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1.  A Meta-analysis of Genome-wide Association Studies for Serum Total IgE in Diverse Study Populations 
Background
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
Objective
To identify the genetic predictors of serum total IgE levels.
Methods
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
Results
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
Conclusion
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
doi:10.1016/j.jaci.2012.10.002
PMCID: PMC3596497  PMID: 23146381
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
2.  Effect of Ezetimibe on Major Atherosclerotic Disease Events and All-Cause Mortality 
The American journal of cardiology  2012;111(4):532-539.
Despite ezetimibe’s ability to reduce serum cholesterol levels, there are concerns over its vascular effects and whether it prevents or ameliorates atherosclerotic disease (AD). Our objective was to estimate the effect of ezetimibe use on major AD events and all-cause mortality and to compare these associations to those observed for hydroxy-methylglutaryl-CoA reductase inhibitor (i.e., statin) use. We identified 367 new ezetimibe users between November 1, 2002 and December 31, 2009. These individuals were ≥18 years of age and had no prior statin use. One to four statin user matches were identified for each ezetimibe user resulting in a total of 1,238 closely matched statin users. Pharmacy data and drug dosage information were used to estimate a moving window of ezetimibe and statin exposure for each day of study follow-up. The primary outcome was a composite of major AD events (coronary heart disease, cerebrovascular disease, and peripheral vascular disease events) and all-cause death. Both ezetimibe use (odds ratio [OR] 0.33, 95% CI 0.13–0.86) and statin use (OR 0.61, 95% CI 0.36–1.04) were associated with reductions in the likelihood of the composite outcome. These protective associations were most significant for cerebrovascular disease events and all-cause death. Subgroup analyses by sex, race-ethnicity, prior history of AD, diabetes status, and estimated renal function showed consistent estimates across strata with no significant differences between ezetimibe and statin use. In conclusion, ezetimibe appeared to have a protective effect on major AD events and all-cause death which was not significantly different from that observed for statin use.
doi:10.1016/j.amjcard.2012.11.002
PMCID: PMC3563770  PMID: 23219178
ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; pharmacoepidemiology; atherosclerosis; cardiovascular disease; all-cause death
3.  Genetic ancestry and its association with asthma exacerbations among African American patients with asthma 
Background
There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American individuals are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care, or whether there is a predisposing genetic component.
Objective
To assess the relationship between genetic ancestry and severe exacerbations among African American individuals with asthma.
Methods
Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These individuals were 12–56 years of age; received care from a single, large health system; and had a physician diagnosis of asthma. Genetic ancestry was estimated using a set of validated ancestry informative markers. Severe exacerbations (i.e., asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.
Results
We assessed genetic ancestry in 392 African American individuals with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among males but not among females. The association among males persisted after adjusting for potential confounders (relative risk of 4.30 for every 20% increase in African ancestry; P-value 0.029).
Conclusions
African ancestry was a significantly and positively associated with severe exacerbations among African American males. These findings suggest that a portion of the risk of asthma exacerbations in this high risk group is attributable to a genetic risk factor which partitions with ancestry.
doi:10.1016/j.jaci.2012.09.001
PMCID: PMC3511609  PMID: 23069492
asthma; continental population groups; African continental ancestry group; genetic association study; health status disparities; minority health
4.  Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid non-adherence 
Background
Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, individuals with asthma may have waxing and waning adherence to controller therapy.
Objective
To measure changes in inhaled corticosteroid (ICS) adherence over time, and to estimate the effect of this changing pattern of use on asthma exacerbations.
Methods
ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). For each individual we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations.
Results
Adherence to ICS medications began to increase prior to the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations, but was only statistically significant among individuals whose adherence was >75% of the prescribed dose (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.41–0.90) when compared with individuals whose adherence was ≤25%. This pattern was largely confined to individuals whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication non-adherence.
Conclusions
Inhaled corticosteroid adherence varies in the time period leading up to and following an asthma exacerbation, and non-adherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events. [ClinicalTrials.gov number NCT01142947]
doi:10.1016/j.jaci.2011.09.011
PMCID: PMC3229671  PMID: 22019090
medication adherence; inhaled corticosteroids; asthma; patient compliance; asthma exacerbations
5.  Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma 
Background
African American patients suffer disproportionately from uncontrolled asthma. Treatment with an inhaled corticosteroid (ICS) is considered first-line therapy for persistent asthma.
