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1.  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
2.  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
3.  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
4.  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
5.  Further Replication Studies of the EVE Consortium Meta-Analysis Identifies Two Asthma Risk Loci in European Americans 
Background
Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.
Objectives
We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.
Methods
We selected 3186 SNPs for replication based on the p-values from the EVE Consortium meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study and the resulting test statistics were combined in a meta-analysis.
Results
Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25) and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not replicate any additional associations in the African American or Latino individuals.
Conclusions
This extended replication study identified two additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latino individuals highlights the difficulty in replicating associations in admixed populations.
doi:10.1016/j.jaci.2012.07.054
PMCID: PMC3666859  PMID: 23040885
Asthma; genetic risk factors; meta-analysis; KLK3
6.  The impact of secondhand smoke on asthma control among Black and Latino children 
Background
Among people with asthma, the clinical impact and relative contribution of maternal smoking during pregnancy (in utero smoking) and current secondhand smoke exposure on asthma control is poorly documented, and there is a paucity of research involving minority populations.
Objectives
To examine the association between poor asthma control and in utero smoking and current secondhand smoke exposure among Latino and Black children with asthma.
Methods
Case-only analysis of 2 multi-center case-control studies conducted from 2008–2010 using similar protocols. We recruited 2,481 Latinos and Blacks with asthma (ages 8–17) from the mainland United States and Puerto Rico. Ordinal logistic regression was used to estimate the effect of in utero smoking and current secondhand smoke exposures on National Heart Lung and Blood Institute-defined asthma control.
Results
Poor asthma control among children 8–17 years of age was independently associated with in utero smoking (odds ratio; 95% confidence interval = 1.5; 1.1–2.0). In utero smoking via the mother was also associated with secondary asthma outcomes, including early onset asthma (1.7; 1.1–2.4), daytime symptoms (1.6; 1.1–2.1), and asthma-related limitation of activities (1.6; 1.2–2.2).
Conclusions
Maternal smoking while in utero is associated with poor asthma control in Black and Latino subjects assessed at 8–17 years of age.
doi:10.1016/j.jaci.2012.03.017
PMCID: PMC3367092  PMID: 22552109
Secondhand smoke; prenatal exposure delayed effects; asthma; health status disparities
7.  Identification of ATPAF1 as a novel candidate gene for asthma in children 
Background
Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification.
Objective
We sought to identify asthma susceptibility genes in children.
Methods
A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n=116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n=112) and normal controls (n=165). A genomic region containing the ATPAF1 gene was significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in eight independent study populations consisting of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in two consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatics and controls.
Results
Asthma was associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene with two SNPs achieving significance at a genome-wide level (p=2.26×10−5 to 2.2×10−8). Asthma severity was also associated with SNPs and haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the four non-Hispanic populations. Haplotype associations were confirmed in the non-Hispanic populations (p=0.045 to 0.0009). ATPAF1 total RNA expression was significantly (p<0.01) higher in bronchial biopsies from asthmatics than controls.
Conclusion
Genetic variation in the ATPAF1 gene predisposes children of different ancestry to asthma.
doi:10.1016/j.jaci.2011.04.058
PMCID: PMC3185108  PMID: 21696813
asthma; ATPAF1; children; gene; genetic; genome-wide association; purinergic; respiratory; single nucleotide polymorphism; SNP
8.  Ethnic Variability in Persistent Asthma After In Utero Tobacco Exposure 
Pediatrics  2011;128(3):e623-e630.
BACKGROUND:
The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent.
OBJECTIVE:
To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children.
PATIENTS AND METHODS:
There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression.
RESULTS:
Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year.
CONCLUSIONS:
Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
doi:10.1542/peds.2011-0640
PMCID: PMC3164096  PMID: 21859918
asthma; tobacco; Latino; African American; pregnancy
9.  ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos 
Background
Understanding the effects of interactions between multiple genes and asthma medications may aid in the understanding of the heterogeneous response to asthma therapies.
Objective
To identify modulating effects of ALOX5AP and LTA4H gene polymorphisms on the drug-drug interaction between leukotriene modifiers and albuterol in Mexicans and Puerto Ricans.
Methods
In a cross-sectional study of 293 Mexicans and 356 Puerto Ricans with asthma, ALOX5AP and LTA4H genes were sequenced, and interactions between gene polymorphisms and bronchodilator responsiveness to albuterol was analyzed between leukotriene modifier users and non-users.
