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Background: Little is known about nasal epithelial gene expression and total IgE in youth., Objective: We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types., Methods: We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma. We then attempted to replicate top findings for each analysis using data from 3 cohorts. Genes with a Benjamini-Hochberg-adjusted P value of less than .05 in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study and a P value of less than .05 in the same direction of association in 1 or more replication cohort were considered differentially expressed genes (DEGs). DEGs for total IgE in subjects with asthma were further dissected into gene modules using coexpression analysis, and such modules were mapped to specific cell types in airway epithelia using public single-cell RNA-sequencing data., Results: A higher number of DEGs for total IgE were identified in subjects with asthma (n = 1179 DEGs) than in all subjects (n = 631 DEGs). In subjects with asthma, DEGs were mapped to 11 gene modules. The top module for positive correlation with total IgE was mapped to myoepithelial and mucus secretory cells in lower airway epithelia and was regulated by IL-4, IL5, IL-13, and IL-33. Within this module, hub genes included CDH26, FETUB, NTRK2, CCBL1, CST1, and CST2. Furthermore, an enrichment analysis showed overrepresentation of genes in signaling pathways for synaptogenesis, IL-13, and ferroptosis, supporting interactions between interleukin- and acetylcholine-induced responses., Conclusions: Our findings for nasal epithelial gene expression support neuroimmune coregulation of total IgE in youth with asthma., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Expression quantitative trait methylation (eQTM) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 megabase)., Objectives: This study sought to identify cis- and trans-methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma., Methods: In this study, the investigators conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. The investigators then attempted to replicate their findings in nasal epithelial samples from 2 studies of children, while also examining whether their results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects., Results: This study identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor and microRNA target genes. Furthermore, significant cytosine-phosphate-guanine sites (CpGs) were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. In this study, 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in 2 smaller cohorts at false discovery rate-adjusted P < .1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (eg, HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways., Conclusions: Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor and microRNA target genes., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Descriptive epidemiological data on incidence rates (IRs) of asthma with recurrent exacerbations (ARE) are sparse., Objectives: This study hypothesized that IRs for ARE would vary by time, geography, age, and race and ethnicity, irrespective of parental asthma history., Methods: The investigators leveraged data from 17,246 children born after 1990 enrolled in 59 US with 1 Puerto Rican cohort in the Environmental Influences on Child Health Outcomes (ECHO) consortium to estimate IRs for ARE., Results: The overall crude IR for ARE was 6.07 per 1000 person-years (95% CI: 5.63-6.51) and was highest for children aged 2-4 years, for Hispanic Black and non-Hispanic Black children, and for those with a parental history of asthma. ARE IRs were higher for 2- to 4-year-olds in each race and ethnicity category and for both sexes. Multivariable analysis confirmed higher adjusted ARE IRs (aIRRs) for children born 2000-2009 compared with those born 1990-1999 and 2010-2017, 2-4 versus 10-19 years old (aIRR = 15.36; 95% CI: 12.09-19.52), and for males versus females (aIRR = 1.34; 95% CI 1.16-1.55). Black children (non-Hispanic and Hispanic) had higher rates than non-Hispanic White children (aIRR = 2.51; 95% CI 2.10-2.99; and aIRR = 2.04; 95% CI: 1.22-3.39, respectively). Children born in the Midwest, Northeast and South had higher rates than those born in the West (P < .01 for each comparison). Children with a parental history of asthma had rates nearly 3 times higher than those without such history (aIRR = 2.90; 95% CI: 2.43-3.46)., Conclusions: Factors associated with time, geography, age, race and ethnicity, sex, and parental history appear to influence the inception of ARE among children and adolescents., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the genetic determinants of severe asthma exacerbations., Objectives: We aimed to identify genetic variants associated with asthma hospitalizations., Methods: We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses., Results: At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10 -8 ); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10 -6 . In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue., Conclusions: We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data-based mendelian randomization analyses., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease., Objective: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma., Methods: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n = 244)., Results: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n = 81) and AsRh (n = 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh., Conclusions: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes., Objective: We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure., Methods: A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study., Results: Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV 1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10 -8 ), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10 -9 for all cohorts). Rs117902240 was positively associated with FEV 1 in children exposed to low dust mite allergen levels, but negatively associated with FEV 1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV 1 /forced vital capacity replicated in the independent cohorts., Conclusions: Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV 1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood., Methods: We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis., Results: CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 (P = 1.5 × 10 -12 ), ACOT7 (P = 2.5 × 10 -11 ), and MND1 (P = 1.4 × 10 -9 )., Conclusions: In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of conflicts of interest This work was supported by grants HL079966 and HL117191 from the U.S. National Institutes of Health (NIH), and by The Heinz Endowments. Dr. Forno’s contribution was partially funded by NIH grant HL125666. The authors have no conflicts of interest to declare.