Objective
To determine the degree to which African American patients respond to ICS medication and whether the level of response is influenced by other factors, including genetic ancestry.
Methods
Patients aged 12-56 years who received care from a large health system in southeast Michigan and who resided in Detroit were recruited to participate if they had a diagnosis of asthma. Patients were treated with 6 weeks of inhaled beclomethasone dipropionate, and pulmonary function was re-measured after treatment. Ancestry was determined by genotyping ancestry informative markers. The main outcome measure was ICS responsiveness defined as the change in pre-bronchodilator FEV1 over the 6-week course of treatment.
Results
Among 147 participating African American patients with asthma, average improvement in FEV1 following 6 weeks of ICS treatment was 11.6%. The mean proportion of African ancestry in this group was 78.4%. The degree of baseline bronchodilator reversibility was the only factor consistently associated ICS responsiveness as measured by both an improvement in FEV1 and in patient reported asthma control (P=0.001 and P=0.021, respectively). The proportion of African ancestry was not significantly associated with ICS responsiveness.
Conclusions
While baseline pulmonary function parameters appear to be associated with the likelihood to respond to ICS treatment, the proportion of genetic African ancestry does not. This study suggests that genetic ancestry may not contribute to differences in ICS controller response among African American patients with asthma.
Clinical Implications
Although African American patients suffer disproportionately from asthma-related complications, response to ICS controller therapy does not appear to be dependent on an individual’s proportion of African ancestry.
Capsule summary
Personalized medicine will be most beneficial to groups disproportionately affected by disease complications. Here we find baseline bronchodilator reversibility but not African ancestry to be associated with ICS responsiveness among African American patients with asthma.
doi:10.1016/j.jaci.2010.08.002
PMCID: PMC2998569  PMID: 20864153
inhaled corticosteroids; asthma; race-ethnicity; continental population groups; ancestry; urban health
6.  Dual specificity phosphatase-1 as a pharmacogenetic modifier of inhaled steroid response among asthma patients 
Background
Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma; yet, there is significant variability in treatment response. Dual specificity phosphatase-1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.
Objective
To determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.
Methods
Study participants with asthma were drawn from the following multi-ethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study, the Study of African Americans, Asthma, Genes & Environments (SAGE), and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICS for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in forced expiratory volume at one second (FEV1) and self-reported asthma control.
Results
DUSP1 polymorphisms, rs881152 and rs34507926, localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA participants. This interaction was also seen for rs881152 among SAPPHIRE, but not SAGE participants. Among the group of SAPPHIRE patients prospectively treated with ICS for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.
Conclusion
DUSP1 polymorphisms were associated with clinical response to ICS therapy, and therefore, may be useful in the future to identify asthma patients more likely to respond to this controller treatment.
Clinical implications
These findings further our understanding of ICS pharmacogenetics and will hopefully result in improved tailoring of this controller therapy among individuals with asthma and in better disease control.
Capsule summary
We identified genetic variants in DUSP1 which appeared to mediate the clinical response to inhaled corticosteroid (ICS) medication. These findings may eventually assist in identifying individuals with asthma most likely to respond this controller therapy.
doi:10.1016/j.jaci.2010.06.007
PMCID: PMC2943151  PMID: 20673984
Asthma; inhaled corticosteroids; dual specificity phosphatase-1; DUSP1; corticosteroid responsiveness
7.  A cluster-randomized trial to provide clinicians inhaled corticosteroid adherence information for their patients with asthma 
Background
Inhaled corticosteroid (ICS) non-adherence is common among patients with asthma; however, interventions to improve adherence have often been complex and not easily applied to large patient populations.
Objective
To assess the effect of supplying patient adherence information to primary care providers.
Methods
Patients and providers were members of a health system serving southeast Michigan. Providers (88 intervention; 105 control) and patients (1,335 intervention; 1,363 control) were randomized together by practice. Patients were age 5–56 years; had a diagnosis of asthma; and had existing prescriptions for ICS medication. Adherence was estimated using prescription and fill data. Unlike clinicians in the control arm, intervention arm providers could view updated ICS adherence information on their patients via electronic prescription software, and further details on patient ICS use could be viewed by selecting that option. The primary outcome was ICS adherence in last 3-months of the study period.
