Elizabeth A. Nguyen

Development of a panel of genome-wide ancestry informative markers to study admixture throughout the americas

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R2>0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.

Early-Life Air Pollution and Asthma Risk in Minority Children. The GALA II and SAGE II Studies

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.

Childhood Obesity and Asthma Control in the GALA II and SAGE II Studies

RATIONALE Obesity is associated with increased asthma morbidity, lower drug responsiveness to inhaled corticosteroids, and worse asthma control. However, most prior investigations on obesity and asthma control have not focused on pediatric populations, considered environmental exposures, or included minority children. OBJECTIVES To examine the association between body mass index categories and asthma control among boys and girls; and whether these associations are modified by age and race/ethnicity. METHODS Children and adolescents ages 8-19 years (n = 2,174) with asthma were recruited from the Genes-environments and Admixture in Latino Americans (GALA II) Study and the Study of African Americans, Asthma, Genes, and Environments (SAGE II). Ordinal logistic regression was used to estimate odds ratios (OR) and their confidence intervals (95% CI) for worse asthma control. MEASUREMENTS AND MAIN RESULTS In adjusted analyses, boys who were obese had a 33% greater chance of having worse asthma control than their normal-weight counterparts (OR, 1.33; 95% CI, 1.04-1.71). However, for girls this association varied with race and ethnicity (P interaction = 0.008). When compared with their normal-weight counterparts, obese African American girls (OR, 0.65; 95% CI, 0.41-1.05) were more likely to have better controlled asthma, whereas Mexican American girls had a 1.91 (95% CI, 1.12-3.28) greater odds of worse asthma control. CONCLUSIONS Worse asthma control is uniformly associated with increased body mass index in boys. Among girls, the direction of this association varied with race/ethnicity.

Genetic ancestry influences asthma susceptibility and lung function among Latinos.

BACKGROUND Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. OBJECTIVE To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. METHODS We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. RESULTS Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively). CONCLUSION Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

Effect of secondhand smoke on asthma control among black and Latino children

BACKGROUND Among patients with asthma, the clinical effect and relative contribution of maternal smoking during pregnancy (in utero smoking) and current secondhand smoke (SHS) exposure on asthma control is poorly documented, and there is a paucity of research involving minority populations. OBJECTIVES We sought to examine the association between poor asthma control and in utero smoking and current SHS exposure among Latino and black children with asthma. METHODS We performed a case-only analysis of 2 multicenter case-control studies conducted from 2008-2010 with similar protocols. We recruited 2481 Latino and black subjects with asthma (ages 8-17 years) from the mainland United States and Puerto Rico. Ordinal logistic regression was used to estimate the effect of in utero smoking and current SHS exposures on National Heart, Lung, and Blood Institute-defined asthma control. RESULTS Poor asthma control among children 8 to 17 years of age was independently associated with in utero smoking (odds ratio [OR], 1.5; 95% CI, 1.1-2.0). In utero smoking through the mother was also associated with secondary asthma outcomes, including early-onset asthma (OR, 1.7; 95% CI, 1.1-2.4), daytime symptoms (OR, 1.6; 95% CI, 1.1-2.1), and asthma-related limitation of activities (OR, 1.6; 95% CI, 1.2-2.2). CONCLUSIONS Maternal smoking while in utero is associated with poor asthma control in black and Latino subjects assessed at 8-17 years of age.

Socioeconomic Status and Childhood Asthma in Urban Minority Youths. The GALA II and SAGE II Studies

RATIONALE The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups. OBJECTIVES To assess the collective effect of maternal educational attainment, annual household income, and insurance type on childhood asthma among minority, urban youth. METHODS We included Mexican American (n = 485), other Latino (n = 217), and African American (n = 1,141) children (aged 8-21 yr) with and without asthma from the San Francisco Bay Area. An index was derived from maternal educational attainment, annual household income, and insurance type to assess the collective effect of socioeconomic status on predicting asthma. Logistic regression stratified by racial and ethnic group was used to estimate adjusted odds ratios (aOR) and their 95% confidence intervals (CI). We further examined whether acculturation explained the socioeconomic-asthma association in our Latino population. MEASUREMENTS AND MAIN RESULTS In the adjusted analyses, African American children had 23% greater odds of asthma with each decrease in the socioeconomic index (aOR, 1.23; 95% CI, 1.09-1.38). Conversely, Mexican American children have 17% reduced odds of asthma with each decrease in the socioeconomic index (aOR, 0.83; 95% CI, 0.72-0.96) and this relationship was not fully explained by acculturation. This association was not observed in the other Latino group. CONCLUSIONS Socioeconomic status plays an important role in predicting asthma, but has different effects depending on race and ethnicity. Further steps are necessary to better understand the risk factors through which socioeconomic status could operate in these populations to prevent asthma.

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

BACKGROUND IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE. OBJECTIVE We sought to identify the genetic predictors of serum total IgE levels. METHODS We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. RESULTS We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P<5.0×10(-6)) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P=.007 and 2.45×10(-7), respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. CONCLUSION This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects.

Determination of Tobacco Smoke Exposure by Plasma Cotinine Levels in Infants and Children Attending Urban Public Hospital Clinics

OBJECTIVE To determine the prevalence of secondhand smoke (SHS) exposure among infants and young children who received preventive care at pediatric preventative care clinics associated with an urban public hospital. Cotinine, a metabolite of nicotine, has been used to study SHS exposure in population-based studies of children 3 years of age or older. DESIGN Retrospective study using a convenience sample. SETTING Urban county pediatric primary care clinics in San Francisco, California. PARTICIPANTS A total of 496 infants and children (mean [SD] age, 2.4 [1.9] years). INTERVENTIONS Discarded plasma samples (which were routinely collected for lead screening) were tested, and medical records were reviewed, for SHS exposure. MAIN OUTCOME MEASURE Secondhand smoke exposure based on cotinine plasma level and history of exposure in the medical record. RESULTS Thirteen percent of parents reported that their child was exposed to SHS, yet biochemical testing detected cotinine in 55% of samples, at a geometric mean (SD) of 0.23 (3.55) ng/mL. There were no significant sex or age differences. African American children had much higher mean cotinine levels than did Latino children (multiplicative factor change in cotinine, 6.01 ng/ml [95% Cl, 4.49-8.05 ng/ml] [correction]. CONCLUSION In a city with a low smoking rate (12%) and public smoking bans, we documented 55% exposure among infants and young children, using a plasma biomarker, compared with 13% exposure reported by parents. Because SHS is associated with significant respiratory diseases and parents underreport exposure, routine biochemical screening should be considered as a tool to identify and reduce SHS exposure.

Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes–Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies

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.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Background Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. Objective We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. Methods We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta‐analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. Results We identified a genome‐wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10−6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07‐1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77‐0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10−3, combined P = 2.6 × 10−7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5′ of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12‐7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. Conclusion Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry‐informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.