Aeroallergen sensitization predicts acute chest syndrome in children with sickle cell anaemia.

Asthma is associated with higher rates of acute chest syndrome (ACS) and vaso-occlusive pain episodes among children with sickle cell anaemia (SCA). Aeroallergen sensitization is a risk factor for asthma. We hypothesized that aeroallergen sensitization is associated with an increased incidence of hospitalizations for ACS and pain. Participants in a multicentre, longitudinal cohort study, aged 4-18 years with SCA, underwent skin prick testing to ten aeroallergens. ACS and pain episodes were collected from birth until the end of the follow-up period. The number of positive skin tests were tested for associations with prospective rates of ACS and pain. Multivariable models demonstrated additive effects of having positive skin tests on future rates of ACS (incidence rate ratio (IRR) for each positive test 1·23, 95% confidence interval [CI] 1·11-1·36, P < 0·001). Aeroallergen sensitization was not associated with future pain (IRR 1·14, 95%CI 0·97-1·33, P = 0·11). Our study demonstrated that children with SCA and aeroallergen sensitization are at increased risk for future ACS. Future research is needed to determine whether identification of specific sensitizations and allergen avoidance and treatment reduce the risk of ACS for children with SCA.

The Association of Maternal Asthma and Early Pregnancy Vitamin D with Risk of Preeclampsia: An Observation From Vitamin D Antenatal Asthma Reduction Trial (VDAART).

BACKGROUND: Maternal asthma, uncontrolled asthma, and low vitamin D levels during pregnancy have been individually linked to increased risk of preeclampsia. OBJECTIVE: To investigate the association of history of physician-diagnosed asthma and uncontrolled asthma status during pregnancy with the risk of preeclampsia and the effects of early pregnancy vitamin D concentrations on this relationship. METHODS: A total of 816 subjects with available pregnancy outcome data and risk factors of interest were analyzed. A group of experienced obstetricians and gynecologists from 3 study centers validated the preeclampsia diagnoses. Vitamin D was measured using the DiaSorin method at 10 to 18 weeks of gestation. The Pregnancy-Asthma Control Test was used to assess asthma control during pregnancy. Criterion-based stepwise variable selection algorithm was applied to investigate the relationships of risk factors of interest (history of asthma diagnosis, uncontrolled asthma during pregnancy, and vitamin D) to preeclampsia. RESULTS: The incidence of preeclampsia was not related to the presence of asthma diagnosis (8.9% with vs 7.4% without). The adjusted odds of preeclampsia controlled for maternal serum 25-hydroxyvitamin D (25OHD) concentrations was higher for women with a higher proportion of uncontrolled asthma months per visit during pregnancy (adjusted odds ratio, 3.55; 95% CI, 1.15-13.0). Adjusting for asthma control status during pregnancy, an additional decrease in the associated preeclampsia risk by 7% was observed for a 10-unit (ng/mL) increase in early pregnancy 25OHD levels (adjusted odds ratio10-unit, 0.60; 95% CI, 0.43-0.82) as compared with the previous risk estimate of preeclampsia associated with low maternal 25OHD unadjusted for asthma control status. CONCLUSIONS: Uncontrolled asthma during pregnancy is associated with an increased risk of preeclampsia. Early pregnancy 25OHD contributes to the association of uncontrolled asthma status with preeclampsia.

Overweight/obesity status in preschool children associates with worse asthma but robust improvement on inhaled corticosteroids.

BACKGROUND: Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults. OBJECTIVE: We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children. METHODS: This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: ≥85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups. RESULTS: Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P = .020) and exacerbations (1.4 vs 0.8, P = .009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0 days, P = .44; short-term ICS: 61.8 vs 52.9 days, P = .46; as-needed ICS: 53.3 vs 47.3 days, P = .53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P = .10; short-term ICS: 1.1 vs 0.8 days, P = .25; as-needed ICS: 1.0 vs 1.1, P = .72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P = .004) and exacerbations (1.4 vs 0.6, P = .006), while similar protective ICS effects were less apparent among NW. CONCLUSIONS: In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy.

Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial.

BACKGROUND: Nutrient trials differ from drug trials because participants have varying circulating levels at entry into the trial. OBJECTIVE: We sought to study the effect of a vitamin D intervention in pregnancy between subjects of different races and the association between 25-hydroxyvitamin D3 (25[OH]D) levels in pregnancy and the risk of asthma/recurrent wheeze in offspring. METHODS: The Vitamin D Antenatal Asthma Reduction Trial is a randomized trial of pregnant women at risk of having children with asthma randomized to 4400 international units/d vitamin D or placebo plus 400 international units/d vitamin D. Asthma and recurrent wheezing until age 3 years were recorded. RESULTS: African American (AA) women (n = 312) had lower initial levels of 25(OH)D (mean [SD], 17.6 ng/mL [8.3 ng/mL]) compared with non-AA women (n = 400; 27.1 ng/mL [9.7 ng/mL], P < .001). No racial difference was found from vitamin D supplementation in pregnancy on asthma/recurrent wheezing in offspring (P for interaction = .77). Having an initial level of greater than 30 ng/mL and being randomized to the intervention group was associated with the lowest risk for asthma/recurrent wheeze by age 3 years compared with having an initial level of less than 20 ng/mL and receiving placebo (adjusted odds ratio, 0.42; 95% CI, 0.19-0.91). CONCLUSIONS: We did not find differences between AA and non-AA mothers in the effect of maternal vitamin D supplementation and asthma/recurrent wheeze in offspring at 3 years. Maternal supplementation of vitamin D, particularly in mothers with initial 25(OH)D levels of greater than 30 ng/mL, reduced asthma/recurrent wheeze in the offspring through age 3 years, suggesting that higher vitamin D status beginning in early pregnancy is necessary for asthma/recurrent wheeze prevention in early life.

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

RATIONALE: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. OBJECTIVES: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. METHODS: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). MEASUREMENTS AND MAIN RESULTS: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. CONCLUSIONS: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).

Early pregnancy vitamin D status and risk of preeclampsia.

BACKGROUND: Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. METHODS: We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. RESULTS: Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity. CONCLUSIONS: Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00920621. FUNDING: Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Lack of Recognition, Diagnosis, and Treatment of Overweight/Obesity in Children Hospitalized for Asthma.

OBJECTIVES: Information is lacking regarding recognition and treatment of overweight and obesity in children hospitalized for asthma. The study objectives were to determine the current practice of recognition, diagnosis, and treatment of overweight and obesity for children hospitalized for asthma and to describe demographic, asthma, and weight characteristics for these patients. METHODS: A retrospective record review was conducted for children admitted to the hospital with asthma in 2012. Charts were reviewed for evidence of recognition, diagnosis, and treatment of overweight and obesity. Subjects were classified into age-adjusted Centers for Disease Control and Prevention weight categories based on BMI percentile and chronic asthma severity categories according to National Asthma Education and Prevention Program guidelines. RESULTS: A total of 510 subjects aged 3 to 17 years were studied. Obesity was present in 19.6% and overweight in 13.3% of subjects. BMI percentile was recorded in only 3.3% of all charts, in only 11% of subjects with obesity, and in 0% of subjects with overweight. BMI percentile was documented more often in subjects with severe obesity (P = .013) and with moderate to severe persistent asthma (P = .035). Only 9 of 168 subjects who were overweight or obese (5.6%) were given a discharge diagnosis indicating overweight or obesity, and 14 (8.3%) received treatment. Chronic asthma severity differed by BMI weight category (P < .001), with a significant relationship between obesity status and chronic asthma severity in older subjects (P = .033). There were no differences in severity of acute episodes based on weight group. CONCLUSIONS: Overweight and obesity were underrecognized, underdiagnosed, and undertreated in children hospitalized for asthma.

What Are Parents Willing to Discuss with Their Pediatrician About Firearm Safety? A Parental Survey.

OBJECTIVE: To determine if parents are receptive to discussing firearm safety with their pediatrician. STUDY DESIGN: Parents completed a self-administered paper survey during a pediatric office visit. Responses of those who confirmed and denied household firearms were compared using Fisher exact test. RESULTS: Between March 23 and May 21, 2015, 1246 of 1363 eligible parents (91.4%) completed the survey (22.6% African American, 79.5% at least some college education); 36% of respondents reported household firearms (owners). An additional 14.3% reported that their child was often in homes that contained firearms. Of the 447 owners, 25.1% reported ≥1 firearm was stored loaded, and 17.9% carried a firearm when leaving the house. Seventy-five percent of parents thought the pediatrician should advise about safe storage of firearms (owners 71.1%, others 77.5%), 16.9% disagreed (owners 21.9%, others 13.4%), and 8.2% were uncertain. Sixty-six percent thought pediatricians should ask about the presence of household firearms (owners 58.4%, others 70.9%), 23.2% disagreed (owners 31.5%, others 17.8%), and 10.5% were uncertain. Differences in parental opinions between owners and other parents were statistically significant. Twenty-two percent of owners would ignore advice to not have household firearms for safety reasons, and 13.9% would be offended by such advice. Only 12.8% of all parents reported a discussion about firearms with the pediatrician. CONCLUSIONS: Avoiding direct questioning about firearm ownership and extending the discussion about why and how to ensure safe storage of firearms to all parents may be an effective strategy to decrease firearm-related injuries and fatalities in children.

Exhaled nitric oxide: Not associated with asthma, symptoms, or spirometry in children with sickle cell anemia.

BACKGROUND: The significance of fractional exhaled nitric oxide (Feno) levels in children with sickle cell anemia (SCA) is unclear, but increased levels can be associated with features of asthma and thus increased morbidity. OBJECTIVES: We sought to determine factors associated with Feno and whether Feno levels are associated with increased rates of acute chest syndrome (ACS) and pain. METHODS: All participants had SCA, were part of the prospective observational Sleep and Asthma Cohort study, and had the following assessments: Feno levels, spirometry, blood samples analyzed for hemoglobin, white blood cell counts, eosinophil counts and total serum IgE levels, questionnaires about child medical and family history, and review of medical records. RESULTS: The analytic sample included 131 children with SCA (median age, 11.2 years; age range, 6-18 years) followed for a mean of 16.2 years, including a mean of 5.1 years after baseline Feno data measurements. In multivariable analyses higher Feno levels were associated with ln(IgE) levels (P < .001) and the highest quartile of peripheral eosinophil counts (P = .03) but not wheezing symptoms, baseline spirometric indices, or response to bronchodilator. Multivariable analyses identified that the incident rate of ACS was associated with ln(Feno) levels (P = .03), as well as male sex (P = .025), wheezing causing shortness of breath (P = .002), and ACS at less than 4 years of age (P < .001). Feno levels were not associated with future pain episodes. CONCLUSIONS: Steady-state Feno levels were not associated with an asthma diagnosis, wheezing symptoms, lung function measures, or prior sickle cell morbidity but were associated with markers of atopy and increased risk of future ACS events.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

RATIONALE: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. OBJECTIVES: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. METHODS: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. MEASUREMENTS AND MAIN RESULTS: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. CONCLUSIONS: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia.

Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management.

Pattern of Lung Function Is Not Associated with Prior or Future Morbidity in Children with Sickle Cell Anemia.

