Nasal epithelial gene expression and total IgE in children and adolescents with asthma.

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.

Persistent cat ownership and asthma in a longitudinal study of Puerto Rican youth.

BACKGROUND: Epidemiologic studies have reported conflicting findings for cat or dog exposure and childhood asthma. No study has examined whether persistent pet exposure from early life to school age is associated with asthma or allergic sensitization in youth. OBJECTIVE: To examine whether persistent ownership of a cat or a dog throughout childhood is associated with asthma in Puerto Rican youth, a group disproportionately affected with asthma. METHODS: Prospective study of 384 youth who completed a baseline visit at ages 6 to 14 years and a second visit at ages 9 to 20 years. Persistent cat or dog ownership was defined as ownership of a cat or a dog in early life (during pregnancy or the first year of life) at either study visit (at school age). An allergen-specific IgE was considered positive if ≥0.35 IU/ml. Logistic regression was used for the multivariable analysis of asthma and allergic sensitization. RESULTS: In an analysis adjusting for household income, family history of atopy, persistent overweight or obesity, a persistent unhealthy diet, the time interval between study visits, and other covariates, persistent cat ownership was significantly associated with 68% reduced odds of asthma (95% confidence interval for odds ratio= 0.11- 0.92) but not with any allergic sensitization or sensitization to cat allergen. In contrast, persistent dog ownership was not significantly associated with asthma or allergic sensitization. CONCLUSION: Among school-aged Puerto Rican youth followed for an average of 5 years, persistent cat ownership from early life to school age was inversely associated with asthma.

Cis- and trans-eQTM analysis reveals novel epigenetic and transcriptomic immune markers of atopic asthma in airway epithelium.

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.

Incidence rates of childhood asthma with recurrent exacerbations in the US Environmental influences on Child Health Outcomes (ECHO) program.

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.

Parental psychopathology and posttraumatic stress in Puerto Ricans: the role of childhood adversity and parenting practices.

BACKGROUND: Parental psychopathology is associated with their children's posttraumatic stress symptoms (PTSS). However, the mechanisms through which this occurs remain unclear. We hypothesized that exposure to childhood adversities is the mechanism linking parental psychopathology to child PTSS and that parenting practices moderated these associations. METHODS: Participants (N = 1,402) with an average age of 24.03 years old (SD = 2.20), were all Puerto Ricans (50% Male and 50% Female) from the Boricua Youth Study, which is a four-wave longitudinal study spanning almost 20 years, following individuals from childhood (ages 5-13 at Wave 1) to young adulthood. Measured variables include parental psychopathology at Wave 1, childhood adversities and parenting practices at Waves 2-3, and PTSS at Wave 4. A traditional mediation model estimated the association between parental psychopathology and child PTSS via childhood adversities. A moderated mediation model was used to examine whether parenting practices moderated this mediation model. RESULTS: Results showed that the total effect of parental psychopathology at Wave 1 on PTSS at Wave 4 was fully mediated by childhood adversities at Waves 2-3 (direct effect b = 1.72, 95% CI = [-0.09, 3.83]; indirect effect b = 0.40, 95% CI = [0.15, 0.81]). In addition, the magnitude of this pathway varied by levels of parenting practices (i.e. parental monitoring and parent-child relationship quality). Specifically, the indirect effect of additional adversities in the psychopathology-PTSS link was stronger with higher levels of parental monitoring but weaker with higher parent-child relationship quality scores. CONCLUSIONS: Intergenerational continuity of psychopathology may be mitigated through the prevention of additional childhood adversities via upstream interventions, emphasizing providing parents with mental health needs with parenting tools. Family-based interventions focused on providing families with the tools to improve parent-child relationships may reduce the negative impact of childhood adversities on mental health across the life course.

Low parental numeracy and severe asthma exacerbations in a prospective study of Puerto Rican youth.