Results
At study end for the intention-to-treat analysis, ICS adherence was not different among patients in the intervention arm when compared with those in the control arm (21.3% vs. 23.3%, respectively; P=0.553). However, adherence was significantly higher among patients whose clinician elected to view their detailed adherence information (35.7%) when compared with both control arm patients (P=0.026) and intervention arm patients whose provider did not view adherence data (P=0.002).
Conclusions
Overall, providing adherence information to clinicians did not improve ICS use among patients with asthma. However, patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use.
doi:10.1016/j.jaci.2010.03.034
PMCID: PMC2917519  PMID: 20569973
Medication adherence; inhaled corticosteroids; asthma; randomized controlled trial
8.  Differences in Allergic Sensitization by Self-reported Race and Genetic Ancestry 
Background
Many allergic conditions occur more frequently in African-American patients when compared with white patients; however it is not known whether this represents genetic predisposition or disparate environmental exposures.
Objective
To assess the relationship of self-reported race and genetic ancestry to allergic sensitization.
Methods
We included 601 women enrolled in a population-based cohort study whose self-reported race was African-American or white. Genetic ancestry was estimated using markers that differentiate West African and European ancestry. We assessed the relationship between allergic sensitization (defined as ≥1 allergen-specific IgE result) and both self-reported race and genetic ancestry. Regression models adjusted for socio-demographic variables, environmental exposures, and location of residence.
Results
The average proportion of West African ancestry in African-American participants was 0.69, whereas the mean proportion of European ancestry in white participants was 0.79. Self-reported African-American race was associated with allergic sensitization when compared with those who reported being white (adjusted odds ratio [aOR] 2.19; 95% confidence interval [CI] 1.22 – 3.93) even after adjusting for other variables. Genetic ancestry was not significantly associated with allergic sensitization after accounting for location of residence (aOR 2.09 for urban vs. suburban residence, 95% CI 1.32 −3.31).
Conclusion
Self-reported race and location of residence appeared to be more important predictors of allergic sensitization when compared with genetic ancestry, suggesting that the disparity in allergic sensitization by race may be primarily due to environmental factors rather than genetic differences.
Clinical Implications
These data suggest that efforts to eliminate disparities in allergic sensitization should focus on contributing environmental factors.
doi:10.1016/j.jaci.2008.07.044
PMCID: PMC2951327  PMID: 19014772
self-reported race; race-ethnicity; continental population group; immunoglobulin E; allergic sensitization
9.  Relationship between thiazolidinedione use and cardiovascular outcomes and all-cause mortality among patients with diabetes: A time-updated propensity analysis 
Purpose
To investigate the association of the thiazolidinediones (TZDs), rosiglitazone and pioglitazone, together and individually on the risk of cardiovascular outcomes and all-cause mortality, using time-updated propensity score adjusted analysis
Methods
We conducted a retrospective cohort study in a large vertically integrated health system in southeast Michigan. Cohort inclusion criteria included adult patients with diabetes treated with oral medications and followed longitudinally within the health system between January 1, 2000 and December 1, 2006. The primary outcome was fatal and non-fatal acute myocardial infarction. Secondary outcomes included hospitalizations for congestive heart failure, fatal and non-fatal cerebrovascular accidents and transient ischemic attacks, combined coronary heart disease events, and all-cause mortality.
Results
19,171 patients were included in this study. Use of TZDs (adjusted hazard ratio [aHR] with propensity adjustment [PA], 0.92; 95% confidence interval [CI] 0.73–1.17), rosiglitazone (aHR with PA, 1.06; 95% CI 0.66–1.70), and pioglitazone (aHR with PA, 0.91; 95% CI 0.69–1.21) was not associated with a higher risk of acute myocardial infarction. However, pioglitazone use was associated with a reduction in all-cause mortality (aHR with PA, 0.60; 95% CI 0.42–0.96). Compared with rosiglitazone, pioglitazone use was associated with a lower risk of all outcomes assessed, particularly congestive heart failure (P = 0.013) and combined coronary heart disease events (P = 0.048).