Background: Whether adiposity indicators other than body mass index (BMI) should be used in studies of childhood asthma is largely unknown. The role of atopy in "obese asthma" is also unclear., Objectives: To examine the relationship among adiposity indicators, asthma, and atopy in Puerto Rican children, and to assess whether atopy mediates the obesity-asthma association., Methods: In a study of Puerto Rican children with (n = 351) and without (n = 327) asthma, we measured BMI, percent of body fat, waist circumference, and waist-to-hip ratio. The outcomes studied included asthma, lung function, measures of atopy, and, among cases, indicators of asthma severity or control. We performed mediation analysis to assess the contribution of atopy to the relationship between adiposity and asthma., Results: BMI, percent of body fat, and waist circumference were associated with increased odds of asthma. Among cases, all 3 measures were generally associated with lung function, asthma severity/control, and atopy; however, there were differences depending on the adiposity indicator analyzed. Atopy considerably mediated the adiposity-asthma association in this population: allergic rhinitis accounted for 22% to 53% of the association with asthma, and sensitization to cockroach mediated 13% to 20% of the association with forced vital capacity and 29% to 42% of the association with emergency department visits for asthma., Conclusions: Adiposity indicators are associated with asthma, asthma severity/control, and atopy in Puerto Rican children. Atopy significantly mediates the effect of adiposity on asthma outcomes. Longitudinal studies are needed to further investigate the causal role, if any, of adiposity distribution and atopy on "obese asthma" in childhood., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Puerto Rican children share a disproportionate burden of prematurity and asthma in the United States. Little is known about prematurity and childhood asthma in Puerto Rican subjects., Objective: We sought to examine whether prematurity is associated with asthma in Puerto Rican children., Methods: We performed a case-control study of 678 children aged 6 to 14 years with (n = 351) and without (n = 327) asthma living in San Juan, Puerto Rico. Prematurity was defined by parental report for our primary analysis. In a secondary analysis, we only included children whose parents reported prematurity that required admission to the neonatal intensive care unit. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for analysis. All multivariate models were adjusted for age, sex, household income, atopy (≥1 positive IgE level to common allergens), maternal history of asthma, and early-life exposure to environmental tobacco smoke., Results: In a multivariate analysis there was a significant interaction between prematurity and atopy on asthma (P = .006). In an analysis stratified by atopy, prematurity was associated with a nearly 5-fold increased odds of asthma in atopic children (adjusted odds ratio, 4.7; 95% CI, 1.5-14.3; P = .007). In contrast, there was no significant association between prematurity and asthma in nonatopic children. Similar results were obtained in our analysis of prematurity requiring admission to the neonatal intensive care unit and asthma., Conclusions: Our results suggest that atopy modifies the estimated effect of prematurity on asthma in Puerto Rican children. Prematurity might explain, in part, the high prevalence of atopic asthma in this ethnic group., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Puerto Rican and African American subjects share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults., Objective: We sought to examine whether a greater proportion of African ancestry is associated with lower FEV(1) and forced vital capacity (FVC) in Puerto Rican children independently of socioeconomic status, health care access, or key environmental/lifestyle factors., Methods: We performed a cross-sectional case-control study of 943 Puerto Rican children aged 6 to 14 years with (n= 520) and without (n= 423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford, Connecticut (n= 383), and San Juan, Puerto Rico (n= 560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV(1) and FVC using linear regression. Multivariate models were adjusted for indicators of socioeconomic status and health care and selected environmental/lifestyle exposures., Results: After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower prebronchodilator FEV(1) (-105 mL; 95% CI, -159 to -51 mL; P< .001) and FVC (-133 mL; 95% CI, -197 to -69 mL; P< .001) and postbronchodilator FEV(1) (-152 mL; 95% CI, -210 to -94 mL; P< .001) and FVC (-145 mL; 95% CI, -211 to -79 mL; P< .001) in children with asthma. Similar but weaker associations were found for prebronchodilator and postbronchodilator FEV(1) (change for each 20% increment in African ancestry, -78 mL; 95% CI, -131 to -25 mL; P= .004) and for postbronchodilator FVC among children without asthma., Conclusions: Genetic factors, environmental/lifestyle factors, or both correlated with African ancestry might influence childhood lung function in Puerto Rican subjects., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

The report "Healthy people" from the US Department of Health and Human Services defines health literacy (HL) as follows: "The degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions." The same report identifies asthma as a public health problem of high priority. Unfortunately, impaired HL is prevalent in our society, and patients with low HL and asthma face multiple challenges as they attempt to manage their disease. Indeed, the National Asthma Education and Prevention Program's current guidelines require patients to have considerable HL and self-management skills. Numerous studies have linked inadequate literacy with poor health outcomes. Unlike many sociodemographic variables, HL can potentially be addressed in the health care setting. The purpose of this review is to raise awareness of the problem, summarize the current evidence linking HL and asthma, and offer strategies to strengthen the communication between patients and health care providers to decrease asthma health disparities. In addition, we discuss potential future directions for research in this field., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Little is known about paternal psychosocial factors and