BACKGROUND: Numeracy is the mathematical knowledge required to understand and act on instructions from health care providers. Whether persistently low parental numeracy is linked to childhood asthma exacerbations is unknown. OBJECTIVE: To evaluate whether low parental numeracy at 2 time points is associated with asthma exacerbations and worse lung function in Puerto Rican youth. METHODS: Prospective study of 225 youth with asthma in San Juan (PR) who participated in 2 visits approximately 5.3 years apart, with the first at ages 6 to 14 years and the second at ages 9 to 20 years. Parental numeracy was assessed with a modified version of the Asthma Numeracy Questionnaire (score range = 0-3 points), and persistently low parental numeracy was defined as a score less than or equal to 1 point at both visits. Asthma exacerbation outcomes included more than or equal to 1 emergency department (ED) visit, more than or equal to 1 hospitalization, and more than or equal to 1 severe exacerbation (≥1 ED visit or ≥1 hospitalization) for asthma in the year before the second visit. Spirometry was conducted using an EasyOne spirometer (NDD Medical Technologies, Andover, Massachusetts). RESULTS: In an analysis adjusting for age, sex, parental education, use of inhaled corticosteroids, and the time between study visits, persistently low parental numeracy was associated with more than or equal to 1 ED visit for asthma (odds ratio [ORs], 2.17; 95% confidence interval [CI], 1.10-4.26), more than or equal to 1 hospitalization for asthma (OR, 3.92; 95% CI, 1.42-10.84), and more than or equal to 1 severe asthma exacerbation (OR, 1.99; 95% CI, 1.01-3.87) in the year before the follow-up visit. Persistently low parental numeracy was not significantly associated with change in lung function measures. CONCLUSION: Persistently low parental numeracy is associated with asthma exacerbation outcomes in Puerto Rican youth.

Does Context and Adversity Shape Sexual Behavior in Youth? Findings from Two Representative Samples of Puerto Rican Youth.

Sexual risk behaviors often co-occur. Understanding the heterogeneity in patterns of sexual behavior among youth and how context of majority and minoritized status may be related to these behaviors can inform targeted STIs/HIV interventions. Data are from the Boricua Youth Study, a longitudinal study of two probability samples of Puerto Rican youth recruited in the South Bronx (SBx) and the metropolitan area in Puerto Rico (PR). We identified patterns of sexual behaviors among young adults (ages 15-24) with sexual experience (N = 1,203) using latent class analysis. Analyses examined context differences and the prospective relationship between adverse childhood experiences (ACEs) (childhood maltreatment/violence, family/parental dysfunction) and patterns of sexual behaviors (age at first sex, number of sex partners, sex with a high-risk partner, condom use, sex while intoxicated, oral sex, anal sex). We identified five classes of sexual behaviors: (1) currently inactive (16.51%); (2) single partner, low activity (13.49%); (3) single partner, inconsistent condom use (32.19%); (4) single partner, sex without a condom (27.65%); and (5) multirisk (10.16%). Young adults from the SBx (minoritized context), those who identified as male, and those with higher child maltreatment/violence ACEs were more likely to be in the multi-risk class relative to the single partner, inconsistent condom use class. Those from the SBx were also more likely to be in the single partner, sex without condom class, relative to the single partner, inconsistent condom use class. Differences in young adults' patterns of sexual behaviors between the two contexts, one representing the minoritized context (SBx) contrasted to the majority context (PR), were not explained by ACEs. Findings highlight the heterogeneity in the patterns of sexual behaviors among Puerto Rican young adults as well as how such patterns vary based on sociocultural contexts. Exposure to child maltreatment/violence ACEs was related to the riskier patterns; however, they did not explain why riskier patterns of sexual behaviors were found in the SBx compared to PR. Results underscore the need for tailored interventions and more in-depth examination of differences across contexts.

Violence-related distress and lung function in two longitudinal studies of youth.