Conclusions
Our findings suggest that pioglitazone may have a more favorable risk profile when compared to rosiglitazone, arguing against a singular effect for TZDs on cardiovascular outcomes.
doi:10.1002/pds.1722
PMCID: PMC2919167  PMID: 19235778
Thiazolidinediones; Coronary Heart Disease; Congestive Heart Failure; Cerebrovascular Accident; Mortality
10.  Race-Ethnic Differences in Factors Associated with Inhaled Steroid Adherence among Adults with Asthma 
Rationale: Adherence to inhaled corticosteroid (ICS) medication is known to be low overall, but tends to be lower among African-American patients when compared with white patients.
Objectives: To understand the factors that contribute to ICS adherence among African-American and white adults with asthma.
Methods: Eligible individuals had a prior diagnosis of asthma, one or more ICS prescriptions, and were members of a large health maintenance organization in southeast Michigan. Individuals were sent a survey that included questions about internal factors (e.g., patient beliefs, knowledge, and motivation) and external factors (e.g., socioeconomic status, barriers to care, social support, and stressors) potentially related to ICS adherence. Adherence was calculated using electronic prescription and fill data. Stepwise regression was used to identify factors associated with adherence before and after stratifying by race-ethnicity.
Measurements and Main Results: Surveys were returned by 1,006 (56.3%) of 1,787 eligible patients. Adjusting for internal factors, but not external factors, diminished the relationship between race-ethnicity and ICS adherence. Among African-American patients, readiness to take ICS medication was the only internal or external factor significantly associated with ICS adherence; it explained 5.6% of the variance in adherence. Among white patients, perceived ICS necessity, ICS knowledge, doctors being perceived as the source of asthma control, and readiness to take medication were the internal factors associated with ICS adherence; these accounted for 19.8% of the variance in adherence.
Conclusions: Factors associated with ICS adherence appear to differ between African-American and white patients, suggesting that group-specific approaches are needed to improve adherence.
doi:10.1164/rccm.200808-1233OC
PMCID: PMC2599867  PMID: 18849496
medication adherence; inhaled corticosteroids; asthma; race-ethnicity; patient compliance
11.  Gene-environment interactions between CD14 C-260T and endotoxin exposure on Foxp3+ and Foxp3− CD4+ lymphocyte numbers and total serum IgE levels in early childhood 
Background
Innate immune system stimuli, such as endotoxin, seem to affect allergy risk. Previously, we described gene-environment interactions between the endotoxin receptor polymorphism C-260T of the CD14 gene and endotoxin exposure on total serum IgE level; however, the mechanism of this interaction is not known.
Objective
To examine whether this gene-environment interaction affects early CD4+Foxp3− or CD4+Foxp3+ lymphocyte numbers.
Methods
Participating children were part of a birth cohort in the Detroit metropolitan area. Participants were genotyped for the CD14 C-260T polymorphism. Endotoxin exposure was estimated from dust measured in the home when children were 6 months old. Intracellular Foxp3 protein expression, a regulatory T-cell marker, was used to characterize CD4+ lymphocytes in blood samples collected at the age of 12 months; total serum IgE level was also measured at this time. Because race/ethnicity may confound or modify genetic associations, all analyses were stratified by race/ethnicity.
Results
We observed a significant gene-environment interaction between CD14 C-260T genotype and endotoxin exposure on CD4+ lymphocyte numbers, particularly CD4+Foxp3− lymphocytes. Stratified analyses suggest effect modification by race/ethnicity on CD4+Foxp3+ lymphocyte numbers, with a significant interaction in African American children but not in white children. The interaction between CD14 C-260T genotype and endotoxin exposure on total IgE levels was opposite that observed for CD4+ lymphocyte numbers, suggesting reciprocal relationships.
Conclusions
A gene-environment interaction between endotoxin and CD14 C-260T genotype on IgE levels may be the result of an upstream, opposing effect on CD4+Foxp3+ and CD4+Foxp3− lymphocyte numbers. Race/ethnicity may affect which of these cell populations is affected by this gene-environment interaction.
PMCID: PMC2646830  PMID: 18320914
12.  Relationship between recent short-acting β-agonist use and subsequent asthma exacerbations 
Background
US national guidelines recommend assessing short-acting β-agonist (SABA) medication use as a marker of asthma severity and control. However, the relationship between recent SABA use and asthma exacerbations is not currently known.
Objective
To evaluate the proximal relationship between the type and frequency of SABA use and asthma-related outcomes.
Methods
We evaluated SABA use among patients with asthma ages 5 to 56 years who were members of a large health maintenance organization in southeast Michigan. Frequency of use was estimated from pharmacy data assessing the timing and amount of SABA fills. Cox proportional hazards models were used to examine the prospective relationship between average daily SABA use for 3 months and outcomes associated with poor asthma control (ie, oral corticosteroids use, asthma-related emergency department visits, and asthma-related hospitalizations). We separately accounted for SABA metered-dose inhaler (MDI) and SABA nebulizer use.
Results
Of the 2,056 patients who met study criteria, 1,569 (76.3%) had used a SABA medication in their baseline year. After adjusting for potential confounders, SABA nebulizer use was associated with asthma-related emergency department visits (adjusted hazard ratio [aHR], 6.32; 95% confidence interval [CI], 2.38 to 16.80) and asthma-related hospitalizations (aHR, 21.62; 95% CI, 3.17 to 147.57). In contrast, frequency of SABA MDI use was not associated with these outcomes.
Conclusions
Frequency of SABA use during a 3-month period was associated with poor asthma outcomes. The relationship with poor asthma outcomes was strongest for SABA nebulizer use, suggesting that the type of SABA used is also of prognostic importance.
PMCID: PMC2646829  PMID: 19055201
13.  The role of endotoxin and its receptors in allergic disease 
Objective
To summarize the existing literature on the association of endotoxin with respiratory diseases and allergic sensitization and to review the potentially modifying effects of endotoxin receptor polymorphisms.
Data Sources
English-language articles were identified from the MEDLINE and PubMed databases using combinations of the following search terms: endotoxin, toll-like receptor, polymorphisms, atopy, asthma, and allergy. Other sources included experts in the field and the bibliographies of pertinent articles.
Study Selection
Relevant articles were selected based on the authors’ expert opinion.
Results
Cross-sectional studies, particularly those of children raised in rural European communities, suggest that early endotoxin exposure may protect against the development of allergic sensitization and atopic asthma. However, endotoxin exposure may also contribute to other nonatopic respiratory disorders and may exacerbate disease in individuals with preexisting asthma. Paradoxically, among individuals exposed to high levels of endotoxin, carriers of a functional mutation in toll-like receptor 4, which reduces cellular responsiveness to endotoxin, may be at lower risk of developing allergic sensitization.
Conclusions
The effect of endotoxin exposure on allergic sensitization and asthma appears to be influenced by the timing of exposure, the presence or absence of preexisting disease, and polymorphisms in the genes that encode endotoxin receptors. Further studies are needed to define the window period for this effect, as well as the underlying immunologic mechanism.
PMCID: PMC1351105  PMID: 15801242
14.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
15.  Genome-Wide Association Study of Lung Function Phenotypes in a Founder Population 
Background
Lung function is a long-term predictor of mortality and morbidity.
Objective
We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function.
Methods
We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs.
Results
Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B.
Conclusion
This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function.
doi:10.1016/j.jaci.2013.06.018
PMCID: PMC4270121  PMID: 23932459
FEV1/FVC; FEV1; FVC; GWAS; LASSO regression; GRAIL
16.  Socioeconomic Status and Childhood Asthma in Urban Minority Youths. The GALA II and SAGE II Studies 
Rationale: The burden of asthma is highest among socioeconomically disadvantaged populations; however, its impact is differentially distributed among racial and ethnic groups.
Objectives: To assess the collective effect of maternal educational attainment, annual household income, and insurance type on childhood asthma among minority, urban youth.
Methods: We included Mexican American (n = 485), other Latino (n = 217), and African American (n = 1,141) children (aged 8–21 yr) with and without asthma from the San Francisco Bay Area. An index was derived from maternal educational attainment, annual household income, and insurance type to assess the collective effect of socioeconomic status on predicting asthma. Logistic regression stratified by racial and ethnic group was used to estimate adjusted odds ratios (aOR) and their 95% confidence intervals (CI). We further examined whether acculturation explained the socioeconomic-asthma association in our Latino population.
Measurements and Main Results: In the adjusted analyses, African American children had 23% greater odds of asthma with each decrease in the socioeconomic index (aOR, 1.23; 95% CI, 1.09–1.38). Conversely, Mexican American children have 17% reduced odds of asthma with each decrease in the socioeconomic index (aOR, 0.83; 95% CI, 0.72–0.96) and this relationship was not fully explained by acculturation. This association was not observed in the other Latino group.
