we identified several population-specific genetic associations.
Asunto(s)
Asma/genética , Predisposición Genética a la Enfermedad , Hispánicos o Latinos/genética , Adolescente , Adulto , Asma/etnología , Niño , Femenino , Hispánicos o Latinos/etnología , Humanos , Masculino , Americanos Mexicanos/genética , México/etnología , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Puerto Rico/etnología , Factores de Riesgo , Adulto JovenRESUMEN
RATIONALE: Disparities in pediatric asthma exist in that Latino children have higher prevalence and greater morbidity from asthma than non-Latino white children. The factors behind these disparities are poorly understood, but ethnic-related variations in children's ability to accurately recognize and report their pulmonary functioning may be a contributing process. OBJECTIVES: To determine (1) if differences exist between Latino and non-Latino white children's perceptual accuracy and (2) whether these differences are related to asthma outcomes. METHODS: Five hundred and twelve children, aged 7-16 years (290 island Puerto Ricans, 115 Rhode Island Latinos, and 107 Rhode Island non-Latino white children) participated in a 5-week home-based protocol in which twice daily they entered subjective estimates of their peak expiratory flow rate into a hand-held, programmable spirometer and then performed spirometry. Their accuracy was summarized as three perceptual accuracy scores. Demographic data, asthma severity, intelligence, emotional expression, and general symptom-reporting tendencies were assessed and covaried in analyses of the relationship of perceptual accuracy to asthma morbidity and health care use. MEASUREMENTS AND MAIN RESULTS: Younger age, female sex, lower intelligence, and poverty were associated with lower pulmonary function perception scores. Island Puerto Rican children had the lowest accuracy and highest magnification scores, followed by Rhode Island Latinos; both differed significantly from non-Latino white children. Perceptual accuracy scores were associated with most indices of asthma morbidity. CONCLUSIONS: Controlling for other predictive variables, ethnicity was related to pulmonary function perception ability, as Latino children were less accurate than non-Latino white children. This difference in perceptual ability may contribute to recognized asthma disparities.
Asunto(s)
Asma/etnología , Asma/psicología , Conocimientos, Actitudes y Práctica en Salud , Hispánicos o Latinos , Percepción , Adolescente , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Puerto Rico , Rhode Island , Factores Sexuales , Factores Socioeconómicos , Espirometría/psicologíaRESUMEN
BACKGROUND: Short-acting inhaled beta2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The beta2-adrenergic receptor (beta2AR) is the target for beta2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to beta2-agonists. OBJECTIVE: We hypothesized that there are pharmacogenetic interactions between GSNOR and beta2AR gene variants that are associated with variable response to albuterol. METHODS: We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and beta2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants. RESULTS: Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3'UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04-0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and beta2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*beta2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response. CONCLUSION: Genotyping of GSNOR and beta2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.
Asunto(s)
Albuterol/farmacología , Albuterol/uso terapéutico , Asma/tratamiento farmacológico , Broncodilatadores/farmacología , Broncodilatadores/uso terapéutico , Albuterol/administración & dosificación , Aldehído Oxidorreductasas , Asma/genética , Asma/fisiopatología , Broncodilatadores/administración & dosificación , Interacciones Farmacológicas/genética , Genes , Genotipo , Haplotipos , Hispánicos o Latinos/genética , Humanos , Modelos Lineales , Americanos Mexicanos/genética , México , Oxidorreductasas/genética , Oxidorreductasas/farmacología , Polimorfismo de Nucleótido Simple , S-Nitrosoglutatión/farmacología , S-Nitrosoglutatión/uso terapéuticoRESUMEN
BACKGROUND: Epidemiologic studies have documented higher rates of asthma prevalence and morbidity in minority children compared to non-Latino white (NLW) children. Few studies focus on the mechanisms involved in explaining this disparity, and fewer still on the methodological challenges involved in rigorous disparities research. OBJECTIVES AND METHODS: This article provides an overview of challenges and potential solutions to research design for studies of health disparities. The methodological issues described in this article were framed on an empirical model of asthma health disparities that views disparities as resulting from several factors related to the healthcare system and the individual/community system. The methods used in the Rhode Island-Puerto Rico Asthma Center are provided as examples, illustrating the challenges in executing disparities research. RESULTS: Several methods are described: distinguishing ethnic/racial differences from methodological artifacts, identifying and adapting culturally sensitive measures to explain disparities, and addressing the challenges involved in determining asthma and its severity in Latino and other minority children. The measures employed are framed within each of the components of the conceptual model presented. CONCLUSIONS: Understanding ethnic and/or cultural disparities in asthma morbidity is a complicated process. Methodologic approaches to studying the problem must reflect this complexity, allowing us to move from documenting disparities to understanding them, and ultimately to reducing them.