childhood asthma., Objective: We sought to examine the link between maternal and paternal psychosocial stress and asthma outcomes in young children., Methods: Parents of 339 pairs of Puerto Rican twins were interviewed individually about their own psychosocial stress and about asthma in their children at age 1 year and again about their child's asthma at age 3 years. Fathers were asked about symptoms of posttraumatic stress disorder (PTSD), depression, and antisocial behavior. Mothers were asked about depressive symptoms. Outcomes assessed in children included recent asthma symptoms, oral steroid use and hospitalizations for asthma in the prior year, and asthma diagnosis. Generalized estimated equation models were used for the multivariate analysis of parental psychosocial stress and asthma morbidity in childhood., Results: After multivariable adjustment, paternal PTSD symptoms, depression, and antisocial behavior were each associated with increased asthma symptoms at age 1 year (eg, odds ratio, 1.08 for each 1-point increase in PTSD score; 95% CI, 1.03-1.14). Maternal depressive symptoms were associated with an increased risk of asthma hospitalizations at age 1 year. At age 3 years, maternal depressive symptoms were associated with asthma diagnosis and hospitalizations for asthma (odds ratio for each 1-point increase in symptoms, 1.16; 95% CI, 1.00-1.36). In an analysis combining 1- and 3-year outcomes, paternal depression was associated with oral steroid use, maternal depressive symptoms were associated with asthma hospitalizations and asthma diagnosis, and parental depression was associated with hospitalizations for asthma., Conclusions: Both paternal and maternal psychosocial factors can influence asthma morbidity in young Puerto Rican children., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The lifetime prevalence of self-reported asthma among Puerto Ricans is very high, with increased asthma hospitalizations, emergency department visits, and mortality rates. Differences in asthma severity between the mainland and island, however, remain largely unknown., Objective: We sought to characterize differences in asthma severity and control among 4 groups: (1) Island Puerto Ricans, (2) Rhode Island (RI) Puerto Ricans, (3) RI Dominicans, and (4) RI whites., Methods: Eight hundred five children aged 7 to 15 years completed a diagnostic clinic session, including a formal interview, physical examination, spirometry, and allergy testing. Using a visual grid adapted from the Global Initiative for Asthma, asthma specialists practicing in each site determined an asthma severity rating. A corresponding level of asthma control was determined by using a computer algorithm., Results: Island Puerto Ricans had significantly milder asthma severity compared with RI Puerto Ricans, Dominicans, and whites (P < .001). Island Puerto Ricans were not significantly different from RI whites in asthma control. RI Puerto Ricans showed a trend toward less control compared with island Puerto Ricans (P = .061). RI Dominicans had the lowest rate of controlled asthma. Paradoxically, island Puerto Ricans had more emergency department visits in the past 12 months (P < .001) compared with the 3 RI groups., Conclusions: Potential explanations for the paradoxic finding of milder asthma in island Puerto Ricans in the face of high health care use are discussed. Difficulties in determining guideline-based composite ratings for severity versus control are explored in the context of disparate groups.

Substantial research has documented pervasive disparities in the prevalence, severity, and morbidity of asthma among minority populations compared with non-Latino white subjects. The underlying causes of these disparities are not well understood, and as a result, the leverage points to address them remain unclear. A multilevel framework for integrating research in asthma health disparities is proposed to advance both future research and clinical practice. The components of the proposed model include health care policies and regulations, operation of the health care system, provider/clinician-level factors, social/environmental factors, and individual/family attitudes and behaviors. The body of research suggests that asthma disparities have multiple, complex, and interrelated sources. Disparities occur when individual, environmental, health system, and provider factors interact with one another over time. Given that the causes of asthma disparities are complex and multilevel, clinical strategies to address these disparities must therefore be comparably multilevel and target many aspects of asthma care. Several strategies that could be applied in clinical settings to reduce asthma disparities are described, including the need for routine assessment of the patient's beliefs, financial barriers to disease management, and health literacy and the provision of cultural competence training and communication skills to health care provider groups.

Background: Island and mainland Puerto Rican children have the highest rates of asthma and asthma morbidity of any ethnic group in the United States., Objective: We evaluated the effectiveness of a culturally adapted family asthma management intervention called CALMA (an acronym of the Spanish for "Take Control, Empower Yourself and Achieve Management of Asthma") in reducing asthma morbidity in poor Puerto Rican children with asthma., Methods: Low-income children with persistent asthma were selected from a national health plan insurance claims database by using a computerized algorithm. After baseline, families were randomly assigned to either the intervention or a control group., Results: No significant differences between control and intervention group were found for the primary outcome of symptom-free days. However, children in the CALMA intervention group had 6.5% more symptom-free nights, were 3 times more likely to have their asthma under control, and were less likely to visit the emergency department and be hospitalized as compared to the control group. Caregivers receiving CALMA were significantly less likely to feel helpless, frustrated, or upset because of their child's asthma and more likely to feel confident to manage their child's asthma., Conclusion: A home-based asthma intervention program tailored to the cultural needs of low income Puerto Rican families is a promising intervention for reducing asthma morbidity.