BACKGROUND: Exposure to violence has been associated with lower lung function in cross-sectional studies. METHODS: We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9-16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)). RESULTS: In a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI -6.44- -0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI -4.86- -0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI -0.50- -0.10 points; p<0.01). Similar findings for FEV1 and FVC were obtained in the prospective study of Puerto Rican youth. CONCLUSIONS: Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

How Ethnic Minority Context Alters the Risk for Developing Mental Health Disorders and Psychological Distress for Latinx Young Adults.

Policy Points In low-income communities in the South Bronx and Puerto Rico, Puerto Rican youth are exposed to many of the same risk and protective factors for developing depression, anxiety, or psychological distress; yet it is unclear how the ethnic minority context of the South Bronx and ethnic majority context of Puerto Rico influence risk. Results from our quasi-experimental, longitudinal study demonstrate the importance of addressing social factors (parent-child relationships, youth peer relationships) for youth living in the majority context, and neighborhood and cultural factors (residential mobility, perceived discrimination, perceived social position in the neighborhood) for youth living in the minority context. Our findings support the need for tailoring programs specific to the needs of youth who reside in an ethnic majority or a minority context, since some of the risk factors might operate differently depending on context. Housing and neighborhood environment policies that address discrimination and eliminate structural inequities for ethnic minority groups may protect against the harm of minoritization on young people's mental health. CONTEXT: Puerto Rican youth growing up in low-income communities in the South Bronx and Puerto Rico are exposed to many of the same risk factors for major depressive disorder, generalized anxiety disorder, and psychological distress. One potentially powerful factor differs: Puerto Ricans have been socially marginalized as an ethnic minority group in the South Bronx, but are the ethnic majority of the population in Puerto Rico. A growing body of literature demonstrates the influence of neighborhood, cultural, and social factors and parental psychopathology in the development of mental health problems. An important unanswered question is whether these risk and protective factors have the same impact for youth raised as members of an ethnic majority versus minority group. METHODS: Using a population-based cohort study, with four waves of assessment from early childhood into young adulthood, we investigated whether ethnic minority context alters risk and protective factors for depression, anxiety, and psychological distress. Our longitudinal data set includes 2,491 young children at baseline (82.8% retained at wave 4). Using a quasi-experimental design, we examine how ethnic minority context can alter the development of mental health disorders as Latinx children transition to late adolescence and young adulthood. FINDINGS: Some risk and protective factors operated differently across minority and majority contexts. Higher discrimination and social position were more powerful risk and protective factors, respectively, in the minority context, whereas positive peer relationships mattered more in the majority context. Children of mothers with depression were significantly more likely to develop anxiety in late adolescence and young adulthood in the majority context (60.0%) compared to the minority context (4.5%). CONCLUSIONS: Preventing depression and anxiety disorders in Latinx young adults may require targeting different childhood factors depending on whether they reside within the ethnic majority or minority context. People in the ethnic minority context may benefit more from policies aimed at reducing discrimination and improving economic opportunity, while people in the majority context may benefit more from opportunities for strengthening family and peer relationships.

Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma.

BACKGROUND: The mechanisms underlying the known link between overweight/obesity and childhood asthma are unclear. We aimed to identify differentially expressed genes and pathways associated with obesity-related asthma through a transcriptomic analysis of nasal airway epithelium. METHODS: We compared the whole transcriptome in nasal airway epithelium of youth with overweight or obesity and asthma with that of youth of normal weight and asthma, using RNA sequencing data from a cohort of 235 Puerto Ricans aged 9-20 years (EVA-PR) and an independent cohort of 66 children aged 6-16 years in Pittsburgh (VDKA). Differential expression analysis adjusting for age, sex, sequencing plate number, and sample sorting protocol, and the first five principal components were performed independently in each cohort. Results from the two cohorts were combined in a transcriptome-wide meta-analysis. Gene enrichment and network analyses were performed on top genes. RESULTS: In the meta-analysis, 29 genes were associated with obesity-related asthma at an FDR-adjusted p <.05, including pro-inflammatory genes known to be differentially expressed in adipose tissue of obese subjects (e.g., CXCL11, CXCL10, and CXCL9) and several novel genes. Functional enrichment analyses showed that pathways for interferon signaling, and innate and adaptive immune responses were down-regulated in overweight/obese youth with asthma, while pathways related to ciliary structure or function were up-regulated. Upstream regulatory analysis predicted significant inhibition of the IRF7 pathway. Network analyses identified "hub" genes like GBP5 and SOCS1. CONCLUSION: Our transcriptome-wide analysis of nasal airway epithelium identified biologically plausible genes and pathways for obesity-related asthma in youth.

Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Persistent overweight or obesity, lung function, and asthma exacerbations in Puerto Rican youth.

BACKGROUND: Whether persistent overweight or obesity affects lung function or asthma morbidity in youth is unclear. OBJECTIVE: To evaluate overweight or obesity that persists between school age and adolescence and change in lung function and total immunoglobulin (Ig)E and severe asthma exacerbations in Puerto Rican youth. METHODS: Prospective study of 340 Puerto Rican youth assessed at 2 visits, the first at ages 6 to 14 years and the second at ages 9 to 20 years. Persistent overweight or obesity was defined as a body mass index z-score greater than or equal to 85th percentile at both visits. Outcomes of interest were change in percent predicted (%pred) lung function measures and total IgE between study visits and severe asthma exacerbations in the year before visit 2. Logistic or linear regression was used for multivariable analysis. RESULTS: In multivariable analysis, persistently overweight or obese subjects had changes in %pred forced expiratory volume in 1 second (FEV1) (ß = -5.07%; 95% confidence interval, -1.51% to -8.62%; P < .01) and %pred FEV1 to forced vital capacity (FVC) ratio (ß = -2.85%; 95% confidence interval, -0.18% to -5.51%; P = .04) which were lower than those observed in subjects with normal weight at both study visits (control subjects). Compared with control subjects, those who were persistently overweight or obese and those who became overweight or obese at visit 2 had increased odds of more than or equal to 1 severe asthma exacerbation in the year before visit 2. There was no significant association between persistent overweight or obesity and change in %pred FVC or total IgE (P > .20 for both instances). CONCLUSION: In a prospective study of Puerto Rican youth, persistently overweight or obese subjects had lower changes in FEV1 or FEV1 to FVC ratio and higher odds of severe asthma exacerbations than subjects of normal weight.

Outcomes of serious antisocial behavior from childhood to early adulthood in two Puerto Rican samples in two contexts.

PURPOSE: The patterns or trajectories of serious antisocial behavior (ASB) in children are examined to determine the extent to which context, gender, and the severity and persistence of ASB from childhood/early adolescence to later adolescence/early adulthood is associated with negative outcomes. METHODS: A four wave longitudinal study obtained data on two multi-stage probability household samples of Puerto Rican background children (5-13 years at baseline) living in the San Juan Metropolitan Area of Puerto Rico (PR) and the South Bronx (SBx) of New York. The outcomes studied were any psychiatric disorder including substance use disorders and teenage pregnancy. RESULTS: Both males and females raised in the SBx had much higher risk of serious ASB (42.3%) as compared to those in PR (17.8%). Concurrent ASB4 + in the fourth wave was strongly related to SUD and MDD for both males and females at Wave 4. CONCLUSIONS: Serious ASB is likely to persist at least to the next developmental period of a child and is likely to be associated with substance use disorders and major depression later in life.

An integrative association method for omics data based on a modified Fisher's method with application to childhood asthma.

