W. James Gauderman

Asthma in exercising children exposed to ozone: a cohort study

BACKGROUND Little is known about the effect of exposure to air pollution during exercise or time spent outdoors on the development of asthma. We investigated the relation between newly-diagnosed asthma and team sports in a cohort of children exposed to different concentrations and mixtures of air pollutants. METHODS 3535 children with no history of asthma were recruited from schools in 12 communities in southern California and were followed up for up to 5 years. 265 children reported a new diagnosis of asthma during follow-up. We assessed risk of asthma in children playing team sports at study entry in six communities with high daytime ozone concentrations, six with lower concentrations, and in communities with high or low concentrations of nitrogen dioxide, particulate matter, and inorganic-acid vapour. FINDINGS In communities with high ozone concentrations, the relative risk of developing asthma in children playing three or more sports was 3.3 (95% CI 1.9-5.8), compared with children playing no sports. Sports had no effect in areas of low ozone concentration (0.8, 0.4-1.6). Time spent outside was associated with a higher incidence of asthma in areas of high ozone (1.4, 1.0-2.1), but not in areas of low ozone. Exposure to pollutants other than ozone did not alter the effect of team sports. INTERPRETATION Incidence of new diagnoses of asthma is associated with heavy exercise in communities with high concentrations of ozone, thus, air pollution and outdoor exercise could contribute to the development of asthma in children.

Effect of exposure to traffic on lung development from 10 to 18 years of age: a cohort study

BACKGROUND Whether local exposure to major roadways adversely affects lung-function growth during the period of rapid lung development that takes place between 10 and 18 years of age is unknown. This study investigated the association between residential exposure to traffic and 8-year lung-function growth. METHODS In this prospective study, 3677 children (mean age 10 years [SD 0.44]) participated from 12 southern California communities that represent a wide range in regional air quality. Children were followed up for 8 years, with yearly lung-function measurements recorded. For each child, we identified several indicators of residential exposure to traffic from large roads. Regression analysis was used to establish whether 8-year growth in lung function was associated with local traffic exposure, and whether local traffic effects were independent of regional air quality. FINDINGS Children who lived within 500 m of a freeway (motorway) had substantial deficits in 8-year growth of forced expiratory volume in 1 s (FEV(1), -81 mL, p=0.01 [95% CI -143 to -18]) and maximum midexpiratory flow rate (MMEF, -127 mL/s, p=0.03 [-243 to -11), compared with children who lived at least 1500 m from a freeway. Joint models showed that both local exposure to freeways and regional air pollution had detrimental, and independent, effects on lung-function growth. Pronounced deficits in attained lung function at age 18 years were recorded for those living within 500 m of a freeway, with mean percent-predicted 97.0% for FEV1 (p=0.013, relative to >1500 m [95% CI 94.6-99.4]) and 93.4% for MMEF (p=0.006 [95% CI 89.1-97.7]). INTERPRETATION Local exposure to traffic on a freeway has adverse effects on childrens lung development, which are independent of regional air quality, and which could result in important deficits in attained lung function in later life.

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.

Childhood Asthma and Exposure to Traffic and Nitrogen Dioxide

Background: Evidence for a causal relationship between traffic-related air pollution and asthma has not been consistent across studies, and comparisons among studies have been difficult because of the use of different indicators of exposure. Methods: We examined the association between traffic-related pollution and childhood asthma in 208 children from 10 southern California communities using multiple indicators of exposure. Study subjects were randomly selected from participants in the Childrens Health Study. Outdoor nitrogen dioxide (NO2) was measured in summer and winter outside the home of each child. We also determined residential distance to the nearest freeway, traffic volumes on roadways within 150 meters, and model-based estimates of pollution from nearby roadways. Results: Lifetime history of doctor-diagnosed asthma was associated with outdoor NO2; the odds ratio (OR) was 1.83 (95% confidence interval = 1.04–3.22) per increase of 1 interquartile range (IQR = 5.7 ppb) in exposure. We also observed increased asthma associated with closer residential distance to a freeway (1.89 per IQR; 1.19–3.02) and with model-based estimates of outdoor pollution from a freeway (2.22 per IQR; 1.36–3.63). These 2 indicators of freeway exposure and measured NO2 concentrations were also associated with wheezing and use of asthma medication. Asthma was not associated with traffic volumes on roadways within 150 meters of homes or with model-based estimates of pollution from nonfreeway roads. Conclusions: These results indicate that respiratory health in children is adversely affected by local exposures to outdoor NO2 or other freeway-related pollutants.

Exploiting Gene-Environment Interaction to Detect Genetic Associations

Complex disease by definition results from the interplay of genetic and environmental factors. However, it is currently unclear how gene-environment interaction can best be used to locate complex disease susceptibility loci, particularly in the context of studies where between 1,000 and 1,000,000 markers are scanned for association with disease. We present a joint test of marginal association and gene-environment interaction for case-control data. We compare the power and sample size requirements of this joint test to other analyses: the marginal test of genetic association, the standard test for gene-environment interaction based on logistic regression, and the case-only test for interaction that exploits gene-environment independence. Although for many penetrance models the joint test of genetic marginal effect and interaction is not the most powerful, it is nearly optimal across all penetrance models we considered. In particular, it generally has better power than the marginal test when the genetic effect is restricted to exposed subjects and much better power than the tests of gene-environment interaction when the genetic effect is not restricted to a particular exposure level. This makes the joint test an attractive tool for large-scale association scans where the true gene-environment interaction model is unknown.

Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene

Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 x 10(-07) for rs1588265 and 9.7 x 10(-07) for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 x 10(-04) for rs1588265 and 9.2 x 10(-04) for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications.

Traffic-Related Air Pollution and Asthma Onset in Children: A Prospective Cohort Study with Individual Exposure Measurement

Background The question of whether air pollution contributes to asthma onset remains unresolved. Objectives In this study, we assessed the association between asthma onset in children and traffic-related air pollution. Methods We selected a sample of 217 children from participants in the Southern California Children’s Health Study, a prospective cohort designed to investigate associations between air pollution and respiratory health in children 10–18 years of age. Individual covariates and new asthma incidence (30 cases) were reported annually through questionnaires during 8 years of follow-up. Children had nitrogen dioxide monitors placed outside their home for 2 weeks in the summer and 2 weeks in the fall–winter season as a marker of traffic-related air pollution. We used multilevel Cox models to test the associations between asthma and air pollution. Results In models controlling for confounders, incident asthma was positively associated with traffic pollution, with a hazard ratio (HR) of 1.29 [95% confidence interval (CI), 1.07–1.56] across the average within-community interquartile range of 6.2 ppb in annual residential NO2. Using the total interquartile range for all measurements of 28.9 ppb increased the HR to 3.25 (95% CI, 1.35–7.85). Conclusions In this cohort, markers of traffic-related air pollution were associated with the onset of asthma. The risks observed suggest that air pollution exposure contributes to new-onset asthma.

Gene-Environment Interaction in Genome-Wide Association Studies

It is a commonly held belief that most complex diseases (e.g., diabetes, asthma, cancer) are affected in part by interactions between genes and environmental factors. However, investigators conducting genome-wide association studies typically test for only the marginal effects of each genetic marker on disease. In this paper, the authors propose an efficient and easily implemented 2-step analysis of genome-wide association study data aimed at identifying genes involved in a gene-environment interaction. The procedure complements screening for marginal genetic effects and thus has the potential to uncover new genetic signals that have not been identified previously.

Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins

Objective: To address the role of childhood sun exposure on the risk of multiple sclerosis (MS) after controlling for genetic susceptibility, we investigated the association between sun exposure and MS comparing disease-discordant monozygotic (MZ) twins. Method: Twins with MS were sought by yearly newspaper advertisements throughout North America from 1980 to 1992. Diagnosis was verified by updated medical documentation through 2005. This analysis was restricted to 79 disease- and exposure-discordant monozygotic twin pairs who had ranked themselves before 1993 in relation to each of nine childhood sun exposure activities. A sun exposure index (SI) was defined as the sum of those exposures for which one twin ranked higher than his or her co-twin. The SI difference within each twin pair was calculated by subtracting the SI value of the affected twin from the SI value of the unaffected twin (range −9 to +9). The results were then analyzed using conditional logistic models. Result: Each of the nine sun exposure–related activities during childhood seemed to convey a strong protection against MS within MZ twin pairs. Depending on the activity, the odds ratio (OR) ranged from 0.25 to 0.57. For example, the risk of subsequent MS was substantially lower (OR 0.40, 95% CI 0.19 to 0.83) for the twin who spent more time suntanning in comparison with the co-twin. For each unit increase in SI, the relative risk of MS decreased by 25%. Conclusion: Early sun avoidance seems to precede the diagnosis of multiple sclerosis (MS). This protective effect is independent of genetic susceptibility to MS.

The effects of ambient air pollution on school absenteeism due to respiratory illnesses

We investigated the relations between ozone (O3), nitrogen dioxide (NO2), and respirable particles less than 10 &mgr;m in diameter (PM10) and school absenteeism in a cohort of 4th-grade school children who resided in 12 southern California communities. An active surveillance system ascertained the numbers and types of absences during the first 6 months of 1996. Pollutants were measured hourly at central-site monitors in each of the 12 communities. To examine acute effects of air pollution on absence rates, we fitted a two-stage time-series model to the absence count data that included distributed lag effects of exposure adjusted for long-term pollutant levels. Short-term change in O3, but not NO2 or PM10, was associated with a substantial increase in school absences from both upper and lower respiratory illness. An increase of 20 ppb of O3 was associated with an increase of 62.9% [95% confidence interval (95% CI) = 18.4–124.1%] for illness-related absence rates, 82.9% (95% CI = 3.9–222.0%) for respiratory illnesses, 45.1% (95% CI = 21.3–73.7%) for upper respiratory illnesses, and 173.9% (95% CI = 91.3–292.3%) for lower respiratory illnesses with wet cough. The short-term effects of a 20-ppb change of O3 on illness-related absenteeism were larger in communities with lower long-term average PM10 [223.5% (95% CI = 90.4–449.7)] compared with communities with high average levels [38.1% (95% CI = 8.5–75.8)]. Increased school absenteeism from O3 exposure in children is an important adverse effect of ambient air pollution worthy of public policy consideration.