A Unified Model for the Analysis of Gene-Environment Interaction.

Gene-environment (G × E) interaction is important for many complex traits. In a case-control study of a disease trait, logistic regression is the standard approach used to model disease as a function of a gene (G), an environmental factor (E), G × E interaction, and adjustment covariates. We propose an alternative model with G as the outcome and show how it provides a unified framework for obtaining results from all of the common G × E tests. These include the 1-degree-of-freedom (df) test of G × E interaction, the 2-df joint test of G and G × E, the case-only and empirical Bayes tests, and several 2-step tests. In the context of this unified model, we propose a novel 3-df test and demonstrate that it provides robust power across a wide range of underlying G × E interaction models. We demonstrate the 3-df test in a genome-wide scan of G × sex interaction for childhood asthma using data from the Children's Health Study (Southern California, 1993-2001). This scan identified a strong G × sex interaction at the phosphodiesterase gene 4D locus (PDE4D), a known asthma-related locus, with a strong effect in males (per-allele odds ratio = 1.70; P = 3.8 × 10-8) and virtually no effect in females. We describe a software program, G×EScan (University of Southern California, Los Angeles, California), which can be used to fit standard and unified models for genome-wide G × E studies.

Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up.

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ß-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. CONCLUSIONS: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Reporting Quality of Randomized Controlled Trials of Periodontal Diseases in Journal Abstracts-A Cross-sectional Survey and Bibliometric Analysis.

OBJECTIVE: Randomized controlled trials (RCTs) by proper design, conduct, analysis, and reporting provide reliable information in clinical care. Reporting of RCT abstracts is of equal importance as there is evidence that many clinicians will change their clinical decisions based on RCT abstracts. The reporting quality of RCT abstracts has been suboptimal. It is not clear whether the reporting quality is related to the journal metrics. The main objective of this study is to conduct a cross-sectional survey to evaluate the reporting quality of RCTs of periodontal diseases in journal abstracts and to perform a bibliometric analysis. The null hypothesis was that there is no association between the journal metrics (5-year impact factor, Eigenfactor score, and Article Influence Score), abstract metrics (word count, and number of authors), journal endorsement of Consolidated Standards of Reporting Trials (CONSORT), and the overall quality of reporting of CONSORT RCT abstract-modified checklist questions. MATERIALS: CONSORT RCT abstract extension checklist with explanation and elaboration was used and modified to assess the quality of reporting of RCT abstracts of periodontal diseases in the journal abstracts in the year 2012. Bibliometric analysis of journal metrics (5-year impact factor, Eigenfactor score, and Article Influence Score) and abstract metrics (number of authors and abstract word count), the geographic distribution, and the CONSORT-endorsing journal abstracts was compared with the reporting quality of RCT abstracts in periodontal diseases. Calibration and intrarater agreement were done before the data collection and analysis. A second reviewer was consulted for independent evaluation and clarification as needed. For descriptive analysis, the values of continuous variables were expressed as median and interquartile ranges (IQRs) and as proportion percent for binary categorical variables. For association analysis between the binary (yes/no) response variable and the continuous variable, the Mann-Whitney test (for independent samples) was used. For examining the association between 2 categorical variables, Fisher's exact test was used. The chi-square test was performed to examine the association between 2 sets of binary response variables (yes/no). A P value of < .05 was considered statistically significant. All analyses were conducted using SAS, version 9.4. RESULTS: A total of 198 RCT abstracts of periodontal diseases in the year 2012 from 57 journals were included in the study. Fifteen journals, listed as endorsers of CONSORT, contributed 108 RCT abstracts. Four journals (Journal of Periodontology, Journal of Clinical Periodontology, Clinical Oral Implants Research, and European Journal of Oral Implantology) contributed 84 of 198 RCT abstracts in 2012. European countries contributed the majority (n = 81, 40.91%) of RCT abstracts. Among 31 countries in this study, United States contributed the most RCTs (n = 28, 14.14%) followed by India (24, 12.12%), Italy (n = 22, 11.11%), and Brazil (n = 20, 10.1%). The frequency of journal metrics were 5-year impact factor (median 2.316; IQR: 1.439-2.970); Eigenfactor score (0.00474; 0.00202-0.01395); and Article Influence Score (0.553; 0.382-0.755). The number of authors in 198 RCT abstracts ranged between 2 and 20 (median n = 5, IQR: 4-6), whereas the word count ranged between 48 and 569 (median 235, IQR: 205-269). All RCT abstracts reported the experimental interventions (checklist question #5, frequency 100%). Some items were almost always reported-participant eligibility criteria (#3, 99%); comparison interventions (#6, 99.5%); specific objective or hypothesis (#7, 99.5%); primary outcome (#8, 99.5%); and reporting trial results as a summary (#16, 98.5%). All RCT abstracts never reported how the allocations were concealed (#11, 0) and the source of funding for the trials (#23, 0). Some items were almost always never reported-the number of participants included in the analysis for each intervention (#15, 2%); trial registration number (#21, 2.5%); name of trial register (#22, 2.5%); and how the randomization or sequence generation was done (#22). Dismal reporting was noted in many checklist questions including the identification of the study as randomized in the title #1, 51%; design of the trial #2, 32.8%; trial setting #4, 3.5%; randomization #10, 3.5%; blinding #12, 21.7%; details about blinding #13, 8.1%; number of participants randomized to each intervention #14, 26.3%; effect size #17, 13.6%; precision of the estimate of the effect #18, 6.1%; and adverse effects #19, 14.1%. Strikingly, there was a very high reporting of statistical significance #25, 92.4%. European countries, in particular, reported relatively better than other countries in essential questions such as #17 effect size reporting, and #18 precision (uncertainty), which have been largely unreported by rest of the countries. Finally, despite the majority of RCTs published in 2012 were by CONSORT-endorsing journals, there was no difference in the quality of reporting in majority of checklist items when compared with journals not listed as CONSORT endorsers. With few exceptions, there was no statistically significant association between the majority of the CONSORT RCT abstract checklist questions and the journal metrics and abstract metrics analyzed in this study. Unexpectedly, lower ranking journals in journal metrics reported certain essential checklist questions relatively better. CONCLUSION: The reporting quality of RCT of periodontal diseases in the journal abstracts published in 2012 needs substantial improvement. These items have been laid out in this study to help all stakeholders-authors, clinicians, researchers, peer reviewers, journal editors, and publishers to take note and help with the improvement of the same. Despite few significant associations in the bibliometric factors analyzed with better reporting, the results overall led to the failure to reject the null hypothesis that there is no association between the journal metrics, word count, and number of authors and the quality of reporting of CONSORT RCT abstract-modified checklist questions.

