Gregory B. Diette

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

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 of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being 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.

Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit

ObjectiveTo determine whether caloric intake is associated with risk of nosocomial bloodstream infection in critically ill medical patients. DesignProspective cohort study. SettingUrban, academic medical intensive care unit. PatientsPatients were 138 adult patients who did not take food by mouth for ≥96 hrs after medical intensive care unit admission. MeasurementsDaily caloric intake was recorded for each patient. Participants subsequently were grouped into one of four categories of caloric intake: <25%, 25–49%, 50–74%, and ≥75% of average daily recommended calories based on the American College of Chest Physicians guidelines. Simplified Acute Physiology Score II and serum albumin were measured on medical intensive care unit admission. Serum glucose (average value and maximum value each day) and route of feeding (enteral, parenteral, or both) were collected daily. Nosocomial bloodstream infections were identified by infection control surveillance methods. Main ResultsThe overall mean (±sd) daily caloric intake for all study participants was 49.4 ± 29.3% of American College of Chest Physicians guidelines. Nosocomial bloodstream infection occurred in 31 (22.4%) participants. Bivariate Cox analysis revealed that receiving ≥25% of recommended calories compared with <25% was associated with significantly lower risk of bloodstream infection (relative hazard, 0.24; 95% confidence interval, 0.10–0.60). Simplified Acute Physiology Score II also was associated with risk of nosocomial bloodstream infection (relative hazard, 1.27; 95% confidence interval, 1.01–1.60). Average daily serum glucose, admission serum albumin, time to initiating nutritional support, and route of nutrition did not affect risk of bloodstream infection. After adjustment for Simplified Acute Physiology Score II in a multivariable analysis, receiving ≥25% of recommended calories was associated with a significantly lower risk of bloodstream infection (relative hazard, 0.27; 95% confidence interval, 0.11–0.68). ConclusionsIn the context of reducing risk of nosocomial bloodstream infections, failing to provide ≥25% of the recommended calories may be harmful. Higher caloric goals may be necessary to achieve other clinically important outcomes.

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

BACKGROUND Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Household mouse allergen exposure and asthma morbidity in inner-city preschool children

BACKGROUND Inner-city children experience disproportionate asthma morbidity, and suspected reasons include indoor environmental exposures. OBJECTIVE To determine if mouse allergen exposure is a risk factor for asthma morbidity. METHODS Preschool children with asthma were recruited from inner-city Baltimore, MD. Skin testing was performed and blood was collected at the baseline visit for quantification of mouse allergen specific IgE. A questionnaire evaluated symptoms, medication, and health care use at baseline, 3 months, and 6 months. A trained technician collected dust samples from the childs home for analysis of Mus m 1 at baseline, 3 months, and 6 months. Outcomes were compared between mouse-sensitized, highly exposed children and all other children. RESULTS A total of 127 children had complete data for mouse sensitization status and bedroom settled dust mouse allergen levels at baseline. The mean age of the children was 4.4 years, 92% were African American, and 26% were sensitized to mouse. Mouse-sensitized children exposed to higher levels of Mus m 1 (>0.5 microg/g) had 50% more days of symptoms (incidence rate ratio [IRR], 1.5; 95% confidence interval [CI], 1.1-2.1) and 80% more days of beta-agonist use than other children (IRR, 1.8; 95% CI, 1.3-2.5). Children in the sensitized and highly exposed group were also more likely to have an unscheduled physician visit (odds ratio [OR], 3.1; 95% CI, 1.6-6.3), emergency department visit (OR, 2.1; 95% CI, 1.1-4.1), and hospitalization (OR, 36.6; 95% CI, 4.1-327.3) than other children. These associations between mouse allergen exposure and asthma symptoms and morbidity remained statistically significant after adjusting for potential confounders, including atopy and cockroach sensitization and exposure. CONCLUSIONS In mouse-sensitized inner-city children, exposure to mouse allergen may be an important cause of asthma morbidity.

Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes

Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10(-91) to 7 × 10(-4)). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10(-6)), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.

A Longitudinal Study of Indoor Nitrogen Dioxide Levels and Respiratory Symptoms in Inner-City Children with Asthma

Background The effect of indoor nitrogen dioxide concentrations on asthma morbidity among inner-city preschool children is uncertain. Objectives Our goal was to estimate the effect of indoor NO2 concentrations on asthma morbidity in an inner-city population while adjusting for other indoor pollutants. Methods We recruited 150 children (2–6 years of age) with physician-diagnosed asthma from inner-city Baltimore, Maryland. Indoor air was monitored over a 72-hr period in the children’s bedrooms at baseline and 3 and 6 months. At each visit, the child’s caregiver completed a questionnaire assessing asthma symptoms over the previous 2 weeks and recent health care utilization. Results Children were 58% male, 91% African American, and 42% from households with annual income <

In-Home Particle Concentrations and Childhood Asthma Morbidity

25,000; 63% had persistent asthma symptoms. The mean (± SD) in-home NO2 concentration was 30.0 ± 33.7 (range, 2.9–394.0) ppb. The presence of a gas stove and the use of a space heater or oven/stove for heat were independently associated with higher NO2 concentrations. Each 20-ppb increase in NO2 exposure was associated significantly with an increase in the number of days with limited speech [incidence rate ratio (IRR) = 1.15; 95% confidence interval (CI), 1.05–1.25], cough (IRR = 1.10; 95% CI, 1.02–1.18), and nocturnal symptoms (IRR = 1.09; 95% CI, 1.02–1.16), after adjustment for potential confounders. NO2 concentrations were not associated with increased health care utilization. Conclusions Higher indoor NO2 concentrations were associated with increased asthma symptoms in preschool inner-city children. Interventions aimed at lowering NO2 concentrations in inner-city homes may reduce asthma morbidity in this vulnerable population.