Results
In heterozygotes and homozygotes for the minor allele at LTA4H SNP rs2540491 and heterozygotes for the major allele at LTA4H SNP rs2540487, leukotriene modifier use was associated with a clinically significant increase in percent change in forced expiratory volume in 1 second (FEV1) after albuterol administration of 7.10% (p=0.002), 10.06% (p=0.001), and 10.03% (p<0.001), respectively. Presence of the major allele at ALOX5AP SNP rs10507391 or the minor allele at ALOX5AP SNP rs9551963 augmented this response. When stratified by ethnicity, these findings held true for Puerto Ricans, but not Mexicans.
Conclusions
LTA4H and ALOX5AP gene polymorphisms modify the augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans but not Mexicans with asthma.
doi:10.1016/j.jaci.2010.06.048
PMCID: PMC2950217  PMID: 20810156
asthma; leukotriene; leukotriene modifier; Latino; albuterol; drug responsiveness; association study; genetic polymorphism
10.  GSNO Reductase and β2 Adrenergic Receptor Gene-gene Interaction: Bronchodilator Responsiveness to Albuterol 
Pharmacogenetics and genomics  2010;20(6):351-358.
Background
Short-acting inhaled β2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The β2-adrenergic receptor (β2AR) is the target for β2-agonist drugs. The enzyme S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to β2-agonists.
Objective
We hypothesized that there are pharmacogenetic interactions between GSNOR and β2AR gene variants which are associated with variable response to albuterol.
Methods
We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these subjects for pharmacogenetic interaction between GSNOR and β2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants.
Results
Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3′UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (p = 0.04 to 0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and β2AR gene variants and the response to albuterol in Puerto Rican (p = 0.03), Mexican (p = 0.15) and combined Puerto Rican and Mexican asthmatics (p = 0.003). Specifically, GSNOR+17059*β2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response.
Conclusion
Genotyping of GSNOR and β2AR genes may be a useful in identifying Latino subjects, who might benefit from adjuvant therapy for refractory asthma.
doi:10.1097/FPC.0b013e328337f992
PMCID: PMC2883564  PMID: 20335826
Asthma; Bronchodilator responsiveness; GSNO Reductase; β2-Adrenergic Receptor; Latinos; Gene-gene interaction; Polymorphisms; Pharmacogenetics
11.  Genetic ancestry modifies pharmacogenetic gene–gene interaction for asthma 
Pharmacogenetics and genomics  2009;19(7):489-496.
Objective
A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.
Methods
Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene–gene interactions were tested by using multiple linear regression analyses.
Results
No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene–gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.
Conclusion
Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.
doi:10.1097/FPC.0b013e32832c440e
PMCID: PMC2768127  PMID: 19503017
asthma genetics; African-Americans; ancestry; effect modification; gene–gene interaction; IL6; IL6 receptor; latinos
12.  Ancestry-related assortative mating in Latino populations 
Genome Biology  2009;10(11):R132.
Examination of ancestry-informative genetic markers shows that Puerto Rican and Mexican populations have shown strong assortative mating that continues to this day.
Background
While spouse correlations have been documented for numerous traits, no prior studies have assessed assortative mating for genetic ancestry in admixed populations.
Results
Using 104 ancestry informative markers, we examined spouse correlations in genetic ancestry for Mexican spouse pairs recruited from Mexico City and the San Francisco Bay Area, and Puerto Rican spouse pairs recruited from Puerto Rico and New York City. In the Mexican pairs, we found strong spouse correlations for European and Native American ancestry, but no correlation in African ancestry. In the Puerto Rican pairs, we found significant spouse correlations for African ancestry and European ancestry but not Native American ancestry. Correlations were not attributable to variation in socioeconomic status or geographic heterogeneity. Past evidence of spouse correlation was also seen in the strong evidence of linkage disequilibrium between unlinked markers, which was accounted for in regression analysis by ancestral allele frequency difference at the pair of markers (European versus Native American for Mexicans, European versus African for Puerto Ricans). We also observed an excess of homozygosity at individual markers within the spouses, but this provided weaker evidence, as expected, of spouse correlation. Ancestry variance is predicted to decline in each generation, but less so under assortative mating. We used the current observed variances of ancestry to infer even stronger patterns of spouse ancestry correlation in previous generations.
Conclusions
Assortative mating related to genetic ancestry persists in Latino populations to the current day, and has impacted on the genomic structure in these populations.
doi:10.1186/gb-2009-10-11-r132
PMCID: PMC3091325  PMID: 19930545

Results 1-12 (12)