Nadia N. Hansel

Detectable clonal mosaicism from birth to old age and its relationship to cancer

We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5–10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

The clinical features of the overlap between COPD and asthma

BackgroundThe coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma.MethodsWe performed a cross-sectional study comparing subjects with COPD and asthma to subjects with COPD alone in the COPDGene Study.Results119 (13%) of 915 subjects with COPD reported a history of physician-diagnosed asthma. These subjects were younger (61.3 vs 64.7 years old, p = 0.0001) with lower lifetime smoking intensity (43.7 vs 55.1 pack years, p = 0.0001). More African-Americans reported a history of asthma (33.6% vs 15.6%, p < 0.0001). Subjects with COPD and asthma demonstrated worse disease-related quality of life, were more likely to have had a severe COPD exacerbation in the past year, and were more likely to experience frequent exacerbations (OR 3.55 [2.19, 5.75], p < 0.0001). Subjects with COPD and asthma demonstrated greater gas-trapping on chest CT. There were no differences in spirometry or CT measurements of emphysema or airway wall thickness.ConclusionSubjects with COPD and asthma represent a relevant clinical population, with worse health-related quality of life. They experience more frequent and severe respiratory exacerbations despite younger age and reduced lifetime smoking history.Trial registrationClinicalTrials.gov: NCT00608764

The minimal important difference of exercise tests in severe COPD

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4–6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St Georges Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohens effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1–20.1 m), 24.2 m (95% CI 23.4–25.4 m), 24.6 m (95% CI 23.4–25.7 m) and 26.4 m (95% CI 25.4–27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0–2.4 W), 3.2 W (95% CI 3.0–3.4 W), 3.2 W (95% CI 3.0–3.4 W) and 3.3 W (95% CI 3.0–3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26±2 m for 6MWD and 4±1 W for MCEC for patients with severe COPD.

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.

Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function

BACKGROUND Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms. METHODS We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest. RESULTS Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids. CONCLUSIONS Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).

The Gene, Environment Association Studies Consortium (GENEVA): Maximizing the Knowledge Obtained from GWAS by Collaboration Across Studies of Multiple Conditions

Genome‐wide association studies (GWAS) have emerged as powerful means for identifying genetic loci related to complex diseases. However, the role of environment and its potential to interact with key loci has not been adequately addressed in most GWAS. Networks of collaborative studies involving different study populations and multiple phenotypes provide a powerful approach for addressing the challenges in analysis and interpretation shared across studies. The Gene, Environment Association Studies (GENEVA) consortium was initiated to: identify genetic variants related to complex diseases; identify variations in gene‐trait associations related to environmental exposures; and ensure rapid sharing of data through the database of Genotypes and Phenotypes. GENEVA consists of several academic institutions, including a coordinating center, two genotyping centers and 14 independently designed studies of various phenotypes, as well as several Institutes and Centers of the National Institutes of Health led by the National Human Genome Research Institute. Minimum detectable effect sizes include relative risks ranging from 1.24 to 1.57 and proportions of variance explained ranging from 0.0097 to 0.02. Given the large number of research participants (N>80,000), an important feature of GENEVA is harmonization of common variables, which allow analyses of additional traits. Environmental exposure information available from most studies also enables testing of gene‐environment interactions. Facilitated by its sizeable infrastructure for promoting collaboration, GENEVA has established a unified framework for genotyping, data quality control, analysis and interpretation. By maximizing knowledge obtained through collaborative GWAS incorporating environmental exposure information, GENEVA aims to enhance our understanding of disease etiology, potentially identifying opportunities for intervention. Genet. Epidemiol. 34: 364–372, 2010.

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.