Mental Illness Is Not Associated with Adherence to Colorectal Cancer Screening: Results from the California Health Interview Survey.

BACKGROUND: Colorectal cancer is the second leading cause of cancer-specific death in the USA. Evidence suggests people with mental illness are less likely to receive preventive health services, including cancer screening. We hypothesized that mental illness is a risk factor for non-adherence to colorectal cancer-screening guidelines. METHODS: We analyzed results of the 2007 California Health Interview Survey to test whether mental illness is a risk factor for non-adherence to colorectal cancer-screening recommendations among individuals age 50 or older (N = 15,535). This cross-sectional dataset is representative of California. Screening was defined as either fecal occult blood testing during the preceding year, sigmoidoscopy, or colonoscopy during the preceding 5 years. Mental illness was identified using the Kessler K6 screening tool. Associations were evaluated using weighted multivariate logistic regressions. RESULTS: Mental illness was not associated with colorectal cancer-screening adherence (OR 0.89; 95% CI 0.63-1.25). Risk factors for non-adherence included being female (OR 1.25; 95% CI 1.09-1.44), delaying accessing health care during the previous year (OR 1.89; 95% CI 1.56-2.29). CONCLUSION: Unlike previous studies, this study did not find a relationship between mental illness and colorectal cancer-screening adherence. This could be due to differences in study populations. State-specific healthcare policies involving care coordination for individuals with mental illness could also influence colorectal cancer-screening adherence in California.

Genome-wide interaction studies reveal sex-specific asthma risk alleles.

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.

Genetic ancestry influences asthma susceptibility and lung function among Latinos.

BACKGROUND: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest. OBJECTIVE: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children. METHODS: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry. RESULTS: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively). CONCLUSION: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.

