5-HTP inhibits eosinophilia via intracellular endothelial 5-HTRs; SNPs in 5-HTRs associate with asthmatic lung function.

Background: Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers. Objective: It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans. Methods: Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts. Results: Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics. Conclusions: Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.

Attention-Deficit Hyperactivity Disorder Symptoms, Underperception of Respiratory Compromise, and Illness Representations in Black and Latino Children With Asthma.

OBJECTIVE: This study examined the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, underperception of respiratory compromise, and illness representations in Black and Latino children with asthma. We hypothesized that increased child-reported ADHD symptoms, as well as parent reports for their child, would be associated with underperception of respiratory compromise, and maladaptive asthma beliefs. METHODS: Two hundred ninety-six parent-child dyads were recruited from pediatric asthma and primary care clinics in the Bronx. Participants completed demographic questionnaires, the Conners-3 ADHD Index to measure ADHD symptoms, and the Asthma Illness Representation Scale to assess asthma beliefs. Perception of respiratory compromise was assessed by programmable electronic peak flow monitors that measured the child's subjective estimates of peak expiratory flow (PEF) and actual PEF, with underperception as the primary measure. RESULTS: Child-reported ADHD symptoms were associated with greater underperception (ß = .117, p = .049) of respiratory compromise. Parent-reported ADHD symptoms were associated with greater underperception (ß = .129, p = .028) of respiratory compromise. Child-reported ADHD symptoms (ß = -.188, p < .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 13.135. Parent-reported ADHD symptoms (ß = -.203, p ≤ .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 15.644. CONCLUSIONS: ADHD symptoms were associated with a greater underperception of respiratory compromise and more maladaptive asthma beliefs. Deficits of attentional processes and/or hyperactivity levels might be contributing factors. We emphasize the need for psychoeducation and interventions that improve perception and health beliefs in children with comorbid ADHD and asthma.

The Relationship Between Pediatric Attention-Deficit/Hyperactivity Disorder Symptoms and Asthma Management.

PURPOSE: Children with comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and asthma are at an increased risk for adverse health outcomes and reduced quality of life. The objective of these analyses was to examine if self-reported ADHD symptoms in children with asthma are associated with asthma control, asthma controller medication adherence, quick relief medication use, pulmonary function, and acute healthcare utilization. METHODS: We analyzed data from a larger study testing a behavioral intervention for Black and Latinx children with asthma aged 10-17 years and their caregivers. Participants completed the Conners-3AI self-report assessment for ADHD symptoms. Asthma medication usage data were collected for 3 weeks following baseline via electronic devices fitted to participants' asthma medications. Other outcome measures included the Asthma Control Test, self-reported healthcare utilization, and pulmonary function measured by spirometry testing. RESULTS: The study sample consisted of 302 pediatric participants with an average age of 12.8 years. Increased ADHD symptoms were directly associated with reduced adherence to controller medications, but no evidence of mediation was observed. Direct effects of ADHD symptoms on quick-relief medication use, health care utilization, asthma control, or pulmonary function were not observed. However, the effect of ADHD symptoms on emergency room visits was mediated by controller medication adherence. DISCUSSION: ADHD symptoms were associated with significantly reduced asthma controller medication adherence and indirectly with emergency room visits. There are significant potential clinical implications to these findings, including the need for the development of interventions for pediatric asthma patients with ADHD.

Reduced asthma morbidity during COVID-19 in minority children: is medication adherence a reason?

OBJECTIVES: Asthma control improved during the COVID-19 pandemic. This study examined objectively measured medication adherence, asthma morbidity and quality of life (QoL) outcomes in Black and Latinx children by month for January-June 2019 (pre-COVID) compared to January-June 2020 (including first peak of COVID). METHODS: Secondary analyses of 94 children with asthma (ages 10-17 years, 64% Latinx, 36% Black) and their caregivers assigned to the comparison group of a longitudinal RCT intervention trial. Outcomes included mean aggregate electronic adherence for controller medications, oral steroid bursts, acute healthcare utilization, caregiver asthma QoL, and the Asthma Control Test. Repeated measures analyses were conducted due to multiple observations. RESULTS: Adherence to controller medications declined 48% from 2019 to 2020 (LS Mean = 33.9% vs. 17.6%, p=.0004, f=.92) with levels reaching a low in May 2020. A reduction in steroid bursts was observed over the same timeframe, 1.29 vs. 0.61, p = 0.006, f=.63. Caregiver QoL increased from 2019 to 2020 on total score (5.18 vs. 5.85, p = 0.002, f=.72), activity limitations (5.04 vs. 5.95), and emotional functioning (5.26 vs. 5.80). Although not statistically significant, a clinically meaningful 62% reduction in acute healthcare visits (p = 0.15) was reported in 2020. Children reported better asthma control (OR = 1.47, 95% CI 1.24, 1.73, p < 0.0001) in 2020 versus 2019 driven by improvements from May to June 2020. CONCLUSIONS: Decreased asthma morbidity in minority children during COVID was coupled with decreased adherence to controller medications. This observed decrease in morbidity is not explained by improvements in adherence.

