Publications by authors named "Shannon Thyne"

60 Publications

An Implementation Science Approach Improves Language Access in the Emergency Department.

J Immigr Minor Health 2021 Jan 2. Epub 2021 Jan 2.

Department of Emergency Medicine, Olive View-UCLA Medical Center, 14445 Olive View Drive, North Annex, Sylmar, CA, 91342, USA.

Background: The underuse of interpreters for limited English proficiency (LEP) patient encounters is pervasive, particularly in the emergency department (ED).

Objective: To measure the outcome of strategies to improve the use of interpreters by ED providers.

Methods: Pre- and post- intervention evaluation of the unmet need for language assistance (LA) in a public ED. Informed by the Behavior Change Wheel (BCW), strategies included: education, training, technology-based facilitators, local champions and environmental cues.

Results: Pre-intervention, of the 110 patient charts with interpreter requests, 17 (15.5%) had documentation of an interpreter-mediated encounter or were seen by a certified bilingual provider (unmet need = 84.5%). Post intervention, of the 159 patient charts with interpreter requests, 47 (29.6%) had documentation of an interpreter-mediated encounter or were seen by a certified bilingual provider (unmet need = 70.4%), difference + 0.14 (95% CI = 0.03-0.23).

Conclusion: In this pilot study, we found a statistically significant increase in the met need for language assistance.
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http://dx.doi.org/10.1007/s10903-020-01127-xDOI Listing
January 2021

Differential asthma odds following respiratory infection in children from three minority populations.

PLoS One 2020 5;15(5):e0231782. Epub 2020 May 5.

Department of Medicine, University of California, San Francisco, CA, United States of America.

Rationale: Severe early-life respiratory illnesses, particularly those caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV), are strongly associated with the development of asthma in children. Puerto Rican children in particular have a strikingly high asthma burden. However, prior studies of the potential associations between early-life respiratory illnesses and asthma in Puerto Rican and other minority populations have been limited.

Objectives: We sought to determine whether early-life respiratory illness was associated with asthma in Puerto Rican, Mexican American, and African American children.

Methods: Using a logistic regression analysis, we examined the association between early-life respiratory illnesses (report of upper respiratory infection (URI), pneumonia, bronchitis, and bronchiolitis/RSV) within the first two years of life and physician-diagnosed asthma after the age of two in a large cohort of Puerto Rican, Mexican American, and African American children.

Measurements And Main Results: While early-life respiratory illnesses were associated with greater asthma odds in Puerto Ricans, Mexican Americans, and African Americans, these associations were stronger among Puerto Rican children. Specifically, in Puerto Ricans, the odds was 6.15 (95% CI: 4.21-9.05) if the child reported at least one of the following respiratory illness: URI, pneumonia, bronchitis or bronchiolitis. The odds were also higher in Puerto Ricans when considering these conditions separately.

Conclusions: We observed population-specific associations between early-life respiratory illnesses and asthma, which were especially significant and stronger in Puerto Ricans. Taken together with the known high burden of RSV in Puerto Rico, our results may help explain the high burden of asthma in Puerto Ricans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231782PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199930PMC
July 2020

Racial/Ethnic-Specific Differences in the Effects of Inhaled Corticosteroid Use on Bronchodilator Response in Patients With Asthma.

Clin Pharmacol Ther 2019 11 23;106(5):1133-1140. Epub 2019 Jul 23.

Department of Medicine, University of California, San Francisco, California, USA.

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.
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http://dx.doi.org/10.1002/cpt.1555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778006PMC
November 2019

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.

Clin Exp Allergy 2019 06 15;49(6):789-798. Epub 2019 Feb 15.

Division of Pediatric Pulmonary Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh, Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.

Objective: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.

Methods: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.

Results: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.

Conclusions And Clinical Relevance: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
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http://dx.doi.org/10.1111/cea.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054824PMC
June 2019

Acculturation is associated with asthma burden and pulmonary function in Latino youth: The GALA II study.

J Allergy Clin Immunol 2019 05 22;143(5):1914-1922. Epub 2019 Jan 22.

Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, Calif.

Background: Acculturation is an important predictor of asthma in Latino youth, specifically Mexican Americans. Less is known about acculturation and pulmonary function measures.

Objective: We sought to estimate the association of acculturation measures with asthma and pulmonary function in Latino youth and determine whether this association varies across Latino subgroups.

Methods: We included 1849 Latinos (302 Caribbean Spanish, 193 Central or South Americans, 1136 Mexican Americans, and 218 other Latino children) aged 8 to 21 years from 4 urban regions in the United States. Acculturation measures include nativity status, age of immigration, language of preference, and generation in the United States. We used multivariable logistic and linear regression models to quantify the association of acculturation factors with the presence of asthma (case-control study) and pulmonary function (case-only study), adjusting for demographic, socioenvironmental, and clinical variables.

Results: For all acculturation measures (nativity status, age of immigration, language of preference, and generation in the United States), greater levels of acculturation were associated with greater odds of asthma. Among cases, high (English preference) and medium (equal preference for Spanish and English) levels of language acculturation were associated with decreased bronchodilator response compared with low (Spanish preference) levels (P = .009 and .02, respectively). Similarly, high language acculturation was associated with increased FEV compared with low language acculturation (P = .02). There was insufficient evidence of heterogeneity for associations across Latino subgroups.

Conclusions: Acculturation was associated with diagnosed asthma and pulmonary function in Latino children and is an important factor to consider in the management of Latino youth with asthma.
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http://dx.doi.org/10.1016/j.jaci.2018.12.1015DOI Listing
May 2019

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Pharmacogenomics J 2019 06 12;19(3):249-259. Epub 2018 Sep 12.

National Laboratory of Genomics for Biodiversity (LANGEBIO), CINVESTAV, Irapuato, Guanajuato, Mexico.

Short-acting β-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.
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http://dx.doi.org/10.1038/s41397-018-0042-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414286PMC
June 2019

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

J Allergy Clin Immunol 2019 03 7;143(3):957-969. Epub 2018 Sep 7.

Veterans Caribbean Health Care System, San Juan, Puerto Rico.

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), 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, combined P = 2.6 × 10). 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.
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http://dx.doi.org/10.1016/j.jaci.2016.08.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927816PMC
March 2019

Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma.

Thorax 2018 11 13;73(11):1041-1048. Epub 2018 Jun 13.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Background: Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported.

Objectives: Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature.

Methods: We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines.

Results: The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures.

Conclusions: Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225993PMC
November 2018

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Am J Respir Crit Care Med 2018 06;197(12):1552-1564

5 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Rationale: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

Objectives: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

Methods: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

Measurements And Main Results: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10) and suggestive (P < 7.06 × 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

Conclusions: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
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http://dx.doi.org/10.1164/rccm.201712-2529OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006403PMC
June 2018

Self-reported racial/ethnic discrimination and bronchodilator response in African American youth with asthma.

PLoS One 2017 13;12(6):e0179091. Epub 2017 Jun 13.

Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.

Importance: Asthma is a multifactorial disease composed of endotypes with varying risk profiles and outcomes. African Americans experience a high burden of asthma and of psychosocial stress, including racial discrimination. It is unknown which endotypes of asthma are vulnerable to racial/ethnic discrimination.

Objective: We examined the association between self-reported racial/ethnic discrimination and bronchodilator response (BDR) among African American youth with asthma ages 8 to 21 years (n = 576) and whether this association varies with tumor necrosis factor alpha (TNF-α) level.

Materials And Methods: Self-reported racial/ethnic discrimination was assessed by a modified Experiences of Discrimination questionnaire as none or any. Using spirometry, BDR was specified as the mean percentage change in forced expiratory volume in one second before and after albuterol administration. TNF-α was specified as high/low levels based on our study population mean. Linear regression was used to examine the association between self-reported racial/ethnic discrimination and BDR adjusted for selected characteristics. An interaction term between TNF-α levels and self-reported racial/ethnic discrimination was tested in the final model.

Results: Almost half of participants (48.8%) reported racial/ethnic discrimination. The mean percent BDR was higher among participants reporting racial/ethnic discrimination than among those who did not (10.8 versus 8.9, p = 0.006). After adjustment, participants reporting racial/ethnic discrimination had a 1.7 (95% CI: 0.36-3.03) higher BDR mean than those not reporting racial/ethnic discrimination. However, we found heterogeneity of this association according to TNF-α levels (p-interaction = 0.040): Among individuals with TNF-α high level only, we observed a 2.78 higher BDR mean among those reporting racial/ethnic discrimination compared with those not reporting racial/ethnic discrimination (95%CI: 0.79-4.77).

Conclusions: We found BDR to be increased in participants reporting racial/ethnic discrimination and this association was limited to African American youth with TNF-α high asthma, an endotype thought to be resistant to traditional asthma medications. These results support screening for racial/ethnic discrimination in those with asthma as it may reclassify disease pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469454PMC
October 2017

Identification of a novel locus associated with skin colour in African-admixed populations.

Sci Rep 2017 03 16;7:44548. Epub 2017 Mar 16.

Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10, rs1426654) and SLC45A2 (minimum p = 9.71 × 10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.
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http://dx.doi.org/10.1038/srep44548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353593PMC
March 2017

Breastfeeding associated with higher lung function in African American youths with asthma.

J Asthma 2017 Oct 8;54(8):856-865. Epub 2016 Dec 8.

a Department of Medicine , University of California San Francisco , San Francisco , CA , USA.

Objective: In the United States, Puerto Ricans and African Americans have lower prevalence of breastfeeding and worse clinical outcomes for asthma compared with other racial/ethnic groups. We hypothesize that the history of breastfeeding is associated with increased forced expiratory volume in 1 second (FEV) % predicted and reduced asthma exacerbations in Latino and African American youths with asthma.

Methods: As part of the Genes-environments & Admixture in Latino Americans (GALA II) Study and the Study of African Americans, asthma, Genes & Environments (SAGE II), we conducted case-only analyses in children and adolescents aged 8-21 years with asthma from four different racial/ethnic groups: African Americans (n = 426), Mexican Americans (n = 424), mixed/other Latinos (n = 255), and Puerto Ricans (n = 629). We investigated the association between any breastfeeding in infancy and FEV% predicted using multivariable linear regression; Poisson regression was used to determine the association between breastfeeding and asthma exacerbations.

Results: Prevalence of breastfeeding was lower in African Americans (59.4%) and Puerto Ricans (54.9%) compared to Mexican Americans (76.2%) and mixed/other Latinos (66.9%; p < 0.001). After adjusting for covariates, breastfeeding was associated with a 3.58% point increase in FEV% predicted (p = 0.01) and a 21% reduction in asthma exacerbations (p = 0.03) in African Americans only.

Conclusion: Breastfeeding was associated with higher FEV% predicted in asthma and reduced number of asthma exacerbations in African American youths, calling attention to continued support for breastfeeding.
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http://dx.doi.org/10.1080/02770903.2016.1266496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130885PMC
October 2017

Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies.

Chest 2017 04 1;151(4):804-812. Epub 2016 Dec 1.

Department of Medicine, University of California, San Francisco, San Francisco; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco.

Background: Asthma disproportionately affects minority populations and is associated with psychosocial stress such as racial/ethnic discrimination. We aimed to examine the association of perceived discrimination with asthma and poor asthma control in African American and Latino youth.

Methods: We included African American (n = 954), Mexican American (n = 1,086), other Latino (n = 522), and Puerto Rican Islander (n = 1,025) youth aged 8 to 21 years from the Genes-Environments and Admixture in Latino Americans study and the Study of African Americans, Asthma, Genes, and Environments. Asthma was defined by physician diagnosis, and asthma control was defined based on the National Heart, Lung, and Blood Institute guidelines. Perceived racial/ethnic discrimination was assessed by the Experiences of Discrimination questionnaire, with a focus on school, medical, and public settings. We examined the associations of perceived discrimination with each outcome and whether socioeconomic status (SES) and global African ancestry modified these associations.

Results: African American children reporting any discrimination had a 78% greater odds of experiencing asthma (OR, 1.78; 95% CI, 1.33-2.39) than did those not reporting discrimination. Similarly, African American children faced increased odds of poor asthma control with any experience of discrimination (OR, 1.97; 95% CI, 1.42-2.76) over their counterparts not reporting discrimination. These associations were not observed among Latino children. We observed heterogeneity of the association between reports of discrimination and asthma according to SES, with reports of discrimination increasing the odds of having asthma among low-SES Mexican American youth (interaction P = .01) and among high-SES other Latino youth (interaction P = .04).

Conclusions: Perceived discrimination is associated with increased odds of asthma and poorer control among African American youth. SES exacerbates the effect of perceived discrimination on having asthma among Mexican American and other Latino youth.
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http://dx.doi.org/10.1016/j.chest.2016.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472516PMC
April 2017

Individualized therapy for persistent asthma in young children.

J Allergy Clin Immunol 2016 12 21;138(6):1608-1618.e12. Epub 2016 Oct 21.

Nemours Children's Health System, Jacksonville, FL.

Background: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications.

Methods: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response.

Results: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/μL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments.

Conclusions: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.
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http://dx.doi.org/10.1016/j.jaci.2016.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148729PMC
December 2016

Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function.

PLoS One 2016 24;11(8):e0157848. Epub 2016 Aug 24.

Division of Allergy-Immunology, Department of Pediatrics, Northwestern University, Chicago, Illinois, United States of America.

Background: Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk.

Methods: We included Latino children, adolescents, and young adults aged 8-21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function.

Results: RSV infection (OR 9.9, 95%CI 4.9-20.2) and other LRI (OR 9.1, 95%CI 7.2-11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3-50.2) and genotype-LRI (OR 11.7, 95% CI 8.8-16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted.

Conclusions: A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157848PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996454PMC
July 2017

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

N Engl J Med 2016 Aug;375(7):619-30

From the Divisions of Allergy and Immunology (W.J.S., S.N.B., W.P.) and Respiratory Diseases (J.M.G.), Boston Children's Hospital and Harvard Medical School, and the Division of Allergy and Pulmonary Medicine, Brigham and Women's Hospital and Harvard Medical School (E.I.) - all in Boston; the Departments of Public Health Sciences (D.T.M., S.J.B.) and Pediatrics (I.M.P.), Penn State College of Medicine, Hershey, and the University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center (F.H.) and the Department of Pediatrics, Allegheny General Hospital (D.A.G.), Pittsburgh - all in Pennsylvania; Stroger Hospital of Cook County and Department of Pediatrics, Rush University Medical Center (J.N.M.), Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), and University of Illinois at Chicago (H.V.K.) - all in Chicago; the Breathing Institute, Children's Hospital Colorado (S.J.S.), and the Departments of Pediatrics (S.J.S.) and Medicine (M.E.W.), University of Colorado School of Medicine, Aurora, and the Department of Pediatrics (R.C., J.T.O.) and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine (M.E.W.), National Jewish Health, Denver - both in Colorado; the Department of Pediatrics, Emory University, Atlanta (A.M.F.); the Section of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health (D.J.J., R.F.L.) and the School of Pharmacy, University of Wisconsin-Madison (C.A.S.) - both in Madison; Washington University School of Medicine in St. Louis and the Department of Pediatrics, St. Louis Children's Hospital (L.B.B., A.B.) - both in St. Louis; the Departments of Pediatrics (M.D.C.) and Medicine (S.C.L.) and the Airway Clinical Research Center (N.L.), University of California, San Francisco, San Francisco, Benioff Children's Hospital Oakland, Oakland (M.B., J.M.), and Olive View UCLA Medical Center and Department of Pediatrics, David Geff

Background: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.

Methods: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial.

Results: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events.

Conclusions: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085065PMC
http://dx.doi.org/10.1056/NEJMoa1515990DOI Listing
August 2016

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.

Am J Respir Crit Care Med 2016 06;193(11):1271-80

20 Centro de Neumología Pediatrica, San Juan, Puerto Rico; and.

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.
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http://dx.doi.org/10.1164/rccm.201508-1706OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910900PMC
June 2016

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial.

JAMA 2015 Nov;314(19):2034-2044

Department of Pediatrics, Washington University in St Louis School of Medicine, St Louis, Missouri (Bacharier, Beigelman, Castro); Cincinnati Children's Hospital and Medical Center, Cincinnati, Ohio (Guilbert); Department of Public Health Sciences, Pennsylvania State University, Hershey (Mauger, Boehmer); Department of Pediatrics, Emory University, Atlanta, Georgia (Fitzpatrick); Pediatrics Section of Allergy, Immunology, and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison (Jackson); Division of Allergy/Immunology, Boston Children's Hospital, Boston, Massachusetts (Baxi, Phipatanakul, Sheehan); Benioff Children's Hospital, Oakland, California (Benson, Meade); Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, Missouri (Burnham); University of California, San Francisco, Medicine, San Francisco (Cabana, Lazarus); Rainbow Babies and Children's Hospital, Cleveland, Ohio (Chmiel, Ross); Department of Pediatrics, National Jewish Health, Denver, Colorado (Covar, Olin); University of Arizona, Arizona Respiratory Center, Tucson (Daines, Morgan); Division of Respiratory Diseases, Boston Children's Hospital, Boston, Massachusetts (Gaffin); Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania (Gentile); The University of Pittsburgh Asthma Institute, Pittsburgh, Pennsylvania (Holguin); Brigham and Women's Hospital, Boston, Massachusetts (Israel); Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico (Kelly); Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison (Lemanske); Airway Clinical Research Center, University of California, San Francisco, San Francisco, California (Ly); Stroger Hospital of Cook County Pediatric Services, Chicago, Illinois (Moy); Wake Forest University School of Medicine, Winston-Salem, North Carolina (Peters); Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois (Pongracic); Department of Pediatrics/Pulmonary, University of New Mexico, Albuquerque (Raissy); University of Wisconsin-Madison, Madison (Sorkness); The Breathing Institute, Children's Hospital Colorado, Denver (Szefler); University of Virginia School of Medicine, Charlottesville (Teague); Department of Pediatrics, San Francisco General Hospital, San Francisco, California (Thyne); Arizona Respiratory Center, University of Arizona, Tucson, Arizona (Martinez).

Importance: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.

Objective: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes.

Design, Setting, And Participants: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment.

Intervention: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period.

Main Outcomes And Measures: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.

Results: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.

Conclusions And Relevance: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.

Trial Registration: clinicaltrials.gov Identifier: NCT01272635.
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http://dx.doi.org/10.1001/jama.2015.13896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757487PMC
November 2015

Obesity and bronchodilator response in black and Hispanic children and adolescents with asthma.

Chest 2015 Jun;147(6):1591-1598

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA; Department of Medicine, University of California, San Francisco, CA.

Background: Obesity is associated with poor asthma control, increased asthma morbidity, and decreased response to inhaled corticosteroids. We hypothesized that obesity would be associated with decreased bronchodilator responsiveness in children and adolescents with asthma. In addition, we hypothesized that subjects who were obese and unresponsive to bronchodilator would have worse asthma control and would require more asthma controller medications.

Methods: In the Study of African Americans, Asthma, Genes, and Environments (SAGE II) and the Genes-environments and Admixture in Latino Americans (GALA II) study, two identical, parallel, case-control studies of asthma, we examined the association between obesity and bronchodilator response in 2,963 black and Latino subjects enrolled from 2008 to 2013 using multivariable logistic regression. Using bronchodilator responsiveness, we compared asthma symptoms, controller medication usage, and asthma exacerbations between nonobese (< 95th% BMI) and obese (≥ 95th% BMI) subjects.

Results: The odds of being bronchodilator unresponsive were 24% (OR, 1.24; 95% CI, 1.03-1.49) higher among obese children and adolescents compared with their not obese counterparts after adjustment for age, race/ethnicity, sex, recruitment site, baseline lung function (FEV1/FVC), and controller medication. Bronchodilator-unresponsive obese subjects were more likely to report wheezing (OR, 1.38; 95% CI, 1.13-1.70), being awakened at night (OR, 1.34; 95% CI, 1.09-1.65), using leukotriene receptor inhibitors (OR, 1.33; 95% CI, 1.05-1.70), and using inhaled corticosteroid with long-acting β2-agonist (OR, 1.37; 95% CI, 1.05-1.78) than were their nonobese counterpart. These associations were not seen in the bronchodilator-responsive group.

Conclusions: Obesity is associated with bronchodilator unresponsiveness among black and Latino children and adolescents with asthma. The findings on obesity and bronchodilator unresponsiveness represent a unique opportunity to identify factors affecting asthma control in blacks and Latinos.
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http://dx.doi.org/10.1378/chest.14-2689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451713PMC
June 2015

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

J Allergy Clin Immunol 2015 Jun 6;135(6):1502-10. Epub 2014 Dec 6.

Department of Allergy and Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif.

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.
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http://dx.doi.org/10.1016/j.jaci.2014.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458233PMC
June 2015

Genetic ancestry influences asthma susceptibility and lung function among Latinos.

J Allergy Clin Immunol 2015 Jan 6;135(1):228-35. Epub 2014 Oct 6.

Veterans Caribbean Health Care System, San Juan, Puerto Rico.

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.
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http://dx.doi.org/10.1016/j.jaci.2014.07.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289103PMC
January 2015

Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma.

PLoS One 2014 12;9(8):e104396. Epub 2014 Aug 12.

Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104396PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130548PMC
April 2015

Socioeconomic status and asthma control in African American youth in SAGE II.

J Asthma 2014 Sep 14;51(7):720-8. Epub 2014 May 14.

Department of Medicine, Division of Pulmonary and Critical Care Medicine .

Objective: African Americans are disproportionately burdened by asthma. We assessed the individual and joint contribution of socioeconomic status (SES) on asthma morbidity among African American youth.

Methods: We examined 686 African Americans (8-21 years) with asthma. To account for the joint effects of SES, a composite index was derived from maternal educational attainment, household income, and insurance status. Ordinal logistic regression was used to estimate the individual and joint effect of SES on asthma control. Models were adjusted for age, sex, controller medication use, in utero smoke exposure, family history of asthma, family history of rhinitis, breastfeeding, daycare attendance, and mold exposure.

Results: Participants were classified as Poorly Controlled Asthma (40.8%), Partially Controlled Asthma (29.7%), or Controlled Asthma (30.2%). Of the individual SES indicators, low income was the strongest predictor of poor asthma control. Children with low income had worse asthma control than those with higher income (OR 1.39; 95% CI 0.92-2.12). The SES index ranged from 4-9. SES was associated with 17% increased odds of poor asthma control with each decrease in the index (95% CI 1.05-1.32). The SES index was associated with asthma-related symptoms, nocturnal awakenings, limited activity, and missed school days.

Conclusions: The negative effects of SES were observed along the entire socioeconomic gradient, and the adverse asthma outcomes observed in African American youth were not limited to the very poor. We also found that the SES index may be a more consistent and useful predictor of poor asthma outcomes than each indicator alone.
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http://dx.doi.org/10.3109/02770903.2014.905593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257058PMC
September 2014

Validation of parental reports of asthma trajectory, burden, and risk by using the pediatric asthma control and communication instrument.

J Allergy Clin Immunol Pract 2014 Mar-Apr;2(2):186-92. Epub 2014 Jan 17.

Department of Preventive Medicine, University of Southern California, Los Angeles, Calif.

Background: Despite a growing interest, few pediatric asthma questionnaires assess multiple dimensions of asthma morbidity, as recommended by national asthma guidelines, or use patient-reported outcomes.

Objective: To evaluate a questionnaire that measures multiple dimensions of parent-reported asthma morbidity (Direction, Bother, and Risk).

Methods: We administered the Pediatric Asthma Control and Communication Instrument (PACCI) and assessed asthma control (PACCI Control), quality of life, and lung function among children who presented for routine asthma care. The PACCI was evaluated for discriminative validity.

Results: A total of 317 children participated (mean age, 8.2 years; 58% boys; 44% African American). As parent-reported PACCI Direction changed from "better" to "worse," we observed poorer asthma control (P < .001), mean Pediatric Asthma Caregiver Quality of Life Questionnaire (PACQLQ) scores (P < .001), and FEV1% (P = .025). Linear regression showed that, for each change in PACCI Direction, the mean PACQLQ score decreased by -0.6 (95% CI, -0.8 to -0.4). As parent-reported PACCI Bother changed from "not bothered" to "very bothered," we observed poorer asthma control (P < .001) and lower mean PACQLQ scores (P < .001). Linear regression showed that, for each change in PACCI Bother category, the mean PACQLQ score decreased by -1.1 (95% CI, -1.3 to -0.9). Any reported PACCI Risk event (emergency department visit, hospitalization, or use of an oral corticosteroid) was associated with poorer asthma control (P < .05) and PACQLQ scores (P < .01).

Conclusions: PACCI Direction, Bother, and Risk are valid measures of parent-reported outcomes and show good discriminative validity. The PACCI is a simple clinical tool to assess multiple dimensions of parent-reported asthma morbidity, in addition to risk and control.
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http://dx.doi.org/10.1016/j.jaip.2013.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361408PMC
May 2014

Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies.

Am J Respir Crit Care Med 2013 Nov;188(10):1202-9

1 Department of Medicine.

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.
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http://dx.doi.org/10.1164/rccm.201306-1016OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863734PMC
November 2013

A genome-wide association study of bronchodilator response in Latinos implicates rare variants.

J Allergy Clin Immunol 2014 Feb 29;133(2):370-8. Epub 2013 Aug 29.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.

Background: The primary rescue medication to treat acute asthma exacerbation is the short-acting β₂-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR).

Objective: To identify genetic variation associated with bronchodilator drug response in Latino children with asthma.

Methods: We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity.

Results: We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10(-8)), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells.

Conclusion: Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.
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http://dx.doi.org/10.1016/j.jaci.2013.06.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938989PMC
February 2014

Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies.

Am J Respir Crit Care Med 2013 Aug;188(3):309-18

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.

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.
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http://dx.doi.org/10.1164/rccm.201302-0264OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778732PMC
August 2013

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.

J Allergy Clin Immunol 2013 Oct 16;132(4):896-905.e1. Epub 2013 May 16.

Division of Allergy and Immunology, Children's Memorial Hospital, and the Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Ill. Electronic address:

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[β] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[β] [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.
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http://dx.doi.org/10.1016/j.jaci.2013.02.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788073PMC
October 2013