RATIONALE: Patient factors associated with development of abnormal lung function in children with sickle cell anemia (SCA) have not been fully characterized. OBJECTIVES: To characterize lung function abnormalities among children with SCA and to determine whether these steady-state lung function results were associated with morbidity before or after testing among children with SCA. METHODS: This study was part of the prospective National Institutes of Health-funded Sleep and Asthma Cohort Study. Children with HbSS or Hb Sß(o) (SCA) were enrolled without regard for sickle cell-related comorbidities or diagnosis of asthma. Lung function was measured by spirometry and plethysmography on the same day, when free of acute disease. Standardized asthma symptom questionnaires and review of the medical records were also performed. MEASUREMENTS AND MAIN RESULTS: A total of 149 children aged 6 to 19 years completed lung function testing, of whom 139 participants had retrospective morbidity data from birth to the test date, and 136 participants were followed prospectively for a median of 4.3 years from the test date. At baseline, percentages with normal, obstructive, restrictive, nonspecific, and mixed lung function patterns were 70, 16, 7, 6, and 1, respectively. Neither retrospective rates of pain nor acute chest syndrome was associated with lung function patterns. Furthermore, baseline lung function pattern was not predictive of future pain or acute chest syndrome episodes. CONCLUSIONS: The majority of children with SCA have lung function that is within the normal range. Abnormal lung function patterns were not associated with prior vasoocclusive pain or acute chest syndrome episodes, and baseline lung function patterns did not predict future vasoocclusive pain or chest syndrome episodes.

Practice Variation in Management of Childhood Asthma Is Associated with Outcome Differences.

BACKGROUND: Although specialist asthma care improves children's asthma outcomes, the impact of primary care management is unknown. OBJECTIVE: To determine whether variation in preventive and acute care for asthma in pediatric practices affects patients' outcomes. METHODS: For 22 practices, we aggregated 12-month patient data obtained by chart review and parent telephone interviews for 948 children, 3 to 12 years old, diagnosed with asthma to obtain practice-level measures of preventive (≥1 asthma maintenance visit/year) and acute (≥1 acute asthma visit/year) asthma care. Relationships between practice-level measures and individual asthma outcomes (symptom-free days, parental quality of life, emergency department [ED] visits, and hospitalizations) were explored using generalized estimating equations, adjusting for seasonality, specialist care, Medicaid insurance, single-family status, and race. RESULTS: For every 10% increase in the proportion of children in the practice receiving preventive care, symptom-free days per child increased by 7.6 days (P = .02) and ED visits per child decreased by 16.5% (P = .002), with no difference in parental quality of life or hospitalizations. Only the association between more preventive care and fewer ED visits persisted in adjusted analysis (12.2% reduction; P = .03). For every 10% increase in acute care provision, ED visits per child and hospitalizations per child decreased by 18.1% (P = .02) and 16.5% (P < .001), respectively, persisting in adjusted analyses (ED visits 8.6% reduction, P = .02; hospitalizations 13.9%, P = .03). CONCLUSIONS: Children cared for in practices providing more preventive and acute asthma care had improved outcomes, both impairment and risk. Persistence of improved risk outcomes in the adjusted analyses suggests that practice-level interventions to increase asthma care may reduce childhood asthma disparities.

Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial.

IMPORTANCE: Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring. OBJECTIVE: To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood. DESIGN, SETTING, AND PARTICIPANTS: The Vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States. Enrollment began in October 2009 and completed follow-up in January 2015. Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were randomized at 10 to 18 weeks' gestation. Five participants were deemed ineligible shortly after randomization and were discontinued. INTERVENTIONS: Four hundred forty women were randomized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D, and 436 women were randomized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D. MAIN OUTCOMES AND MEASURES: Coprimary outcomes of (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third trimester maternal 25-hydroxyvitamin D levels. RESULTS: Eight hundred ten infants were born in the study, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%-28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%-73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6-1.0; P = .051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%-47.5%, P < .001). CONCLUSIONS AND RELEVANCE: In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00920621.

Increased circulating fibrocytes are associated with higher reticulocyte percent in children with sickle cell anemia.

BACKGROUND: Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease. PROCEDURE: Cross-sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study. RESULTS: Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated α-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels. CONCLUSIONS: Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction.

Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation.

Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100 kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10(-04)), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2-2.0, P < 10(-11)) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5-2.3, P < 10(-11)). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3-10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization.

The metabolomics of asthma control: a promising link between genetics and disease.

Short-acting ß agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking ß agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative "omics" approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), - using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites-monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.