Impact of caregiver depression on child asthma outcomes in Mexicans and Puerto Ricans.

OBJECTIVE: Examine whether caregiver depressive symptoms at baseline predict longitudinal child asthma outcomes in the two populations with the largest asthma disparities: Mexicans and Puerto Ricans. METHODS: Two hundred and sixty-seven Hispanic caregiver-child dyads (Mexican = 188, Puerto Rican = 79; children 5-12 years) were recruited from clinics and hospitals in Phoenix, AZ and the Bronx, NY. The Center for Epidemiological Studies Depression Scale assessed caregiver depressive symptoms; higher scores indicate greater depressive symptomology. Medical records verified child asthma diagnosis. Assessments for outcome variables occurred at baseline, 3, 6, 9, and 12-month follow-ups. Pulmonary function was measured by spirometry, asthma control was measured by the Asthma Control Test, steroid bursts and acute healthcare utilization were assessed by caregiver report and medical records, and adherence was measured by doser devices on controller medications. Structural equation modeling analyzed baseline caregiver depressive symptoms as a predictor of longitudinal child asthma outcomes, and differences between subgroups. RESULTS: Higher caregiver depressive symptoms predicted better pulmonary function (ß = .02, p = .001) in Mexican children, and fewer steroid bursts (ß = -.41, p = .01) and better medication adherence (ß = .02, p = .07) in Puerto Rican children. Caregiver depressive symptoms did not predict pediatric asthma control or acute healthcare utilization in either subgroup. CONCLUSIONS: Caregiver depressive symptomology had unexpected effects on child asthma outcomes. Results may be explained by the Hispanic paradox, caregiver resilience, acculturation, and the study's longitudinal nature. Further research is needed on social determinants of health that may influence differences in child asthma outcomes in heterogeneous Hispanic communities.

A randomized trial of subcutaneous allergy immunotherapy in inner-city children with asthma less than 4 years of age.

BACKGROUND: Allergic sensitization to environmental allergens in the first years of life is a strong predictor of asthma morbidity in children. Allergy immunotherapy can improve asthma and allergy outcomes, but its efficacy in inner-city, atopic children of less than 4 years of age with recurrent wheezing has not yet been established. OBJECTIVE: To determine whether subcutaneous allergy immunotherapy improves asthma in a population of US inner-city children when started at less than 4 years of age. METHODS: In a randomized controlled, open-label phase I-II single-center trial in the Bronx, New York, 58 children with recurrent wheezing or physician-diagnosed asthma were randomized to receive asthma standard of care treatment with or without a 3-year course of multiple allergen subcutaneous immunotherapy. RESULTS: A total of 23 children in the control group and 27 children in the immunotherapy group began the study. A total of 20 of 27 children commencing immunotherapy completed at least 2 years of immunotherapy. There was no difference in asthma medication and symptom scores between the treatment or control groups over time. Similarly, naso-ocular symptoms and allergy medication use were similar in both groups over time. Nevertheless, asthma-related quality of life improved in the immunotherapy group compared with the control group (P = .03). CONCLUSION: With the exception of asthma-related quality of life, allergy immunotherapy was ineffective in improving asthma outcomes in this population of inner-city children of less than 4 years of age. These findings suggest that the effects of allergy immunotherapy depend on population-specific factors and highlight the importance of precise predictors of immunotherapy efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01028560.

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

RATIONALE: Severe early-life respiratory illnesses, particularly those caused by respiratory syncytial virus (RSV) and human rhinovirus (HRV), are strongly associated with the development of asthma in children. Puerto Rican children in particular have a strikingly high asthma burden. However, prior studies of the potential associations between early-life respiratory illnesses and asthma in Puerto Rican and other minority populations have been limited. OBJECTIVES: We sought to determine whether early-life respiratory illness was associated with asthma in Puerto Rican, Mexican American, and African American children. METHODS: Using a logistic regression analysis, we examined the association between early-life respiratory illnesses (report of upper respiratory infection (URI), pneumonia, bronchitis, and bronchiolitis/RSV) within the first two years of life and physician-diagnosed asthma after the age of two in a large cohort of Puerto Rican, Mexican American, and African American children. MEASUREMENTS AND MAIN RESULTS: While early-life respiratory illnesses were associated with greater asthma odds in Puerto Ricans, Mexican Americans, and African Americans, these associations were stronger among Puerto Rican children. Specifically, in Puerto Ricans, the odds was 6.15 (95% CI: 4.21-9.05) if the child reported at least one of the following respiratory illness: URI, pneumonia, bronchitis or bronchiolitis. The odds were also higher in Puerto Ricans when considering these conditions separately. CONCLUSIONS: We observed population-specific associations between early-life respiratory illnesses and asthma, which were especially significant and stronger in Puerto Ricans. Taken together with the known high burden of RSV in Puerto Rico, our results may help explain the high burden of asthma in Puerto Ricans.

Explanatory Model for Asthma Disparities in Latino Children: Results from the Latino Childhood Asthma Project.

BACKGROUND: Little research has been conducted that integrates, in one explanatory model, the multitude of factors potentially leading to disparities among Latino children. PURPOSE: A longitudinal, observational study tested an explanatory model for disparities in asthma control between Mexican and Puerto Rican children with persistent asthma requiring daily controller medication use. METHODS: Mexican and Puerto Rican children aged 5-12 years (n = 267) and their caregivers (n = 267) were enrolled and completed interviews and child spirometry at baseline and 3, 6, 9, and 12 months postenrollment. A 12 month retrospective children's medical record review was completed. Participants were recruited from two school-based health clinics and the Breathmobile in Phoenix, AZ, and two inner-city hospital asthma clinics in the Bronx, NY. RESULTS: Statistically significant differences in the social/contextual predictors of asthma illness representations (IRs) were noted between Mexican and Puerto Rican caregivers. The structural equation model results revealed differences in asthma control over time by ethnicity. This model accounted for 40%-48% of the variance in asthma control test scores over 12 months. Caregivers' IRs aligned with the professional model of asthma management were associated with better children's asthma control across 1 year. These results also supported the theoretical notion that IRs change over time impacting caregivers' treatment decisions and children's asthma control. CONCLUSIONS: These findings extend a previous cross-sectional model test using a more comprehensive model and longitudinal data and highlight the importance of considering within-group differences for diagnosis and treatment of children coming from the vastly heterogeneous Latino umbrella group. TRIAL REGISTRATION: Trial number NCT01099800.

The Adaptive Effect of Illness-Specific Panic-Fear on Asthma Outcomes in Mexican and Puerto Rican Children.

OBJECTIVE: To examine baseline measures of illness-specific panic-fear (ie, the level of anxiety experienced specifically during asthma exacerbations) as a protective factor in pediatric asthma outcomes over a 1-year period. STUDY DESIGN: The sample comprised 267 children (Mexican, n = 188; Puerto Rican, n = 79; age 5-12 years) from a longitudinal observational study conducted in Phoenix, AZ and Bronx, NY. Assessments were done at baseline and 3, 6, 9, and 12 months. The Childhood Asthma Symptom Checklist was administered at baseline to children and caregivers to assess children's illness-specific panic-fear. Asthma outcome variables quantified longitudinally included pulmonary function, the Asthma Control Test, acute healthcare utilization, and medication adherence, measured by devices attached to inhaled corticosteroids. RESULTS: Child report of illness-specific panic-fear at baseline predicted higher forced expiratory volume in 1 second (FEV1) % across 1-year follow-up in Mexican children (ß = 0.17, P = .02), better asthma control in Puerto Rican children (ß = 0.45, P = .007), and less acute healthcare utilization for asthma in both groups (Mexicans: ß = -0.39, P = .03; Puerto Ricans: ß = -0.47, P = .02). Caregiver report of child panic-fear predicted higher FEV1% in Mexican (ß = 0.30; P = .02) and Puerto Rican (ß = 0.19; P = .05) children. Panic-fear was not related to medication adherence. CONCLUSIONS: Illness-specific panic-fear had beneficial effects on asthma outcomes in both groups of Latino children. The heightened vigilance associated with illness-specific panic-fear may lead children to be more aware of their asthma symptoms and lead to better strategies for asthma management.

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

American Thoracic Society guidelines recommend inhaled corticosteroid (ICS) therapy, plus a short-acting bronchodilator, in patients with persistent asthma. However, few prior studies have examined the efficacy of this combination in children of all racial/ethnic groups. We evaluated the association between ICS use and bronchodilator response (BDR) in three pediatric populations with persistent asthma (656 African American, 916 Puerto Rican, and 398 Mexican American children). The association was assessed using multivariable quantile regression. After adjusting for baseline forced expiratory volume in one second and use of controller medications, ICS use was significantly associated with increased BDR only among Mexican Americans (1.56%, P = 0.028) but not African Americans (0.49%, P = 0.426) or Puerto Ricans (0.16%, P = 0.813). Our results demonstrate that ICS augmentation is disproportionate across racial/ethnic groups, where improved BDR is observed in Mexican Americans only. This study highlights the complexities of treating asthma in children, and reinforces the importance of investigating the influence of race/ethnicity on pharmacological response.