Indoor Air Pollution and Asthma in Children

Background Although outdoor particulate matter (PM) has been linked to mortality and asthma morbidity, the impact of indoor PM on asthma has not been well established. Objective This study was designed to investigate the effect of in-home PM on asthma morbidity. Methods For a cohort of 150 asthmatic children (2–6 years of age) from Baltimore, Maryland, a technician deployed environmental monitoring equipment in the children’s bedrooms for 3-day intervals at baseline and at 3 and 6 months. Caregivers completed questionnaires and daily diaries during air sampling. Longitudinal data analyses included regression models with generalized estimating equations. Results Children were primarily African Americans (91%) from lower socioeconomic backgrounds and spent most of their time in the home. Mean (± SD) indoor PM2.5–10 (PM with aerodynamic diameter 2.5–10 μm) and PM2.5 (aerodynamic diameter < 2.5 μm) concentrations were 17.4 ± 21.0 and 40.3 ± 35.4 μg/m3. In adjusted models, 10-μg/m3 increases in indoor PM2.5–10 and PM2.5 were associated with increased incidences of asthma symptoms: 6% [95% confidence interval (CI), 1 to 12%] and 3% (95% CI, –1 to 7%), respectively; symptoms causing children to slow down: 8% (95% CI, 2 to 14%) and 4% (95% CI, 0 to 9%), respectively; nocturnal symptoms: 8% (95% CI, 1 to 14%) and 6% (95% CI, 1 to 10%), respectively; wheezing that limited speech: 11% (95% CI, 3 to 19%) and 7% (95% CI, 0 to 14%), respectively; and use of rescue medication: 6% (95% CI, 1 to 10%) and 4% (95% CI, 1 to 8%), respectively. Increases of 10 μg/m3 in indoor and ambient PM2.5 were associated with 7% (95% CI, 2 to 11%) and 26% (95% CI, 1 to 52%) increases in exercise-related symptoms, respectively. Conclusions Among preschool asthmatic children in Baltimore, increases in in-home PM2.5–10 and PM2.5 were associated with respiratory symptoms and rescue medication use. Increases in in-home and ambient PM2.5 were associated with exercise-related symptoms. Although reducing PM outdoors may decrease asthma morbidity, reducing PM indoors, especially in homes of inner-city children, may lead to improved asthma health.

Home indoor pollutant exposures among inner-city children with and without asthma

The purpose of this article is to review indoor air pollution factors that can modify asthma severity, particularly in inner-city environments. While there is a large literature linking ambient air pollution and asthma morbidity, less is known about the impact of indoor air pollution on asthma. Concentrating on the indoor environments is particularly important for children, since they can spend as much as 90% of their time indoors. This review focuses on studies conducted by the Johns Hopkins Center for Childhood Asthma in the Urban Environment as well as other relevant epidemiologic studies. Analysis of exposure outcome relationships in the published literature demonstrates the importance of evaluating indoor home environmental air pollution sources as risk factors for asthma morbidity. Important indoor air pollution determinants of asthma morbidity in urban environments include particulate matter (particularly the coarse fraction), nitrogen dioxide, and airborne mouse allergen exposure. Avoidance of harmful environmental exposures is a key component of national and international guideline recommendations for management of asthma. This literature suggests that modifying the indoor environment to reduce particulate matter, NO(2), and mouse allergen may be an important asthma management strategy. More research documenting effectiveness of interventions to reduce those exposures and improve asthma outcomes is needed.

A Randomized Trial of Air Cleaners and a Health Coach to Improve Indoor Air Quality for Inner-City Children With Asthma and Secondhand Smoke Exposure

Background Evidence for environmental causes of asthma is limited, especially among African Americans. To look for systematic differences in early life domestic exposures between inner-city preschool children with and without asthma, we performed a study of home indoor air pollutants and allergens. Methods Children 2–6 years of age were enrolled in a cohort study in East Baltimore, Maryland. From the child’s bedroom, air was monitored for 3 days for particulate matter ≤ 2.5 and ≤ 10 μm in aerodynamic diameter (PM2.5, PM10), nitrogen dioxide, and ozone. Median baseline values were compared for children with (n = 150) and without (n = 150) asthma. Housing characteristics related to indoor air pollution were assessed by caregiver report and home inspection. In addition, indoor allergen levels were measured in settled dust. Results Children were 58% male, 91% African American, and 88% with public health insurance. Housing characteristics related to pollutant exposure and bedroom air pollutant concentrations did not differ significantly between asthmatic and control subjects [median: PM2.5, 28.7 vs. 28.5 μg/m3; PM10, 43.6 vs. 41.4 μg/m3; NO2, 21.6 vs. 20.9 ppb; O3, 1.4 vs. 1.8 ppb; all p > 0.05]. Settled dust allergen levels (cat, dust mite, cockroach, dog, and mouse) were also similar in bedrooms of asthmatic and control children. Conclusions Exposures to common home indoor pollutants and allergens are similar for inner-city preschool children with and without asthma. Although these exposures may exacerbate existing asthma, this study does not support a causative role of these factors for risk of developing childhood asthma.