PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (54)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
Document Types
1.  Asthma and Ethnic Minorities: Socioeconomic Status and Beyond 
Purpose of review
We aim to discuss current insights into our understanding of the mechanisms by which socioeconomic status (SES) influences the prevalence and severity of asthma in ethnic minorities. In addition, we review potential risk factors for ethnic disparities in asthma that are not mediated by SES.
Recent findings
Exposures and factors correlated with ethnicity through SES (e.g. indoor and outdoor air quality, smoke exposure, and access to healthcare) are likely to explain a significant proportion of the observed ethnic differences in asthma morbidity. However, other factors correlated with ethnicity (e.g., genetic variation) can impact ethnic disparities in asthma independently of and/or interacting with SES-related factors.
Summary
SES is a rough marker of a variety of environmental/behavioral exposures and a very important determinant of differences in asthma prevalence and severity among ethnic minorities in the U.S. However, SES is unlikely to be the sole explanation for ethnic disparities in asthma, which may also be due to differences in genetic variation and gene-by-environment interactions among ethnic groups.
PMCID: PMC3920741  PMID: 19326508
Childhood asthma; asthma epidemiology; socioeconomic status; ethnicity; race; minorities
2.  ADCYAP1R1 and Asthma in Puerto Rican Children 
Rationale: Epigenetic and/or genetic variation in the gene encoding the receptor for adenylate-cyclase activating polypeptide 1 (ADCYAP1R1) has been linked to post-traumatic stress disorder in adults and anxiety in children. Psychosocial stress has been linked to asthma morbidity in Puerto Rican children.
Objectives: To examine whether epigenetic or genetic variation in ADCYAP1R1 is associated with childhood asthma in Puerto Ricans.
Methods: We conducted a case-control study of 516 children ages 6–14 years living in San Juan, Puerto Rico. We assessed methylation at a CpG site in the promoter of ADCYAP1R1 (cg11218385) using a pyrosequencing assay in DNA from white blood cells. We tested whether cg11218385 methylation (range, 0.4–6.1%) is associated with asthma using logistic regression. We also examined whether exposure to violence (assessed by the Exposure to Violence [ETV] Scale in children 9 yr and older) is associated with cg11218385 methylation (using linear regression) or asthma (using logistic regression). Logistic regression was used to test for association between a single nucleotide polymorphism in ADCYAP1R1 (rs2267735) and asthma under an additive model. All multivariate models were adjusted for age, sex, household income, and principal components.
Measurements and Main Results: Each 1% increment in cg11218385 methylation was associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.0–1.6; P = 0.03). Among children 9 years and older, exposure to violence was associated with cg11218385 methylation. The C allele of single nucleotide polymorphism rs2267735 was significantly associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.02–1.67; P = 0.03).
Conclusions: Epigenetic and genetic variants in ADCYAP1R1 are associated with asthma in Puerto Rican children.
doi:10.1164/rccm.201210-1789OC
PMCID: PMC3733434  PMID: 23328528
methylation; ADCYAP1R1; childhood asthma; Puerto Ricans; violence
3.  Vitamin D and Asthma 
Vitamin D deficiency and asthma are common conditions that share risk factors such as African American ethnicity, inner-city residence, and obesity. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between vitamin D status and asthma or asthma morbidity, including potential protective mechanisms such as antiviral effects and enhanced steroid responsiveness. Because most published epidemiologic studies of vitamin D and asthma or asthma morbidity are observational, a recommendation for or against vitamin D supplementation as preventive or secondary treatment for asthma is not advisable and must await results of ongoing clinical trials. Should these trials confirm a beneficial effect of vitamin D, others will be needed to assess the role of vitamin D supplementation to prevent or treat asthma in different groups such as infants, children of school age, and ethnic minorities.
doi:10.1164/rccm.201108-1502CI
PMCID: PMC3297088  PMID: 22016447
vitamin D; asthma; asthma morbidity
4.  Exposure to dust mite allergen and endotoxin in early life and asthma and atopy in childhood 
Background
There has been no longitudinal study of the relation between concurrent exposure to dust mite allergen and endotoxin in early life and asthma and atopy at school age.