Pediatric Asthma: A Global Epidemic.

The global prevalence, morbidity and mortality related to childhood asthma among children has increased significantly over the last 40 years. Although asthma is recognized as the most common chronic disease in children, issues of underdiagnosis and undertreatment persist. There are substantial global variations in the prevalence of asthma symptoms in children, with up to 13-fold differences between countries. The rising number of hospital admissions for asthma may reflect an increase in asthma severity, poor disease management and/or the effect of poverty. The financial burden of asthma is relatively high within developed countries (those for which data is available) spending 1 to 2% of their healthcare budget on this condition. Established in 1989, the Global Initiative for Asthma (GINA) attempts to raise awareness about the increasing prevalence of asthma, improve management and reduce the burden of asthma worldwide. Despite global efforts, GINA has not achieved its goal, even among developed nations. There are multiple barriers to reducing the global burden of asthma, including limited access to care and/or medications, and lack of prioritization as a public healthcare priority. In addition, the diversity of healthcare systems worldwide and large differences in access to care require that asthma management guidelines be tailored to local needs.

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

BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

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

BACKGROUND: Acculturation is an important predictor of asthma in Latino youth, specifically Mexican Americans. Less is known about acculturation and pulmonary function measures. OBJECTIVE: We sought to estimate the association of acculturation measures with asthma and pulmonary function in Latino youth and determine whether this association varies across Latino subgroups. METHODS: We included 1849 Latinos (302 Caribbean Spanish, 193 Central or South Americans, 1136 Mexican Americans, and 218 other Latino children) aged 8 to 21 years from 4 urban regions in the United States. Acculturation measures include nativity status, age of immigration, language of preference, and generation in the United States. We used multivariable logistic and linear regression models to quantify the association of acculturation factors with the presence of asthma (case-control study) and pulmonary function (case-only study), adjusting for demographic, socioenvironmental, and clinical variables. RESULTS: For all acculturation measures (nativity status, age of immigration, language of preference, and generation in the United States), greater levels of acculturation were associated with greater odds of asthma. Among cases, high (English preference) and medium (equal preference for Spanish and English) levels of language acculturation were associated with decreased bronchodilator response compared with low (Spanish preference) levels (P = .009 and .02, respectively). Similarly, high language acculturation was associated with increased FEV1 compared with low language acculturation (P = .02). There was insufficient evidence of heterogeneity for associations across Latino subgroups. CONCLUSIONS: Acculturation was associated with diagnosed asthma and pulmonary function in Latino children and is an important factor to consider in the management of Latino youth with asthma.

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

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

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

Short-acting ß2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

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

BACKGROUND: Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported. OBJECTIVES: Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature. METHODS: We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines. RESULTS: The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures. CONCLUSIONS: Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.

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

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

Food Allergy and Anxiety and Depression among Ethnic Minority Children and Their Caregivers.

OBJECTIVE: To investigate the relationship between food allergy and symptoms of anxiety and depression among ethnic minority, low socioeconomic status (SES) children and their caregivers. STUDY DESIGN: Pediatric patients ages 4-12 years with and without food allergy and their caregivers were recruited from urban pediatric outpatient clinics. Statistical analyses were used to examine the prevalence of symptoms of anxiety and depression among patients and their caregivers with and without food allergy, adjusting for asthma. RESULTS: Eighty patients ranging from ages 4 to 12 years, with a mean age of 8.1 years, and their caregivers participated in the study. Food allergy was associated with significantly higher t scores on the Multidimensional Anxiety Scale for Children (MASC) Total (P = .007), MASC Humiliation Rejection, (P = .02) and MASC Social Anxiety (P = .02) among pediatric patients, adjusting for asthma. Food allergy was not associated with child depression symptoms, nor was there a significant difference in anxiety or depression symptoms among caregivers of patients with and without food allergy. CONCLUSIONS: Food allergy appears to be associated with increased symptoms of social anxiety and higher levels of anxiety overall, but not depression, in ethnic minority children of lower socioeconomic status. This finding was not due to confounding by asthma. Food allergy was not associated with higher levels of depression or anxiety symptoms among caregivers of pediatric patients with food allergy. Future studies should investigate potential pathways between food allergy and anxiety that may be unique to children in underserved populations, and develop interventions to reduce anxiety in children with food allergy.

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

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10-5 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10-14, rs1426654) and SLC45A2 (minimum p = 9.71 × 10-10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10-9, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.

Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures.

Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both self-identified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2×10-64) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.