The effect of protease inhibitors on the cervical mucus of HIV-positive women taking norethindrone contraception.

OBJECTIVE: To compare cervical mucus score (CMS) with and without protease inhibitors (PI) before and after taking norethindrone (NET). STUDY DESIGN: This two-arm, researcher blinded, non-randomised, prospective study was conducted to evaluate cervical mucus quality in HIV-positive women taking progestin only pills. The study group was taking a PI, and compared to women taking ARV regimens that have demonstrated no significant interaction with NET in prior pharmacokinetic trials with combined oral contraceptives. The women had a cervical mucus score prior to NET administration. Mucus Scoring was repeated after 21 days of steady state exposure to oral NET 0.35 milligrams. Cervical mucus quality was quantified according to the World Health Organisation criteria, which include: volume, consistency, cellularity, spinnbarkeit, and ferning. RESULTS: Sixteen women took PI and 17 were controls. Baseline CMS were similar (p ≥ 0.1). After 21 days CMS were similar among the two groups (p = 1). CONCLUSIONS: HIV-positive women taking PI demonstrated thickened cervical mucus with oral norethindrone 0.35 mg and are similar to HIV-positive women taking no PI therapy. This may suggest no difference in contraceptive efficacy of progestin only pills in HIV-positive women taking PI.

Associations of children's lung function with ambient air pollution: joint effects of regional and near-roadway pollutants.

BACKGROUND: Previous studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures. OBJECTIVES: To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children's Health Study. METHODS: Lung function was measured on 1811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO) and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter <10 µm (PM10) and 2.5 µm (PM2.5) was measured continuously at community monitors. RESULTS: An increase in near-roadway NOx of 17.9 ppb (2 SD) was associated with deficits of 1.6% in forced vital capacity (FVC) (p=0.005) and 1.1% in forced expiratory volume in 1 s (FEV1) (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2-3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2 across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. The effects of NRAP were not modified by regional pollutant concentrations. CONCLUSIONS: The results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.

Use of regadenoson for measurement of fractional flow reserve.

OBJECTIVE: To compare the use of regadenoson to adenosine for measurement of fractional flow reserve (FFR). BACKGROUND: FFR is an accepted method to assess the functional significance of intermediate coronary artery stenoses and uses adenosine to induce maximal hyperemia. The use of the selective A2a receptor agonist regadenoson for FFR is not established. METHODS: Fifty-seven patients undergoing clinically indicated FFR assessment of intermediate coronary stenoses were included. For the initial assessment of FFR, hyperemia was achieved by a standard intravenous adenosine infusion (140 mcg/kg/min). After a washout period of 10 min, FFR was reassessed using regadenoson as a single 0.4 mg intravenous bolus. FFR measurements were recorded at baseline and following maximal hyperemia with both agents. RESULTS: Mean age was 57 ± 8 years and 47 were male. Sixty coronary lesions were evaluated and were located in the left anterior descending in 34, the left circumflex in 9, right coronary in 15, and left main coronary artery in 2. Mean ( ± SD) FFR following adenosine and regadenoson was 0.79 ( ± 0.09) and 0.79 (±0.09), respectively, P = NS. Time to FFR nadir was shorter with regadenoson compared to adenosine, 36.6 ± 24 versus 66 ± 0.19 sec, P < 0.0001, respectively. No patients experienced any significant side effects related to regadenoson. CONCLUSIONS: Regadenoson is a viable alternative to intravenous adenosine for achieving maximal hyperemia during FFR assessment. Compared to adenosine, regadenoson has a similar hemodynamic response, achieves more rapid hyperemia, is easier to use, and has an excellent side-effect profile.

Further replication studies of the EVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans.

BACKGROUND: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. OBJECTIVES: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. METHODS: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. RESULTS: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. CONCLUSIONS: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

Genetic variation in the glutathione synthesis pathway, air pollution, and children's lung function growth.