Objectives
To examine the relation between exposure to dust mite allergen and endotoxin at age 2 to 3 months and asthma, wheeze, and atopy in high-risk children.
Methods
Birth cohort study of 440 children with parental history of atopy in the Boston metropolitan area.
Results
In multivariate analyses, early exposure to high levels of dust mite allergen (≥10 μg/g) was associated with increased risks of asthma at age 7 years (odds ratio [OR], 3.0; 95% CI, 1.1-7.9) and late-onset wheeze (OR, 5.0; 95% CI, 1.5-16.4). Exposure to endotoxin levels above the lowest quartile at age 2 to 3 months was associated with reduced odds of atopy at school age (OR, 0.5; 95% CI, 0.2-0.9). In contrast with its inverse association with atopy, endotoxin exposure in early life was associated with an increased risk of any wheeze between ages 1 and 7 years that did not change significantly with time (hazard ratio for each quartile increment in endotoxin levels, 1.23; 95% CI, 1.07-1.43).
Conclusion
Among children at risk of atopy, early exposure to high levels of dust mite allergen is associated with increased risks of asthma and late-onset wheeze. In these children, endotoxin exposure is associated with a reduced risk of atopy but an increased risk of wheeze.
Clinical implications
Early endotoxin exposure may be a protective factor against atopy but a risk factor for wheeze in high-risk children.
doi:10.1016/j.jaci.2007.03.037
PMCID: PMC3737770  PMID: 17507083
Endotoxin; dust mite; wheeze; atopy; asthma
5.  Multiple Microbial Exposures in the Home May Protect Against Asthma or Allergy in Childhood 
Background
Experimental animal data on the gram-negative bacterial biomarker endotoxin suggest that persistence, dose and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram-positive as well as gram-negative bacteria, that may influence allergy and asthma through components (pathogen-associated molecular patterns) that signal through innate Toll-like receptor pathways.
Objective
To determine the influence of current gram-negative and gram-positive bacterial exposures on asthma and allergic sensitization in school-aged children.
Methods
We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school-aged children in a birth-cohort study. We then evaluated the effects of school-age endotoxin, after controlling for exposure in early life.
Results
Exposure to gram-negative bacteria was inversely associated with asthma and allergic sensitization at school-age (for > median endotoxin: prevalence odds ratio [POR] =0.34 [95% CI=0.2 to 0.7] for current asthma and prevalence ratio [PR]=0.77 [95% CI=0.6 to 0.97] for allergic sensitization). In contrast, elevated gram-positive bacteria in the bed was inversely associated with current asthma (POR= 0.41, 95% CI=0.2 to 0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8 to 1.4). School-age endotoxin exposure remained protective in models for allergic disease adjusted for early-life endotoxin.
Conclusion
Both gram-negative and gram-positive bacterial exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early life exposure; it has independent protective effects on allergic disease.
doi:10.1111/j.1365-2222.2010.03509.x
PMCID: PMC3730840  PMID: 20412140
childhood asthma; allergic sensitization; endotoxin; peptidoglycan
6.  IL1B Polymorphisms Modulate Cystic Fibrosis Lung Disease 
Pediatric pulmonology  2009;44(6):580-593.
Summary
Rationale: Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. Methods: We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for ΔF508, and categories of “severe” (cases) or “mild” (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV1) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR ≤ 0.5or > 1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children’s Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed. Results: SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value < 0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status. Conclusion: Our findings suggest that IL1β is a clinically relevant modulator of CF lung disease.
doi:10.1002/ppul.21026
PMCID: PMC3716579  PMID: 19431193
gene modifiers; cystic fibrosis; CFTR; IL-1 gene family
7.  Genes and COPD 
SYNOPSIS
The marked variability in individual susceptibility to the detrimental effects of smoking on lung function and findings suggest a significant genetic contribution to COPD, which has been demonstrated in several studies. The only known genetic risk factor for COPD, severe alpha 1 antitrypsin (AAT) deficiency, explains only 1–2% of cases of this disease. Screening for severe AAT should be conducted in all cases of COPD. Intravenous augmentation therapy should be combined with currently recommended treatment modalities for COPD when treating patients with COPD due to severe AAT deficiency. There is considerable interest in identifying susceptibility genes for COPD unrelated to severe AAT deficiency, as this could greatly enhance current efforts to prevent, diagnose and treat this disease by yielding novel insights into its pathogenesis. Genome-wide association studies (GWAS) of COPD and its intermediate phenotypes (e.g., lung function measures) have identified novel susceptibility loci for COPD. Some of these susceptibility loci may also influence lung function in the general population (e.g., HHIP and FAM13A), while others may affect not only COPD but other diseases related to smoking behavior (e.g., CHRNA3/CHRNA5). Although much work remains to be done, recent advances and the implementation of novel approaches to study COPD genetics (e.g., sequencing) and epigenetics are promising, and could have a profound impact on COPD management.
doi:10.1016/j.mcna.2012.02.006
PMCID: PMC3399759  PMID: 22793939
COPD; genetics; alpha 1 antitrypsin deficiency
8.  Maternal intestinal flora and wheeze in early childhood 
Background
Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood.
Objective
To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy.
Methods
Sixty pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children’s health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log10colony-forming units(CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analyzed as a secondary outcome.
Results
In multivariate models adjusted for breastfeeding, daycare attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze.
Conclusions & Clinical Relevance
In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.
doi:10.1111/j.1365-2222.2011.03950.x
PMCID: PMC3428746  PMID: 22909161
infant wheeze; eczema; asthma; microbiota; intestinal flora; maternal flora
9.  Health Disparities in Asthma 
doi:10.1164/rccm.201202-0350ED
PMCID: PMC3359893  PMID: 22589306
10.  Genome‐wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica 
Thorax  2006;62(3):224-230.
Background
Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma‐related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans.
Methods
Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV1) and FEV1/ forced vital capacity (FVC; both pre‐bronchodilator and post‐bronchodilator) and BDR were performed in these eight families (pre‐bronchodilator spirometry, n = 640; post‐bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking.
Results
Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV1 (post‐bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV1/FVC (pre‐bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near‐significant evidence of linkage to FEV1/FVC (post‐bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV1 on chromosomes 3q (pre‐bronchodilator, LOD = 2.74) and 4q (post‐bronchodilator, LOD = 2.66).
Conclusions
In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV1 on chromosome 7q34–35. In these families, FEV1/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
doi:10.1136/thx.2006.067934
PMCID: PMC2117166  PMID: 17099076
11.  Difference in airflow obstruction between Hispanic and non-Hispanic white female smokers 
COPD  2008;5(5):274-281.
Rationale
Smoking-related respiratory diseases are a major cause of morbidity and mortality. However, the relationship between smoking and respiratory disease has not been well-studied among ethnic minorities in general and among women in particular.
Objective
The objective of this cross-sectional study was to evaluate the risk of airflow obstruction and to assess lung function among Hispanic and non-Hispanic white (NHW) female smokers in a New Mexico cohort.
Methods
Participants completed a questionnaire detailing smoking history and underwent spirometry testing. Outcomes studied included airflow obstruction, selected lung function parameters, and chronic mucus hyper-secretion. Chi square, logistic, and linear regression techniques were utilized.
Main findings
Of the 1,433 eligible women participants, 248 (17.3%) were Hispanic; and 319 had airflow obstruction (22.3%). Hispanic smokers were more likely to be current smokers, and report lower pack-years of smoking, compared to NHW smokers (p < 0.05 for all analyses). Further, Hispanic smokers were at a reduced risk of airflow obstruction compared to NHW smokers, with an O.R. of 0.51, 95% C.I. 0.34, 0.78 (p = 0.002) after adjustment for age, BMI, pack-years and duration of smoking, and current smoking status. Following adjustment for covariates, Hispanic smokers also had a higher mean absolute and percent predicted post-bronchodilator FEV1/FVC ratio, as well as higher mean percent predicted FEV1 (p < 0.05 for all analyses).
Principal conclusions
Hispanic female smokers in this New Mexico-based cohort had lower risk of airflow obstruction and better lung function than NHW female smokers. Further, smoking history did not completely explain these associations.
doi:10.1080/15412550802363345
PMCID: PMC3616889  PMID: 18972275
Hispanic ethnicity; Smokers; Airflow obstruction; Pulmonary function; Chronic mucus hyper-secretion; Women
12.  Psychosocial stress and asthma morbidity 
Purpose of review
The objective of this review is to provide an overview and discussion of recent epidemiologic and mechanistic studies of stress in relation to asthma incidence and morbidity.
Recent findings
Recent findings suggest that stress, whether at the individual- (i.e., epigenetics, perceived stress), family- (i.e., prenatal maternal stress, early life exposure or intimate partner violence) or community- (i.e.., neighborhood violence; neighborhood disadvantage) level influences asthma and asthma morbidity. Key recent findings regarding how psychosocial stress may influence asthma through Post Traumatic Stress Disorder (PTSD), pre-and post-natal maternal/caregiver stress, and community violence and deprivation are highlighted.
Summary
New research illustrates the need to further examine, characterize and address the influence of social and environmental factors (i.e., psychological stress) on asthma. Further research and innovative methodologies are needed to characterize the relationship and pathways associated with stress at multiple levels to more fully understand and address asthma morbidity, and to design potential interventions, especially to address persistent disparities in asthma in ethnic minorities and economically disadvantaged communities.
doi:10.1097/ACI.0b013e32835090c9
PMCID: PMC3320729  PMID: 22266773
asthma; allergy; stress; psychosocial; cytokines; maternal; violence; community
13.  Chronic Obstructive Pulmonary Disease in Hispanics 
Hispanics are individuals whose ancestry can be traced to Spain and/or areas previously under Spanish control (e.g., Mexico, Puerto Rico). They are a rapidly growing subset of the population of the United States and are quite diverse in their racial ancestry, country of origin, area of residence, socioeconomic status, tobacco use, and access to health care. Current evidence suggests that the prevalence and morbidity of chronic obstructive pulmonary disease (COPD) vary widely among Hispanic-American nations, with similar but limited findings among Hispanic subgroups in the United States. Potential reasons for such variation include differences in racial ancestry and genetic susceptibility, exposure to tobacco smoke and/or biomass smoke, access to health care, and disease management. Future studies of COPD in Hispanics should include large samples of subgroups that are well defined with regard to self-reported ethnicity, country of origin, area of residence, tobacco use, and socioeconomic status. Areas that need to be carefully examined include validation of COPD diagnoses for epidemiologic studies (e.g., by radiologic assessment), COPD in high-risk groups (e.g., Puerto Ricans), impact of biomass smoke (in rural areas) and air pollution (in urban areas) on COPD morbidity, effects of migration and acculturation on COPD prevalence and morbidity among Hispanic subgroups in the United States, development of reference values for spirometry, smoking cessation, and overcoming barriers to management. Public health measures, such as effective smoking prevention and cessation programs, reduction of air pollution and exposure to biomass smoke, and improved access to health care, would help reduce the burden of COPD among Hispanics in the United States and Latin America.
doi:10.1164/rccm.200708-1274PP
PMCID: PMC2258442  PMID: 18029789
chronic obstructive pulmonary disease; genetics; Hispanics; risk factors
14.  A Genome Wide Association Study of Plasma Total IgE Concentration in the Framingham Heart Study 
Background
Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation.
Objective
To ascertain the genetic risk factors which lead to IgE dysregulation.
Methods
A genome wide association study (GWAS) was performed in 6,819 participants from the Framingham Heart Study (FHS). Seventy of the top SNPs were selected based on p-values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with five independent populations from the KORA, B58C, and CAMP cohorts.
Results
Thirteen SNPs located in the region of three genes, FCER1A, STAT6, and IL-13, were found to have genome-wide significance in the FHS GWAS. The most significant SNPs from the three regions were rs2251746 (FCER1A, p-value 2.11×10-12), rs1059513 (STAT6, p-value 2.87×10-08), and rs1295686 (IL-13, p-value 3.55×10-08). Four additional gene regions - HLA-G, HLA-DQA2, HLA-A, and DARC - reached genome-wide statistical significance in meta-analysis combining FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene.
Conclusion
This GWAS of the FHS has identified genetic loci in HLA genes that may have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of known susceptibility loci, FCER1A, STAT6, and IL-13, for the dysregulation of total IgE.
doi:10.1016/j.jaci.2011.09.029
PMCID: PMC3293994  PMID: 22075330
total IgE; atopy; asthma; GWAS
15.  Genome-wide association study reveals class I MHC–restricted T cell–associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations 
Background
It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.
Objective
We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation. Methods: We conducted a genome-wide study of gene–vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort. Results: We identified 3 common variants in the class I MHC–restricted T cell–associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P =.00028–.00097; combined odds ratio, 3.28–5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8+ and natural killer T cells, both of which have been implicated in asthmatic patients.
Conclusion
The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8+ and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients.
doi:10.1016/j.jaci.2011.09.034
PMCID: PMC3360942  PMID: 22051697
Gene-environment interaction; genome-wide association study; vitamin D; asthma exacerbation
16.  Asthma in Hispanics 
Hispanic individuals trace their ancestry to countries that were previously under Spanish rule, including Mexico, large parts of Central and South America, and some Caribbean islands. Most—but not all—Hispanics have variable proportions of European, Amerindian, and African ancestry. Hispanics are diverse with regard to many factors, including racial ancestry, country of origin, area of residence, socioeconomic status, education, and access to health care. Recent findings suggest that there is marked variation in the prevalence, morbidity, and mortality of asthma in Hispanics in the United States and in Hispanic America. The reasons for differences in asthma and asthma morbidity among and within Hispanic subgroups are poorly understood but are likely due to the interaction between yet-unidentified genetic variants and other factors, including environmental tobacco smoke exposure, obesity, allergen exposure, and availability of health care. Barriers to optimal management of asthma in Hispanics in the United States and in Hispanic America include inadequate access to health care, suboptimal use of antiinflammatory medications, and lack of reference values for spirometric measures of lung function in many subgroups (e.g., Puerto Ricans). Future studies of asthma in Hispanics should include large samples of subgroups that are well characterized with regard to self-reported ethnicity, country of origin, place of birth, area of residence, and indicators of socioeconomic status. Because Hispanics are disproportionately represented among the poor in the United States, implementation of adequate access to health care and social reforms (e.g., improving housing conditions) would likely have a major impact on reducing asthma morbidity in this population.
doi:10.1164/rccm.200508-1232SO
PMCID: PMC2662985  PMID: 16210666
asthma; genetics; Hispanics; risk factors
17.  Predicting Asthma Exacerbations in Children 
Purpose of the review
To critically assess recently published literature on predicting asthma exacerbations in children, while also providing general recommendations for future research in this field.
Recent findings
Current evidence suggests that every effort should be made to provide optimal treatment to achieve adequate asthma control, as this will significantly reduce the risk of severe disease exacerbations. Children who have had at least one asthma exacerbation in the previous year are at highest risk for subsequent exacerbations, regardless of disease severity and/or control. Although several tools and biomarkers to predict asthma exacerbations have been recently developed, these approaches need further validation and/or have only had partial success in identifying children at risk.
Summary
Although considerable progress has been made, much remains to be done. Future studies should clearly differentiate severe asthma exacerbations due to inadequate asthma control from those occurring in children whose asthma is well controlled, utilize standardized definitions of asthma exacerbations, and use a systematic approach to identify the best predictors after accounting for the multiple dimensions of the problem. Our ability to correctly predict the development of severe asthma exacerbations in an individual child should improve in parallel with increased knowledge and/or understanding of the complex interactions among genetic, environmental (e.g., viral infections) and lifestyle (e.g., adherence to treatment) factors underlying these events.
doi:10.1097/MCP.0b013e32834db288
PMCID: PMC3296525  PMID: 22081091
Childhood asthma; asthma exacerbations; prediction; risk factors; biomarkers
18.  New Mexican Hispanic Smokers Have Lower Odds of Chronic Obstructive Pulmonary Disease and Less Decline in Lung Function Than Non-Hispanic Whites 
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
doi:10.1164/rccm.201103-0568OC
PMCID: PMC3262041  PMID: 21908412
19.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations 
Torgerson, Dara G. | Ampleford, Elizabeth J. | Chiu, Grace Y. | Gauderman, W. James | Gignoux, Christopher R. | Graves, Penelope E. | Himes, Blanca E. | Levin, Albert M. | Mathias, Rasika A. | Hancock, Dana B. | Baurley, James W. | Eng, Celeste | Stern, Debra A. | Celedón, Juan C. | Rafaels, Nicholas | Capurso, Daniel | Conti, David V. | Roth, Lindsey A. | Soto-Quiros, Manuel | Togias, Alkis | Li, Xingnan | Myers, Rachel A. | Romieu, Isabelle | Van Den Berg, David J. | Hu, Donglei | Hansel, Nadia N. | Hernandez, Ryan D. | Israel, Elliott | Salam, Muhammad T. | Galanter, Joshua | Avila, Pedro C. | Avila, Lydiana | Rodriquez-Santana, Jose R. | Chapela, Rocio | Rodriguez-Cintron, William | Diette, Gregory B. | Adkinson, N. Franklin | Abel, Rebekah A. | Ross, Kevin D. | Shi, Min | Faruque, Mezbah U. | Dunston, Georgia M. | Watson, Harold R. | Mantese, Vito J. | Ezurum, Serpil C. | Liang, Liming | Ruczinski, Ingo | Ford, Jean G. | Huntsman, Scott | Chung, Kian Fan | Vora, Hita | Li, Xia | Calhoun, William J. | Castro, Mario | Sienra-Monge, Juan J. | del Rio-Navarro, Blanca | Deichmann, Klaus A. | Heinzmann, Andrea | Wenzel, Sally E. | Busse, William W. | Gern, James E. | Lemanske, Robert F. | Beaty, Terri H. | Bleecker, Eugene R. | Raby, Benjamin A. | Meyers, Deborah A. | London, Stephanie J. | Gilliland, Frank D. | Burchard, Esteban G. | Martinez, Fernando D. | Weiss, Scott T. | Williams, L. Keoki | Barnes, Kathleen C. | Ober, Carole | Nicolae, Dan L.
Nature genetics  2011;43(9):887-892.
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies (GWAS) of asthma in 5,416 asthma cases representing European Americans, African Americans/African Caribbeans, and Latinos, and replicated five regions among the most significant signals in 12,649 individuals from the same ethnic groups. Four were at previously reported loci on 17q21, and near the IL1RL1, TSLP, and IL33, genes, but we report for the first time that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a novel association with asthma in the PYHIN1, gene that was specific to individuals of African descent (p=3.9×10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
doi:10.1038/ng.888
PMCID: PMC3445408  PMID: 21804549
20.  A meta-analysis of Th2 pathway genetic variants and risk for allergic rhinitis 
Pediatric Allergy and Immunology  2011;22(4):378-387.
There is a significant genetic contribution to allergic rhinitis (AR). Genetic association studies for AR have been performed, but varying results make it challenging to decipher the overall potential effect of specific variants. The Th2 pathway plays an important role in the immunological development of AR. We performed meta-analyses of genetic association studies of variants in Th2 pathway genes and AR. PubMed and Phenopedia were searched by double extraction for original studies on Th2 pathway-related genetic polymorphisms and their associations with AR. A meta-analysis was conducted on each genetic polymorphism with data meeting our predetermined selection criteria. Analyses were performed using both fixed and random effects models, with stratification by age-group, ethnicity, and AR definition where appropriate. Heterogeneity and publication bias were assessed. Six independent studies analyzing three candidate polymorphisms and involving a total of 1596 cases and 2892 controls met our inclusion criteria. Overall, the A allele of IL13 SNP rs20541 was associated with increased odds of AR (estimated OR=1.2; 95% CI 1.1–1.3, P value 0.004 in fixed effects model, 95% CI 1.0–1.5, P value 0.056 in random effects model). The A allele of rs20541 was associated with increased odds of AR in mixed age groups using both fixed effects and random effects modeling. IL13 SNP rs1800925 and IL4R SNP 1801275 did not demonstrate overall associations with AR. We conclude that there is evidence for an overall association between IL13 SNP rs20541 and increased risk of AR, especially in mixed-age populations.