Asunto(s)
Asma/etnología , Disparidades en el Estado de Salud , Hispánicos o Latinos , Comparación Transcultural , Humanos , Proyectos de Investigación , Rhode IslandRESUMEN
BACKGROUND: Ethnic-specific interactions between different asthma medications are not well described. OBJECTIVE: To determine whether the use of leukotriene modifiers is associated with the magnitude of bronchodilator responsiveness among Mexican American and Puerto Rican children with persistent asthma. METHODS: A cross-sectional study of 84 Mexican American and 192 Puerto Rican children, with persistent asthma who were aged 8 to 16 years. Within each group, bronchodilator responsiveness to albuterol, objectively assessed via spirometry, was compared between participants using leukotriene modifiers and those not using leukotriene modifiers. RESULTS: Leukotriene modifier use was associated with a clinically significant increase in percentage change in forced expiratory volume in 1 second of 11.8 (P < .001) in Puerto Rican children, but there was no significant change in percentage change in forced expiratory volume in 1 second (-3.2, P=.57) in Mexican American children. This finding persisted after controlling for the use of inhaled corticosteroids. In addition, among the Puerto Rican children, the association between leukotriene modifier use and augmented bronchodilator responsiveness was greatest in those younger than 12 years. CONCLUSIONS: Among children with persistent asthma, use of leukotriene modifiers is associated with augmented bronchodilator responsiveness to albuterol in Puerto Ricans, but not Mexican Americans. This ethnic-specific, drug-drug interaction highlights the need for the further understanding of asthma pharmacogenetics among children from different ethnic groups to improve asthma outcomes.
Asunto(s)
Asma/tratamiento farmacológico , Asma/fisiopatología , Broncodilatadores/administración & dosificación , Interacciones Farmacológicas , Antagonistas de Leucotrieno/administración & dosificación , Adolescente , Albuterol/administración & dosificación , Asma/etnología , Niño , Estudios Transversales , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Hispánicos o Latinos , Humanos , Masculino , Americanos Mexicanos , Resultado del TratamientoRESUMEN
OBJECTIVE: A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients. METHODS: Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses. RESULTS: No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol. CONCLUSION: Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.
Asunto(s)
Asma/tratamiento farmacológico , Asma/genética , Broncodilatadores/uso terapéutico , Farmacogenética , Filogenia , Adolescente , Adulto , Negro o Afroamericano/genética , Indio Americano o Nativo de Alaska/genética , Estudios de Casos y Controles , Niño , Demografía , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Interleucina-6/genética , Modelos Lineales , Desequilibrio de Ligamiento/genética , Masculino , Polimorfismo de Nucleótido Simple/genética , Puerto Rico/etnología , Receptores de Interleucina-6/genéticaRESUMEN
Mouse models have shown the importance of acidic mammalian chitinase activity in settings of chitin exposure and allergic inflammation. However, little is known regarding genetic regulation of AMCase enzymatic activity in human allergic diseases. Resequencing the AMCase gene exons we identified 8 non-synonymous single nucleotide polymorphisms including three novel variants (A290G, G296A, G339T) near the gene area coding for the enzyme active site, all in linkage disequilibrium. AMCase protein isoforms, encoded by two gene-wide haplotypes, and differentiated by these three single nucleotide polymorphisms, were recombinantly expressed and purified. Biochemical analysis revealed the isoform encoded by the variant haplotype displayed a distinct pH profile exhibiting greater retention of chitinase activity at acidic and basic pH values. Determination of absolute kinetic activity found the variant isoform encoded by the variant haplotype was 4-, 2.5-, and 10-fold more active than the wild type AMCase isoform at pH 2.2, 4.6, and 7.0, respectively. Modeling of the AMCase isoforms revealed positional changes in amino acids critical for both pH specificity and substrate binding. Genetic association analyses of AMCase haplotypes for asthma revealed significant protective associations between the variant haplotype in several asthma cohorts. The structural, kinetic, and genetic data regarding the AMCase isoforms are consistent with the Th2-priming effects of environmental chitin and a role for AMCase in negatively regulating this stimulus.
Asunto(s)
Quitinasas/genética , Haplotipos , Polimorfismo de Nucleótido Simple , Negro o Afroamericano/genética , Animales , Asma/etnología , Asma/genética , Sitios de Unión/genética , Catálisis , Línea Celular , Quitinasas/química , Quitinasas/metabolismo , Disacáridos/química , Disacáridos/metabolismo , Frecuencia de los Genes , Genotipo , Hispánicos o Latinos/genética , Humanos , Concentración de Iones de Hidrógeno , Insectos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Desequilibrio de Ligamiento , México , Estructura Molecular , Estructura Terciaria de Proteína , Puerto Rico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidad por SustratoRESUMEN
While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population, which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico's founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico's founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation.