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1.  Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function 
PLoS ONE  2016;11(8):e0157848.
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.
doi:10.1371/journal.pone.0157848
PMCID: PMC4996454  PMID: 27556405
2.  Increased expression of the epithelial anion transporter Pendrin/SLC26A4 in nasal polyps of patients with Chronic Rhinosinusitis 
Background
Chronic rhinosinusitis (CRS) is a multifactorial disease of unknown etiology characterized by sinonasal inflammation, increased mucus production and defective mucociliary clearance. Pendrin, an epithelial anion transporter, is increased in asthma and chronic obstructive pulmonary disease. Pendrin increases mucus production and regulates mucociliary clearance.
Objectives
We sought to investigate the expression of pendrin and the mucus-related protein Muc5AC in sinonasal tissues of control and CRS patients, and to evaluate the regulation of pendrin expression in nasal epithelial cells (NECs) in vitro.
Methods
The expression and distribution of pendrin in sinonasal tissues was analyzed using real-time PCR, immunoblot analysis and immunohistochemistry. Differentiated NECs were used to study the regulation of pendrin expression.
Results
Increased pendrin was observed in NP tissue of CRS patients. Immunohistochemistry analysis revealed that pendrin was largely restricted to the epithelial layer. Pendrin expression significantly correlated with inflammatory cell markers, suggesting that the factors made by these cells may induce pendrin expression. Furthermore, both pendrin and periostin (a biomarker in asthma) correlated with IL-13, suggesting that pendrin may be induced by this cytokine in sinonasal tissues. The mucus component protein Muc5AC, correlated weakly with pendrin, indicating that pendrin might modulate mucus production in NPs. In cultured NECs, pendrin expression was induced by Th2 cytokines and was induced synergistically when Th2 cytokines were combined with IL-17A. Interestingly, human rhinovirus had a potentiating effect on IL-13 induced pendrin expression. Dexamethasone suppressed pendrin expression suggesting that the therapeutic benefit of dexamethasone in asthma and CRS may involve regulation of pendrin expression.
Conclusions
Th2-mediated pendrin expression is increased in nasal polyps of patients with CRS and may lead to increased inflammation, mucus production and a decreased mucociliary clearance.
doi:10.1016/j.jaci.2015.05.024
PMCID: PMC4679496  PMID: 26143180
Pendrin; SLC26A4; Periostin; Muc5AC; Chronic rhinosinusitis; nasal polyp; mucus; mucociliary clearance; nasal epithelial cells
3.  A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome 
Nature Communications  2016;7:12522.
The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.
The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.
doi:10.1038/ncomms12522
PMCID: PMC5062574  PMID: 27725671
4.  Measurement and Comparison of Health Utility Assessments in Chronic Rhinosinusitis 
Background
Chronic rhinosinusitis (CRS) is a common condition encountered in primary care medicine and is estimated to affect 12.5% of the United States population. This study aims to compare methods of assessing health utility in CRS
Methods
A cross-sectional sample of CRS patients (n=137) were interviewed using direct health utility assessment measures: the visual analog scale (VAS), time trade-off (TTO), and standard gamble (SG). General quality of life (QOL) scores were obtained via the 36-item Short Form Health Survey (SF-36) and converted to SF-6D health utility values using a Bayesian algorithm. Disease specific quality of life was measured with the SNOT-22. A selected subgroup of patients (n=51) not initiating surgery or new treatment for CRS were re-interviewed within three weeks.
Results
The mean (±SD) health utilities were VAS 0.69(±0.19), TTO 0.80(±0.27), SG 0.93(±0.11), SF-6D 0.72(±0.12) and differed significantly (p<0.001). Only VAS scores differed based on disease state classification or the presence of nasal polyposis. Correlations between methods of determining health utility were weak, but significant. VAS, TTO and SF-6D scores were significantly associated with SNOT-22 (p<0.001 for all), however SG and SNOT-22 were poorly correlated (Spearman correlation=-0.33). The test-retest reliability of TTO (Spearman correlation=0.71) and SG (0.73) was strong.
Conclusions
CRS patients show significant impairment in quality of life, with health utility values similar to those of patients with AIDS or intermittent claudication using similar methods. The method of ascertainment significantly affects measured health utility, but the degree of impairment warrants improved recognition and appropriate treatment of the condition.
doi:10.1002/alr.21556
PMCID: PMC4607564  PMID: 26077390
chronic rhinosinusitis; quality of life; utility values; time trade-off; standard gamble; visual analog scale; SF-6D
5.  Wheezing exacerbations in early childhood: evaluation, treatment, and recent advances relevant to the genesis of asthma 
Children who begin wheezing during early childhood are seen frequently by health care providers in primary care, in hospitals and emergency departments, and by allergists and pulmonologists. When young children, like the 2 year-old case presented here, are evaluated for wheezing, a frequent challenge for clinicians is to determine whether the symptoms represent transient, viral-induced wheezing, or whether sufficient risk factors are present to suspect that the child may experience recurrent wheezing and develop asthma. Most factors influencing prognosis are not mutually exclusive, are interrelated (i.e., cofactors), and often represent gene-environment interactions. Many of these risk factors have been, and continue to be, investigated in prospective studies in order to decipher their relative importance with the goal of developing new therapies and interventions in the future. The etiologies of wheezing in young children, diagnostic methods, treatment, prognostic factors, and potential targets for prevention of the development of asthma are discussed.
doi:10.1016/j.jaip.2014.06.024
PMCID: PMC4190166  PMID: 25213046
asthma; wheezing; childhood; virus
6.  Genome-wide Association Study and Admixture Mapping Reveal New Loci Associated with Total IgE Levels in Latinos 
Background
Immunoglobulin E (IgE) is a key mediator of allergic inflammation and is frequently elevated in allergic disorders.
Objective
To identify genetic variants associated with IgE levels in Latinos.
Methods
We performed a genome-wide association study (GWAS) and admixture mapping of total IgE levels in 3,334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1,564 European Americans, and 3,187 African Americans from independent studies.
Results
We confirmed associations of six genes identified by previous GWAS and identified a novel genome-wide significant association of a polymorphism in ZNF365 with total IgE (rs200076616, p=2.3x10−8). We next identified four admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) where 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 levels of IgE (p=4.95x10−8). All but 22q13.1 were replicated in an independent sample of Latinos, and two of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified six genome-wide significant single nucleotide polymorphisms in Latinos, two of which replicated in European Americans. Another SNP was peak-wide significant within 14q23.2 in African Americans (rs1741099, p=3.7x10−6), and replicated in non-African American samples (p=0.011).
Conclusion
We confirmed genetic associations at six genes, and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse, multi-ethnic populations to uncover novel loci associated with total IgE levels.
doi:10.1016/j.jaci.2014.10.033
PMCID: PMC4458233  PMID: 25488688
immunoglobulin E; genome-wide association study; admixture mapping; allergy; asthma; next-generation sequencing; Latinos; Hispanics; minority populations
8.  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 5,493 Latinos with and without asthma from three 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% confidence interval [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=0.001). 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 forced expiratory volume in the first second (−77±19 ml, p=5.8×10−5 and −83±19 ml, p=1.1×10−5, respectively) and forced vital capacity (−100±21 ml, p=2.7×10−6 and −107±22 ml, p=1.0×10−6, respectively).
Conclusion
Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.
doi:10.1016/j.jaci.2014.07.053
PMCID: PMC4289103  PMID: 25301036
genetic admixture; childhood asthma; Hispanics; minority; pulmonary function
9.  Vitamin E and D regulation of allergic asthma immunopathogenesis 
International immunopharmacology  2014;23(1):364-372.
Asthma occurs as complex interactions of the environmental and genetics. Clinical studies and animal models of asthma indicate dietary factors such as vitamin E and vitamin D as protective for asthma risk. In this review, we discuss opposing regulatory functions of tocopherol isoforms of vitamin E and regulatory functions of vitamin D in asthma and how the variation in global prevalence of asthma may be explained, at least in part, by these dietary components.
doi:10.1016/j.intimp.2014.08.007
PMCID: PMC4254328  PMID: 25175918
asthma; α-tocopherol; γ-tocopherol; vitamin D; human; animal models
10.  PLASTICITY OF AIRWAY EPITHELIAL CELLS 
doi:10.1016/j.jaci.2011.10.006
PMCID: PMC3229749  PMID: 22133319
Airway epithelial cell; plasticity; transdifferentiation
11.  Genome-wide interaction studies reveal sex-specific asthma risk alleles 
Human Molecular Genetics  2014;23(19):5251-5259.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10−6, of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
doi:10.1093/hmg/ddu222
PMCID: PMC4159149  PMID: 24824216
12.  Viral diversity in asthma 
Synopsis
Asthma exacerbations are precipitated primarily by respiratory virus infection and frequently require immediate medical intervention. Studies of childhood and adult asthma have implicated a wide variety of respiratory viruses in exacerbations. By focusing on both RNA and DNA respiratory viruses and some newly identified viruses, this review illustrates the diversity and highlights some of the uncertainties that exist in our understanding of virus-related asthma exacerbations.
doi:10.1016/j.iac.2010.08.001
PMCID: PMC2967440  PMID: 21029933
asthma; exacerbation; respiratory; newly identified virus
13.  GWAS and admixture mapping identify different asthma-associated loci in Latinos: The GALA II 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
To identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping.
Methods
Latino children with asthma (n = 1,893) and healthy controls (n = 1,881) were recruited from five 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 = 0.01). 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 the 17q21 asthma in Latinos (IKZF3, lowest p-value: rs90792, OR: 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, while genome-wide association confirms the previously identified locus on 17q21.
doi:10.1016/j.jaci.2013.08.055
PMCID: PMC4085159  PMID: 24406073
Asthma; Latinos; Admixture Mapping; Genome-wide Association Study; Local Ancestry; 17q21; 6p21
14.  GREATER IN VITRO SUSCEPTIBILTY TO RHINOVIRUS INFECTION OF BRONCHIAL THAN NASAL AIRWAY EPITHELIAL CELLS FROM HUMAN SUBJECTS 
Background
Human rhinoviruses (HRVs) characteristically cause upper respiratory tract infection but they also infect the lower airways causing acute bronchitis and exacerbating asthma.
Objective
Our purpose was to study ex-vivo the differences in the response to HRV infection of nasal and bronchial epithelial cultures from the same healthy and asthmatic individuals, using conditions favoring development of fully differentiated pseudostratified mucociliary epithelium.
Methods
Cells from the inferior turbinates and bronchial tree of 5 healthy and 6 asthmatic individuals were cultured at an air-liquid interface. Cultures were infected with HRV-16 and after 48hrs the degree of infection was measured.
Results
Baseline median transepithelial resistance (Rte) was lower in human bronchial (HBE) than nasal (HNE) epithelial cell cultures (195Ω.cm2 [95%CI=164–252] vs 366Ω.cm2 [234–408] respectively, p<0.01). Virus replicated more easily in HBEs than HNEs based on virus shedding in apical wash (LogTCID50/0.1ml=2.0 [1.0–2.5] vs. 0.5 [0.5–1.5], p<0.01), and on a 20–30 fold greater viral load and number of infected cells in HBEs than in HNEs. The increases in expression of RANTES and protein kinase PKR were greater in HBE than in HNE cultures, as well as the concentrations of interleukin (IL)-8, IL-1α, RANTES and IP-10 in basolateral medium. However, no significant differences between asthmatic and healthy subjects (including interferon beta1 expression) were found.
Conclusions
Differentiated nasal epithelial cells may have mechanisms of increased resistance to rhinovirus infection compared with bronchial epithelial cells. We could not confirm previous reports of increased susceptibility to HRV infection in epithelial cells from asthmatic subjects.
doi:10.1016/j.jaci.2009.03.010
PMCID: PMC2744461  PMID: 19428098
Human Rhinovirus; nasal and bronchial airway epithelial cells; air-liquid interface
15.  Role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos 
Background
Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of ALOX5AP and LTA4H in asthma have been inconclusive.
Objective
To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans.
Methods
The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single-nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analyzed for associations with asthma and asthma-related phenotypes in 687 parent-child trios of Mexican and Puerto Rican origin.
Results
In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P = 0.007 and 0.05, respectively). Among Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (OR = 0.78, P = 0.02) and baseline lung function (P = 0.018) in Puerto Ricans. A gene-gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P = 0.003, in the combined sample).
Conclusion
Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations.
doi:10.1111/j.1365-2222.2009.03438.x
PMCID: PMC2866051  PMID: 20067482
Asthma; Leukotriene; Latino populations; Association study
16.  Plasminogen activator inhibitor-1 in sputum and nasal fluids increases in asthmatics during common colds 
Capsule Summary
This study showed that sputum and nasal lavage levels of plasminogen activator inhibitor-1 (PAI-1) rise during a common cold in asthmatic patients. This rise may contribute to the progression of airway remodeling.
doi:10.1016/j.jaci.2013.11.009
PMCID: PMC4004714  PMID: 24373352
asthma; plasminogen activator inhibitor-1; common cold
17.  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.
doi:10.1164/rccm.201306-1016OC
PMCID: PMC3863734  PMID: 24050698
asthma; health status disparities; minority health; educational status; poverty
18.  Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The GALA II Study 
Background
Atopy varies by ethnicity even within Latino groups. This variation may be due to environmental, socio-cultural or genetic factors.
Objective
To examine risk factors for atopy within a nationwide study of U.S. Latino children with and without asthma.
Methods
Aeroallergen skin test repsonse was analyzed in 1830 US latino subjects. Key determinants of atopy included: country / region of origin, generation in the U.S., acculturation, genetic ancestry and site to which individuals 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 tests. 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 as many positive skin tests in participants with asthma (95% CI:1.62–5.57) and 3.26 times as many positive skin tests in control participants (95% CI: 1.02–10.39). Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, Puerto Rican [exp(β) (95%CI): 1.31(1.02–1.69)] and mixed ethnicity [exp(β) (95%CI):1.27(1.03–1.56)] asthmatics had a greater probability of positive skin tests compared to Mexican asthmatics. 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 U.S. 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.
doi:10.1016/j.jaci.2013.02.046
PMCID: PMC3788073  PMID: 23684070
Latino; atopy; region of origin; genetic ancestry; immigration; skin test; aeroallergen
19.  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.
doi:10.1164/rccm.201302-0264OC
PMCID: PMC3778732  PMID: 23750510
air pollution; minority; children; asthma
20.  Human rhinovirus infection causes different DNA methylation changes in nasal epithelial cells from healthy and asthmatic subjects 
BMC Medical Genomics  2014;7:37.
Background
Mechanisms underlying the development of virus-induced asthma exacerbations remain unclear. To investigate if epigenetic mechanisms could be involved in virus-induced asthma exacerbations, we undertook DNA methylation profiling in asthmatic and healthy nasal epithelial cells (NECs) during Human Rhinovirus (HRV) infection in vitro.
Methods
Global and loci-specific methylation profiles were determined via Alu element and Infinium Human Methylation 450 K microarray, respectively. Principal components analysis identified the genomic loci influenced the most by disease-status and infection. Real-time PCR and pyrosequencing were used to confirm gene expression and DNA methylation, respectively.
Results
HRV infection significantly increased global DNA methylation in cells from asthmatic subjects only (43.6% to 44.1%, p = 0.04). Microarray analysis revealed 389 differentially methylated loci either based on disease status, or caused by virus infection. There were disease-associated DNA methylation patterns that were not affected by HRV infection as well as HRV-induced DNA methylation changes that were unique to each group. A common methylation locus stood out in response to HRV infection in both groups, where the small nucleolar RNA, H/ACA box 12 (SNORA12) is located. Further analysis indicated that a relationship existed between SNORA12 DNA methylation and gene expression in response to HRV infection.
Conclusions
We describe for the first time that Human rhinovirus infection causes DNA methylation changes in airway epithelial cells that differ between asthmatic and healthy subjects. These epigenetic differences may possibly explain the mechanism by which respiratory viruses cause asthma exacerbations.
doi:10.1186/1755-8794-7-37
PMCID: PMC4080608  PMID: 24947756
21.  Analysis of Latino populations from GALA and MEC studies reveals genomic loci with biased local ancestry estimation 
Bioinformatics  2013;29(11):1407-1415.
Motivation: Local ancestry analysis of genotype data from recently admixed populations (e.g. Latinos, African Americans) provides key insights into population history and disease genetics. Although methods for local ancestry inference have been extensively validated in simulations (under many unrealistic assumptions), no empirical study of local ancestry accuracy in Latinos exists to date. Hence, interpreting findings that rely on local ancestry in Latinos is challenging.
Results: Here, we use 489 nuclear families from the mainland USA, Puerto Rico and Mexico in conjunction with 3204 unrelated Latinos from the Multiethnic Cohort study to provide the first empirical characterization of local ancestry inference accuracy in Latinos. Our approach for identifying errors does not rely on simulations but on the observation that local ancestry in families follows Mendelian inheritance. We measure the rate of local ancestry assignments that lead to Mendelian inconsistencies in local ancestry in trios (MILANC), which provides a lower bound on errors in the local ancestry estimates. We show that MILANC rates observed in simulations underestimate the rate observed in real data, and that MILANC varies substantially across the genome. Second, across a wide range of methods, we observe that loci with large deviations in local ancestry also show enrichment in MILANC rates. Therefore, local ancestry estimates at such loci should be interpreted with caution. Finally, we reconstruct ancestral haplotype panels to be used as reference panels in local ancestry inference and show that ancestry inference is significantly improved by incoroprating these reference panels.
Availability and implementation: We provide the reconstructed reference panels together with the maps of MILANC rates as a public resource for researchers analyzing local ancestry in Latinos at http://bogdanlab.pathology.ucla.edu.
Contact: bpasaniuc@mednet.ucla.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt166
PMCID: PMC3661056  PMID: 23572411
22.  Incidence and associated pre-morbid diagnoses of patients with chronic rhinosinusitis 
Background
Chronic rhinosinusitis (CRS) is a prevalent condition with underexplored risk factors.
Objectives
To determine CRS incidence and evaluate associations with a range of pre-morbid medical conditions for CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) using real-world clinical practice data.
Methods
Electronic health record (EHR) data from 446,480 Geisinger Clinic primary care patients was used for a retrospective longitudinal cohort study for data from 2001–2010. Using logistic regression, newly diagnosed CRS cases between 2007-2009 were compared to frequency-matched controls on pre-morbid factors in the immediate (0-6 months), intermediate (7-24 months) and entire observed timeframes prior to diagnosis.
Results
: The average incidence of CRS was 83 (±13) CRSwNP cases per 100,000 person-years and 1048 (±78) CRSsNP cases per 100,000 person-years. Between 2007-2009, 595 patients with incident CRSwNP and 7523 patients with incident CRSsNP were identified and compared to 8118 controls. Compared to controls and CRSsNP, CRSwNP patients were older and more likely to be male. Prior to diagnosis, CRS patients had a higher prevalence of acute rhinosinusitis, allergic rhinitis, chronic rhinitis, asthma, gastroesophageal reflux disease (GERD), adenotonsillitis, sleep apnea, anxiety and headaches (all p < 0.001). CRSsNP had a higher pre-morbid prevalence of infections of the upper and lower airway, skin/soft tissue and urinary tract (all p < 0.001). In the immediate and intermediate timeframes analyzed, patients who developed CRS had more outpatient encounters and antibiotic prescriptions (p < 0.001) but guideline-recommended diagnostic testing was performed in a minority of cases.
Conclusions
Patients who are diagnosed with CRS have a higher pre-morbid prevalence of anxiety, headaches, GERD, sleep apnea and infections of the respiratory system and some non-respiratory sites that results in higher antibiotic, corticosteroid and health care utilization. The use of guideline-recommended diagnostic testing for confirmation of CRS remains poor.
doi:10.1016/j.jaci.2013.02.002
PMCID: PMC3788631  PMID: 23541327
epidemiology; incidence; sinusitis; nasal polyps; risk factors; asthma; rhinitis; nested case-control study; antibiotics; diagnosis
23.  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.
doi:10.1164/rccm.201211-2116OC
PMCID: PMC3678111  PMID: 23392439
obesity; asthma control; race and ethnicity; age; sex
24.  Genetics of Chronic Rhinosinusitis: State of the Field and Directions Forward 
The etiology of chronic rhinosinusitis (CRS) remains unclear. Study of the genetic susceptibility to CRS may be a valuable strategy to understand the pathogenesis of this burdensome disorder. The purpose of this review is to critically evaluate the current literature regarding the genetics of CRS in a comprehensive fashion. The most promising findings from candidate gene studies include the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR), as well as genes involved in antigen presentation, innate and adaptive immune responses, tissue remodeling, and arachidonic acid metabolism. We also review the few hypothesis-independent genetic studies of CRS (i.e., linkage analysis and pooling-based genome-wide association studies). Interpretation of the current literature is limited by challenges with study design, sparse replication, few functional correlates of associated polymorphisms, and inadequate examination of linkage disequilibrium or expression quantitative trait loci for reported associations. Given the relationship of CRS to other airway disorders with well-characterized genetic components (e.g., asthma), study of the genetics of CRS deserves increased attention and investment, including the organization of large, detailed, and collaborative studies to advance knowledge of the mechanisms that underlie this disorder.
doi:10.1016/j.jaci.2013.01.028
PMCID: PMC3715963  PMID: 23540616
Genetics; genome; variation; chronic rhinosinusitis; nasal polyposis; single nucleotide polymorphism; polymorphism; candidate gene; linkage; genome wide association study; susceptibility; sinusitis
25.  The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study 
Respiratory Research  2014;15(1):31.
Background
Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.
Methods
To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.
Results
In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV1 and FVC at ages 21–55 years.
Conclusion
Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.
doi:10.1186/1465-9921-15-31
PMCID: PMC4003816  PMID: 24629024
α-tocopherol; γ-tocopherol; FEV1; FVC; Human

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