doi:10.1111/j.1399-3038.2010.01124.x
PMCID: PMC3345814  PMID: 21309855
Allergic rhinitis; genetic association; polymorphism; Th2; IL13
21.  Gut Microbiota, Probiotics, and Vitamin D: Interrelated Exposures Influencing Allergy, Asthma, and Obesity? 
Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases and/or obesity. Moreover, certain gut microbial strain or strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (e.g., atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in humans. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway may be important in gut homeostasis and in the signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma and/or obesity.
doi:10.1016/j.jaci.2011.02.015
PMCID: PMC3085575  PMID: 21419479
microbiota; asthma; obesity; allergic; eczema; vitamin D; probiotics; cytokines
22.  Parental psychosocial stress and asthma morbidity in Puerto Rican twins 
Background
Little is known about paternal psychosocial factors and childhood asthma.
Objective
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 and again about their child’s asthma at age 3. Fathers were asked about symptoms of post-traumatic stress disorder (PTSD), depression, and anti-social 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 anti-social behavior were each associated with increased asthma symptoms at age 1 (e.g., OR =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 (OR 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 may influence asthma morbidity in young Puerto Rican children.
doi:10.1016/j.jaci.2010.11.010
PMCID: PMC3057225  PMID: 21194742
psychosocial stress; childhood wheeze; Puerto Rico; parental stress; asthma; paternal stress
23.  Decreased response to inhaled steroids in overweight and obese asthmatic children 
Background
The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear.
Objectives
To determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children.
Methods
We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program (CAMP) trial. Participants were then stratified into overweight/obese and non-overweight, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial.
Results
There was a significant interaction between BMI and budesonide for pre-BD FEV1/FVC (P=0.0007) and bronchodilator response (BDR) (P=0.049), and a non-significant trend for an interaction between BMI and budesonide on pre-BD FEV1 (P=0.15). Non-overweight children showed significant improvement with inhaled budesonide in lung function (FEV1, FEV1/FVC, and BDR) during the early (years 1–2) and late stages (years 3–4) of the trial. Overweight/obese children had improved FEV1 and BDR during the early but not the late stage of the trial, and showed no improvement in FEV1/FVC. When comparing time points where both groups showed significant response, the degree of improvement among non-overweight children was significantly greater than in overweight/obese children at most visits. Non-overweight children had a 44% reduction in the risk of ER visits or hospitalizations throughout the trial (P=0.001); there was no reduction in risk among overweight/obese (P=0.97).
Conclusions
Compared to children of normal weight, overweight/obese children in CAMP showed a decreased response to inhaled budesonide on measures of lung function and ER visits/hospitalizations for asthma.
doi:10.1016/j.jaci.2010.12.010
PMCID: PMC3056233  PMID: 21377042
Asthma; obesity; pediatric asthma; childhood obesity; budesonide
24.  In Utero Smoke Exposure and Impaired Response to Inhaled Corticosteroids in Children with Asthma 
Background
Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in asthmatic children.
Objectives
To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma, and whether IUS modifies the response to treatment with inhaled corticosteroids (ICS).
Methods
To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program (CAMP), a four-year, multicenter, randomized double masked placebo controlled trial of 1041 children ages 5–12 comparing the long term efficacy of ICS with mast cell stabilizing agents or placebo.
Results
Although improvement was seen in both groups, asthmatic children with IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared to unexposed children (p=.01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared to untreated children (1.25 fold-increase, 95% CI 1.03, 1.50, p=.02) the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04 fold-increase, 95% CI 0.65, 1.68, p=.88).
Conclusions
IUS reduces age-related improvements in airway responsiveness among asthmatic children. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
doi:10.1016/j.jaci.2010.06.016
PMCID: PMC2937829  PMID: 20673983
asthma; in utero smoke exposure; airway responsiveness; inhaled corticosteroids
25.  A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma 
Rationale: Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.
Objectives: We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.
Methods: Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV1, FVC, and FEV1/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.
Measurements and Main Results: Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7–16 wk) and the canalicular (gestational age: 17–26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV1 (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV1/FVC (combined P = 0.003).
Conclusions: Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.
doi:10.1164/rccm.200907-1009OC
PMCID: PMC2822972  PMID: 19926868
asthma; lung development; lung function; genetic variation; gene expression

Results 1-25 (54)