Conclusions: Socioeconomic status plays an important role in predicting asthma, but has different effects depending on race and ethnicity. Further steps are necessary to better understand the risk factors through which socioeconomic status could operate in these populations to prevent asthma.
doi:10.1164/rccm.201306-1016OC
PMCID: PMC3863734  PMID: 24050698
asthma; health status disparities; minority health; educational status; poverty
17.  Association of Genetic Variation with Gene Expression and Protein Abundance within the Natriuretic Peptide Pathway 
The natriuretic peptide (NP) system is a critical physiologic pathway in heart failure with wide individual variability in functioning. We investigated the genetic component by testing the association of single nucleotide polymorphisms (SNP) with RNA and protein expression. Samples of DNA, RNA, and tissue from human kidney (n=103) underwent genotyping, RT-PCR, and protein quantitation (in lysates), for four candidate genes (NP-receptor 1 [NPR1], NPR2, NPR3 and membrane metallo-endopeptidase [MME]). The association of genetic variation with expression was tested using linear regression for individual SNPs, and a principal components (PC) method for overall gene variation. Eleven SNPs in NPR2 were significantly associated with protein expression (false discovery rate ≤0.05), but not RNA quantity. RNA and protein quantity correlated poorly with each other. The PC analysis showed only NPR2 as significant. Assessment of the clinical impact of NPR2 genetic variation is needed.
doi:10.1007/s12265-013-9491-y
PMCID: PMC3795918  PMID: 23835779
Natriuretic peptide; heart failure; gene expression; pharmacogenomics; nesiritide; genetic polymorphisms
18.  Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The GALA II Study 
Background
Atopy varies by ethnicity even within Latino groups. This variation may be due to environmental, socio-cultural or genetic factors.
Objective
To examine risk factors for atopy within a nationwide study of U.S. Latino children with and without asthma.
Methods
Aeroallergen skin test repsonse was analyzed in 1830 US latino subjects. Key determinants of atopy included: country / region of origin, generation in the U.S., acculturation, genetic ancestry and site to which individuals migrated. Serial multivariate zero inflated negative binomial regressions, stratified by asthma status, examined the association of each key determinant variable with the number of positive skin tests. In addition, the independent effect of each key variable was determined by including all key variables in the final models.
Results
In baseline analyses, African ancestry was associated with 3 times as many positive skin tests in participants with asthma (95% CI:1.62–5.57) and 3.26 times as many positive skin tests in control participants (95% CI: 1.02–10.39). Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, Puerto Rican [exp(β) (95%CI): 1.31(1.02–1.69)] and mixed ethnicity [exp(β) (95%CI):1.27(1.03–1.56)] asthmatics had a greater probability of positive skin tests compared to Mexican asthmatics. Ancestry associations were abrogated by recruitment site, but not region of origin.
Conclusions
Puerto Rican ethnicity and mixed origin were associated with degree of atopy within U.S. Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.
doi:10.1016/j.jaci.2013.02.046
PMCID: PMC3788073  PMID: 23684070
Latino; atopy; region of origin; genetic ancestry; immigration; skin test; aeroallergen
19.  Real world effects of once vs. greater daily inhaled corticosteroid dosing on medication adherence 
doi:10.1016/j.anai.2013.06.008
PMCID: PMC3763990  PMID: 23987199
Medication adherence; asthma; inhaled corticosteroids; once-daily dosing; anti-asthmatic drugs
20.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
Background
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
Methods
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
Results
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Conclusions
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
doi:10.1186/1755-8794-7-48
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
21.  Variation of dust endotoxin concentrations by location and time within homes of young children 
Endotoxin may affect the development of allergic disease in childhood but little is known about endotoxin variation within homes. We sought to determine endotoxin concentration agreement within homes when five locations were each sampled twice 5 months apart. Endotoxin was measured using the recombinant Limulus factor C assay in dust samples from 585 homes of children enrolled in a prospective study and again in 335 homes 5 months later. The five locations sampled in each home were the child's bedroom floor, child's bed, mother's bedroom floor, mother's bed and living room floor. Concentrations of 4 allergens (Can f 1, Fel d 1, Der f 1 and Bla g 2) were also measured from the child's bedroom floor. In pair-wise comparisons, endotoxin concentrations in all locations within each home were significantly different from all other locations (p < 0.001) except for the child's and mother's bedroom floors (p = 0.272). Spearman correlations between endotoxin concentrations from the different locations were all statistically significant (p < 0.05) but of modest magnitude (r = 0.24–0.54). Similarly, correlations at each site over the 5 month observation interval were statistically significant but modest (r = 0.17–0.44). Pets and season of the year did not affect correlations, although correlations were lower if the floor was not carpeted. Endotoxin concentrations at all locations were minimally correlated with allergen concentrations in both negative and positive directions (r = −0.12 to 0.12). We conclude that a single measurement of endotoxin from a home dust sample provides an imprecise estimate of dust endotoxin concentrations in other locations within the home and over a relatively short observation interval.
doi:10.1111/j.1399-3038.2009.00918.x
PMCID: PMC4025918  PMID: 20088861
endotoxin; house dust; location; cats; dogs; carpets; seasons
22.  Examining the relationship between depression and asthma exacerbations in a prospective follow-up study 
Psychosomatic medicine  2013;75(3):305-310.
Background
While depression has been linked with asthma in numerous studies, its relationship with asthma exacerbations, including emergency room (ER) visits and oral steroid (OS) use has not been well documented. The main aim is to investigate whether comorbid depression increases exacerbations among patients with asthma.
Method
The study included 568 participants with asthma, who were between 18-56 years old, were taking an inhaled corticosteroid, and participated in both baseline and follow-up surveys. Surveys and medical records from a large, integrated health system were collected as part of the Adherence Feedback for Improving Respiratory Medication Use trial (ClinicalTrials.gov: NCT00459368). Number of ER visits and OS prescription fills for asthma were calculated for 12-month periods before and after the follow-up survey. Depression was measured using a standardized two-item instrument on both surveys. Negative binomial regression and modified proportional hazards models were used in the analyses.
Results
Among patients with asthma, those who had depression (n=187; 32.9%) were at increased risk of having an asthma-related ER visit (adjusted relative risk (aRR): 1.96, 95% confidence interval (CI): 1.02 - 3.75), but not an OS fill (aRR: 0.98; 95%CI: 0.72-1.32). Participants with depression and asthma, who also received psychiatric treatment via antidepressant medication (n=126; 22.2%) or psychotherapy (n=39; 6.9%), were more likely to have an ER visit (medication hazard ratio (HR): 2.09, 95%CI: 1.35-3.25; psychotherapy HR: 2.07, 95%CI: 1.38-3.22).
Conclusion
This study suggests a temporal relationship between depression and asthma-related ER visits. Research and practice must further consider the importance of these comorbid conditions.
doi:10.1097/PSY.0b013e3182864ee3
PMCID: PMC3706985  PMID: 23440228
asthma; depression; emergency care; oral steroid; mental health services
25.  Comparison of Beta Blocker Effectiveness in Heart Failure Patients with Preserved Ejection Fraction vs. those with Reduced Ejection Fraction 
Journal of cardiac failure  2013;19(2):73-79.
Background
To compare the benefit of Beta Blockers (BB) in heart failure (HF) with preserved vs. reduced ejection fraction (EF).
Methods and Results
Retrospective study of insured patients who were hospitalized for HF between January 2000 and June 2008. Pharmacy claims were used to estimate BB exposure over six-month rolling windows. The association between BB exposure and all-cause hospitalization or death was tested using time-updated proportional hazards regression, with adjustment for baseline covariates and other HF medication exposure. The groups were compared by stratification (EF <50% vs. ≥50%) and using an EF-group*BB exposure interaction term. 1835 patients met inclusion criteria; 741 (40%) with a preserved EF. Median follow up was 2.1 years. In a fully-adjusted multivariable model, BB exposure was associated with a decreased risk of death or hospitalization in both groups (EF<50% hazard ratio [HR] 0.53, p<0.0001; EF≥50% HR 0.68, p=0.009). There was no significant difference in this protective association between groups (interaction p=0.32).
Conclusion
BB exposure was associated with a similar protective effect in terms of time to death or hospitalization in HF patients regardless of whether EF was preserved or reduced. An adequately powered randomized trial of BB in HF with preserved EF is warranted.
doi:10.1016/j.cardfail.2012.11.011
PMCID: PMC3678365  PMID: 23384631
beta adrenergic receptor blocker; hospitalization; diastolic dysfunction; heart failure with preserved ejection fraction

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