The development of high-throughput biotechnologies allows the collection of omics data to study the biological mechanisms underlying complex diseases at different levels, such as genomics, epigenomics, and transcriptomics. However, each technology is designed to collect a specific type of omics data. Thus, the association between a disease and one type of omics data is usually tested individually, but this strategy is suboptimal. To better articulate biological processes and increase the consistency of variant identification, omics data from various platforms need to be integrated. In this report, we introduce an approach that uses a modified Fisher's method (denoted as Omnibus-Fisher) to combine separate p-values of association testing for a trait and SNPs, DNA methylation markers, and RNA sequencing, calculated by kernel machine regression into an overall gene-level p-value to account for correlation between omics data. To consider all possible disease models, we extend Omnibus-Fisher to an optimal test by using perturbations. In our simulations, a usual Fisher's method has inflated type I error rates when directly applied to correlated omics data. In contrast, Omnibus-Fisher preserves the expected type I error rates. Moreover, Omnibus-Fisher has increased power compared to its optimal version when the true disease model involves all types of omics data. On the other hand, the optimal Omnibus-Fisher is more powerful than its regular version when only one type of data is causal. Finally, we illustrate our proposed method by analyzing whole-genome genotyping, DNA methylation data, and RNA sequencing data from a study of childhood asthma in Puerto Ricans.

A genome-wide association study of asthma hospitalizations in adults.

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.

Intra-session test-retest reliability of functional connectivity in infants.

Resting functional MRI studies of the infant brain are increasingly becoming an important tool in developmental neuroscience. Whereas the test-retest reliability of functional connectivity (FC) measures derived from resting fMRI data have been characterized in the adult and child brain, similar assessments have not been conducted in infants. In this study, we examined the intra-session test-retest reliability of FC measures from 119 infant brain MRI scans from four neurodevelopmental studies. We investigated edge-level and subject-level reliability within one MRI session (between and within runs) measured by the Intraclass correlation coefficient (ICC). First, using an atlas-based approach, we examined whole-brain connectivity as well as connectivity within two common resting fMRI networks - the default mode network (DMN) and the sensorimotor network (SMN). Second, we examined the influence of run duration, study site, and scanning manufacturer (e.g., Philips and General Electric) on ICCs. Lastly, we tested spatial similarity using the Jaccard Index from networks derived from independent component analysis (ICA). Consistent with resting fMRI studies from adults, our findings indicated poor edge-level reliability (ICC = 0.14-0.18), but moderate-to-good subject-level intra-session reliability for whole-brain, DMN, and SMN connectivity (ICC = 0.40-0.78). We also found significant effects of run duration, site, and scanning manufacturer on reliability estimates. Some ICA-derived networks showed strong spatial reproducibility (e.g., DMN, SMN, and Visual Network), and were labelled based on their spatial similarity to analogous networks measured in adults. These networks were reproducibly found across different study sites. However, other ICA-networks (e.g. Executive Control Network) did not show strong spatial reproducibility, suggesting that the reliability and/or maturational course of functional connectivity may vary by network. In sum, our findings suggest that developmental scientists may be on safe ground examining the functional organization of some major neural networks (e.g. DMN and SMN), but judicious interpretation of functional connectivity is essential to its ongoing success.

A genome-wide association study of severe asthma exacerbations in Latino children and adolescents.

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34-1.79, p=6.3×10-9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (ß=0.10, p=2.18×10-7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).

ADHD and risk for subsequent adverse childhood experiences: understanding the cycle of adversity.

BACKGROUND: Children with adverse childhood experiences (ACEs) are more likely to develop Attention-Deficit/Hyperactivity Disorder (ADHD). The reverse relationship - ADHD predicting subsequent ACEs - is vastly understudied, although it may be of great relevance to underserved populations highly exposed to ACEs. METHODS: Participants were 5- to 15-year-olds (48% females) with (9.9%) and without ADHD (DSM-IV criteria except age of onset) in a longitudinal population-based study of Puerto Rican youth. In each wave (3 yearly assessments, W1-3), ten ACEs (covering parental loss and maladjustment and child maltreatment) were examined, plus exposure to violence. Logistic regression models examined ADHD (including subtypes) and subsequent risk for ACEs. Also considered were interactions by age, sex, number of W1 ACEs, and recruitment site. RESULTS: Children with W1 ADHD were more likely to experience subsequent adversity (OR: 1.63; 95% CI: 1.12-2.37) accounting for child age, sex, public assistance, maternal education, site, disruptive behavior disorders, and W1 ACEs. Inattentive (OR: 2.00; 95% CI: 1.09-3.66), but not hyperactive/impulsive or combined ADHD, predicted future ACEs. CONCLUSIONS: ADHD predicts subsequent risk for ACEs, and the inattentive presentation may confer the most risk. Inattentive presentations could pose a bigger risk given differences in symptom persistence, latency to access to treatment, and treatment duration. The present study suggests a pathway for the perpetuation of adversity, where bidirectional relationships between ADHD and ACEs may ensnare children in developmental pathways predictive of poor outcomes. Understanding the mechanism underlying this association can help the development of interventions that interrupt the cycle of adversity exposure and improve the lives of children with ADHD.

Testosterone-to-estradiol ratio and lung function in a prospective study of Puerto Rican youth.

BACKGROUND: Age- and sex-related differences in asthma may be due to changes in sex hormone levels. OBJECTIVE: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth. METHODS: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico. Serum levels of testosterone, estradiol, sex hormone-binding globulin, and progesterone were measured at 2 study visits, approximately 4.9 years apart. Using testosterone and sex hormone-binding globulin levels, we derived free testosterone and the free testosterone-to-estradiol ratio. Multivariable linear regression was used for the analysis of change in lung function and eosinophils, conducted separately by sex. RESULTS: In girls, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 2.03% increment in percent predicted forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) between study visits. In males, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 3.27% increment in percent predicted FEV1 and a 1.81% increment in percent predicted FEV1/FVC between study visits. In girls with asthma, an increased free testosterone-to-estradiol ratio was significantly associated with decreased eosinophils between visits (P=0.03). CONCLUSION: In Puerto Rican youth, increased free testosterone-to-estradiol ratio over time was associated with an increased FEV1/FVC in both sexes, and with an increased FEV1 in males.

Childhood Adversity and Sleep Disturbances: Longitudinal Results in Puerto Rican Children.

BACKGROUND: Exposure to childhood adversities (CA) is associated with sleep disturbances; however, evidence has largely been drawn from cross-sectional data and has not addressed the relationship across developmental stages. Also, most studies have primarily focused on non-Hispanic White cohorts with a dearth of longitudinal evidence about racial/ethnic minorities. We examined the longitudinal association between CA and sleep disturbances in Puerto Rican youth. METHOD: The Boricua Youth Study is a longitudinal study of Puerto Rican youth living in San Juan, Puerto Rico, and the South Bronx, NY (N = 2491). Among youth 5-9 and 10-16 years old, sleep disturbances were assessed through three yearly interviews. Lifetime exposure to CA included parental loss, child maltreatment, parental maladjustment, and exposure to violence. Weighted generalized linear mixed models examined the longitudinal association between CA and sleep disturbances in youth adjusting for sociodemographic and contextual covariates. RESULTS: The prevalence of sleep disturbances was similar in both age groups (ages 5-9 and 10-16). In multivariable mixed models, CA were associated with sleep disturbance across three Waves among 10-16-year-olds. For example, having 2-3 or ≥ 4 types of CA were related to a higher prevalence of trouble falling/staying asleep in models adjusting for social context, gender, welfare status, or mother's education. No associations were observed among 5-9-year-olds. CONCLUSION: The results suggest that cumulative adversities in childhood may lead to sleep problems in adolescence. These findings highlight the utility of addressing CA during childhood to help reduce sleep-wake disorders throughout adolescence, a known risk factor for future mental and physical health problems.