RATIONALE: Glutathione plays an important role in antioxidant and inflammatory processes in the lung. Alterations in glutathione metabolism are a central feature of several chronic lung diseases. OBJECTIVES: To determine whether sequence variation in genes in the glutathione synthesis pathway alters susceptibility to air pollution effects on lung function. METHODS: In this prospective study, 14,821 lung function measurements were taken on 2,106 children from 12 Southern California cities. Tagging single-nucleotide polymorphisms in glutathione metabolism pathway genes GSS, GSR, GCLM, and GCLC were genotyped by GoldenGate assay (Illumina, San Diego, CA). Mixed regression models were used to determine whether particular haplotypes were associated with FEV(1), maximal mid-expiratory flow rate, and FVC and whether any of the genetic associations varied with levels of exposure to air pollutants. MEASUREMENTS AND MAIN RESULTS: We found that variation in the GSS locus was associated with differences in susceptibility of children for lung function growth deficits associated with NO(2), PM(10), PM(2.5), elemental carbon, organic carbon, and O(3). The negative effects of air pollutants were largely observed within participants who had a particular GSS haplotype. The effects ranged from -124.2 to -149.1 for FEV(1), from -92.9 to -126.7 for FVC, and from -193.9 to -277.9 for maximal mid-expiratory flow rate for all pollutants except O(3), which showed a larger decrease in lung function in children without this haplotype. CONCLUSIONS: Variation in GSS was associated with differences in susceptibility to adverse effects of pollutants on lung function growth.

Variation in the GST mu locus and tobacco smoke exposure as determinants of childhood lung function.

RATIONALE: The glutathione S-transferases (GSTs) are important detoxification enzymes. OBJECTIVES: To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure. METHODS: In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV1, maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated. MEASUREMENTS AND MAIN RESULTS: Variation in the GST mu family locus was associated with lower FEV1 (P = 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV1 and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (-164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV1 (-51.3 ml), MMEF (-69.1 ml/s), and FVC (-44.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV(1) among children whose mothers smoked during pregnancy. CONCLUSIONS: Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.

Oral Antibiotics for Treating Children With Community-Acquired Pneumonia Complicated by Empyema.

No consensus exists on management of children with community-acquired pneumonia complicated by empyema (CAP-Em). We evaluated outpatient oral (O-Abx) compared with parenteral antibiotics (OPAT) in children with CAP-Em. We also evaluated inflammatory markers to guide length of treatment. We conducted a retrospective cohort study of patients discharged (2006-2016) with CAP-Em. Primary outcome measured was treatment success (no change in antibiotics or readmission to hospital for treatment of CAP-Em). White blood cell (WBC) count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) serial measurements were identified. Success was achieved in 133/144 (92.4%) O-Abx and 7/12 (58%) OPAT patients (P = .0031). WBC and CRP decreased early; and ESR increased initially (admit and switch to O-Abx) and decreased by end of treatment. O-Abx is the modality of choice for treatment of CAP-Em after hospital discharge. WBC and CRP are useful to monitor success of O-Abx switch; and ESR provides guidance for length of treatment.

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 children's lung development, which are independent of regional air quality, and which could result in important deficits in attained lung function in later life.

The effect of air pollution on lung development from 10 to 18 years of age.

BACKGROUND: Whether exposure to air pollution adversely affects the growth of lung function during the period of rapid lung development that occurs between the ages of 10 and 18 years is unknown. METHODS: In this prospective study, we recruited 1759 children (average age, 10 years) from schools in 12 southern California communities and measured lung function annually for eight years. The rate of attrition was approximately 10 percent per year. The communities represented a wide range of ambient exposures to ozone, acid vapor, nitrogen dioxide, and particulate matter. Linear regression was used to examine the relationship of air pollution to the forced expiratory volume in one second (FEV(1)) and other spirometric measures. RESULTS: Over the eight-year period, deficits in the growth of FEV(1) were associated with exposure to nitrogen dioxide (P=0.005), acid vapor (P=0.004), particulate matter with an aerodynamic diameter of less than 2.5 microm (PM(2.5)) (P=0.04), and elemental carbon (P=0.007), even after adjustment for several potential confounders and effect modifiers. Associations were also observed for other spirometric measures. Exposure to pollutants was associated with clinically and statistically significant deficits in the FEV(1) attained at the age of 18 years. For example, the estimated proportion of 18-year-old subjects with a low FEV(1) (defined as a ratio of observed to expected FEV(1) of less than 80 percent) was 4.9 times as great at the highest level of exposure to PM(2.5) as at the lowest level of exposure (7.9 percent vs. 1.6 percent, P=0.002). CONCLUSIONS: The results of this study indicate that current levels of air pollution have chronic, adverse effects on lung development in children from the age of 10 to 18 years, leading to clinically significant deficits in attained FEV(1) as children reach adulthood.

Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.

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.

Predictors of intra-community variation in air quality.

Air quality has emerged as a key determinant of important health outcomes in children and adults. This study aims to identify factors that influence local, within-community air quality, and to build a model for traffic-related air pollution (TRP).We utilized concentrations of NO(2), NO, and total oxides of nitrogen (NO(x)), which were measured at 942 locations in 12 southern California communities. For each location, population density, elevation, land-use, and several indicators of traffic were calculated. A spatial random effects model was used to study the relationship of these predictors to each TRP.Variation in TRP was strongly correlated with traffic on nearby freeways and other major roads, and also with population density and elevation. After accounting for traffic, categories of land-use were not associated with the pollutants. Traffic had a larger relative impact in small urban (low regional pollution) communities than in large urban (high regional pollution) communities. For example, our best fitting model explained 70% of the variation in NO(x) in large urban areas and 76% in small urban areas. Compared with living at least 1,500 m from a freeway, living within 250 m of a freeway was associated with up to a 41% increase in TRP in a large urban area, and up to a 75% increase in small urban areas.Thus, traffic strongly affects local air quality in large and small urban areas, which has implications for exposure assessment and estimation of health risks.

Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth.

The effects of glutathione-S-transferase (GST) M1, GSTT1, and GSTP1 genotypes on lung function growth were investigated in 1,940 children enrolled in the Children's Health Study as fourth graders (aged 8-11 years) in two cohorts during 1993 and 1996 and were followed annually over a 4-year period. Genotypes for GSTM1 and GSTT1 and GSTP1 codon 105 variants (ile105 and val105) were determined using DNA from buccal cell specimens. We used two-level regression models to estimate the effects of GSTM1, GSTT1, and GSTP1 genotypes on the adjusted annual average lung function growth. GSTM1 null was associated with deficits in annual growth rates for FVC (-0.21%; 95% confidence interval [CI], -0.40, -0.03) and FEV(1) (-0.27%; 95% CI, -0.50, -0.04). Children who were homozygous for the GSTP1 val105 allele had slower lung function growth (FVC -0.35%; 95% CI, -0.62, -0.07; and FEV(1) -0.34%; 95% CI, -0.68, 0.00) than children with one or more ile105 alleles. Children with asthma who were homozygous for the GSTP1 val105 allele had substantially larger deficits in FVC, FEV(1), and maximal mid-expiratory flow than children without asthma. The deficits in FVC and FEV(1) growth associated with both GSTM1 null and the GSTP1 val105 allele were largest and were statistically significant in non-Hispanic white children. We conclude that GSTM1 and GSTP1 genotypes are associated with lung function growth in school children.

Association between air pollution and lung function growth in southern California children: results from a second cohort.

A cohort of 1,678 Southern California children, enrolled as fourth graders in 1996, was followed for 4 years to determine whether the growth in lung function of the children was associated with their exposure to ambient air pollutants. These subjects comprised the second cohort of fourth grade children participating in the Children's Health Study. Significant deficits in lung function growth rate were associated with exposure to acid vapor, NO(2), particles with aerodynamic diameter less than 2.5 microm (PM(2.5)), and elemental carbon. For example, the average annual growth rates of maximal midexpiratory flow and forced expiratory volume in 1 second were reduced by approximately 11% (p = 0.005) and 5% (p = 0.03), respectively, across the observed range of acid exposure. Exposure to acid vapor was also associated with reductions in the ratio of maximal midexpiratory flow to forced vital capacity (p = 0.02), whereas exposure to ozone was correlated with reduced growth in peak flow rate (p = 0.006). Larger deficits in lung function growth rate were observed in children who reported spending more time outdoors. These findings provide important replication of our previous findings of an effect of air pollution on lung function growth that were based on the first fourth-grade cohort from the Children's Health Study (Am J Respir Crit Care Med 2000;162:1383-1390).