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.

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.

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.

Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos.

BACKGROUND: IgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders. OBJECTIVE: We sought to identify genetic variants associated with IgE levels in Latinos. METHODS: We performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies. RESULTS: We confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011). CONCLUSION: We confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

Genome-wide association study and admixture mapping identify different asthma-associated loci in Latinos: the Genes-environments & Admixture in Latino Americans study.

BACKGROUND: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent. OBJECTIVE: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. METHODS: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. RESULTS: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 × 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. CONCLUSIONS: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21.

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.

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.

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.

Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: the Genes-environments and Admixture in Latino Asthmatics (GALA II) study.

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.

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.

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.

Asthma Research for All of the United States.

Asthma disproportionally affects different ethnic/racial groups, with Puerto Ricans and African Americans suffering the highest asthma prevalence and morbidity, Mexicans the lowest, and non-Hispanic whites in between. Genome-wide association studies of asthma have found both shared and race/ethnic-specific genetic risks factors for asthma. However, the majority of genetic asthma research is performed in populations of European descent, which limits the benefits of genetic research to European populations. It is important to biomedical and clinical research to include more diverse and underrepresented populations. The rich genetic diversity of all populations can be leveraged to scientific advantage. For example, admixture mapping provides a more powerful approach than traditional genome-wide allelic association studies in discovering genetic associations for complex diseases. By being more inclusive we can achieve a better understanding of the genetics of asthma, address health disparities, and ensure that scientific advances will benefit populations worldwide.

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.

Differential diagnosis of Jakob-Creutzfeldt disease.

OBJECTIVES: To identify the misdiagnoses of patients with sporadic Jakob-Creutzfeldt disease (sCJD) during the course of their disease and determine which medical specialties saw patients with sCJD prior to the correct diagnosis being made and at what point in the disease course a correct diagnosis was made. DESIGN: Retrospective medical record review. SETTING: A specialty referral center of a tertiary academic medical center. PARTICIPANTS: One hundred sixty-three serial patients over a 5.5-year period who ultimately had pathologically proven sCJD. The study used the subset of 97 patients for whom we had adequate medical records. MAIN OUTCOME MEASURES: Other diagnoses considered in the differential diagnosis and types of medical specialties assessing patients with sCJD. RESULTS: Ninety-seven subjects' records were used in the final analysis. The most common disease categories of misdiagnosis were neurodegenerative, autoimmune/paraneoplastic, infectious, and toxic/metabolic disorders. The most common individual misdiagnoses were viral encephalitis, paraneoplastic disorder, depression, vertigo, Alzheimer disease, stroke, unspecified dementia, central nervous system vasculitis, peripheral neuropathy, and Hashimoto encephalopathy. The physicians who most commonly made these misdiagnoses were primary care physicians and neurologists; in the 18% of patients who were diagnosed correctly at their first assessment, the diagnosis was almost always by a neurologist. The mean time from onset to diagnosis was 7.9 months, an average of two-thirds of the way through their disease course. CONCLUSIONS: Diagnosis of sCJD is quite delayed. When evaluating patients with rapidly progressive dementia with suspected neurodegenerative, autoimmune, infectious, or toxic/metabolic etiology, sCJD should also be included in the differential diagnosis, and appropriate diagnostic tests, such as diffusion brain magnetic resonance imaging, should be considered. Primary care physicians and neurologists need improved training in sCJD diagnosis.