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1.  Automobile Traffic around the Home and Attained Body Mass Index: A Longitudinal Cohort Study of Children aged 10–18 Years 
Preventive medicine  2009;50(0 1):S50-S58.
Objectives
The objective of this study is to examine the relationship between measured traffic density near the homes of children and attained body mass index (BMI) over an eight-year follow up.
Methods
Children aged 9–10 years were enrolled across multiple communities in Southern California in 1993 and 1996 (n = 3318). Children were followed until age 18 or high school graduation to collect longitudinal information, including annual height and weight measurements. Multilevel growth curve models were used to assess the association between BMI levels at age 18 and traffic around the home.
Results
For traffic within 150 m around the child’s home, there were significant positive associations with attained BMI for both sexes at age 18. With the 300 m traffic buffer, associations for both male and female growth in BMI were positive, but significantly elevated only in females. These associations persisted even after controlling for numerous potential confounding variables.
Conclusions
This analysis yields the first evidence of significant effects from traffic density on BMI levels at age 18 in a large cohort of children. Traffic is a pervasive exposure in most cities, and our results identify traffic as a major risk factor for the development of obesity in children.
doi:10.1016/j.ypmed.2009.09.026
PMCID: PMC4334364  PMID: 19850068
Traffic; built environment; children; overweight and obesity; geographic information systems; multilevel models; cohort study
2.  Longitudinal Effects of Air Pollution on Exhaled Nitric Oxide: The Children’s Health Study 
OBJECTIVES
To assess the effects of long-term variations in ambient air pollutants on longitudinal changes in exhaled nitric oxide (FeNO), a potentially useful biomarker of eosinophilic airway inflammation, based on data from the southern California Children’s Health Study.
METHODS
Based on a cohort of 1,211 schoolchildren from 8 Southern California communities with FeNO measurements in 2006/07 and 2007/08, regression models adjusted for short-term effects of air pollution were fitted to assess the association between changes in annual long-term exposures and changes in FeNO.
RESULTS
Increases in annual average concentrations of 24-hr average NO2 and PM2.5 (scaled to the interquartile range (IQR) of 1.8 ppb and 2.4 μg/m3, respectively) were associated with a 2.29 ppb (CI=[0.36,4.21]; p =0.02) and a 4.94 ppb (CI=[1.44,8.47]; p = 0.005) increase in FeNO, respectively, after adjustments for short term effects of the respective pollutants. In contrast, changes in annual averages of PM10 and O3 were not significantly associated with changes in FeNO. These findings did not differ significantly by asthma status.
CONCLUSIONS
Changes in annual average exposure to current levels of ambient air pollutants are significantly associated with changes in FeNO levels in children, independent of short-term exposures and asthma status. Use of this biomarker in population-based epidemiologic research has great potential for assessing the impact of changing real world mixtures of ambient air pollutants on children’s respiratory health.
doi:10.1136/oemed-2013-101874
PMCID: PMC4310696  PMID: 24696513
Air pollution; chronic exposures; Children’s respiratory health; Environmental epidemiology; Exhaled nitric oxide; Airway inflammation
3.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
4.  HDL anti-oxidant function associates with LDL level in young adults 
Atherosclerosis  2013;232(1):165-170.
Objectives
The primary objective was to evaluate predictors of HDL anti-oxidant function in young adults.
Background
High-density lipoprotein (HDL) cholesterol is considered a protective factor for cardiovascular disease (CVD). However, increased levels are not always associated with decreased cardiovascular risk. A better understanding of the importance of HDL functionality and how it affects CVD risk is needed.
Methods
Fifty non-Hispanic white subjects from the Testing Responses on Youth (TROY) study were randomly selected to investigate whether differences in HDL anti-oxidant function are associated with traditional cardiovascular risk factors, including carotid intima media thickness (CIMT), arterial stiffness and other inflammatory/metabolic parameters. HDL anti-oxidant capacity was evaluated by assessing its ability to inhibit low-density lipoprotein (LDL) cholesterol oxidation by air using a DCF-based fluorescent assay and expressed as a HDL oxidant index (HOI). The associations between HOI and other variables were assessed using both linear and logistic regression.
Results
Eleven subjects (25%) had an HOI ≥ 1, indicating a pro-oxidant HDL. Age, LDL, high sensitivity C-reactive protein (hsCRP), and paraoxonase activity (PON1), but not HDL, were all associated with HOI level in univariate linear regression models. In multivariate models that mutually adjusted for these variables, LDL remained the strongest predictor of HOI (0.13 increase in HOI per 1 SD increase in LDL, 95% CI 0.04, 0.22).
Atherogenic index of plasma, pulse pressure, homocysteine, glucose, insulin, CIMT and measurements of arterial stiffness were not associated with HOI in this population.
Conclusions
These results suggest LDL, hsCRP and DBP might predict HDL anti-oxidant function at an early age.
doi:10.1016/j.atherosclerosis.2013.10.034
PMCID: PMC4039385  PMID: 24401232
high density lipoprotein; antioxidant; paraoxonase; atherosclerosis
5.  Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children’s Health Study 
Journal of Thoracic Disease  2015;7(1):46-58.
Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children’s Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children’s health while control measures are being implemented.
doi:10.3978/j.issn.2072-1439.2014.12.20
PMCID: PMC4311073
Air pollution; traffic pollution; asthma; genetic susceptibility; respiratory disease
6.  Native American Ancestry Affects the Risk for Gene Methylation in the Lungs of Hispanic Smokers from New Mexico 
Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer.
Objectives: This study compared the methylation prevalence in sputum of NHWs with Hispanics using the Lovelace Smokers cohort (n = 1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk.
Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific polymerase chain reaction. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between pack-years and risk for lung cancer was assessed in the New Mexico lung cancer study.
Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (odds ratio, 1.18; P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non–small cell lung cancer cases have significantly lower pack-years than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of pack-years (P = 0.058).
Conclusions: NAA may be an important risk modifier for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
doi:10.1164/rccm.201305-0925OC
PMCID: PMC3863742  PMID: 24032348
ethnicity; sputum; diet; risk; lung cancer
7.  MULTIPLE-FLOW EXHALED NITRIC OXIDE, ALLERGY, AND ASTHMA IN A POPULATION OF OLDER CHILDREN 
Pediatric pulmonology  2013;48(9):885-896.
SUMMARY
"Extended" (multiple-flow) measurements of exhaled nitric oxide (FeNO) potentially can distinguish proximal and distal airway inflammation, but have not been evaluated previously in large populations. We performed extended NO testing within a longitudinal study of a school-based population, to relate bronchial flux (J'awNO) and peripheral NO concentration (CalvNO) estimates with respiratory health status determined from questionnaires. We measured FeNO at 30, 50, 100, and 300 ml/sec in 1640 subjects aged 12–15 from 8 communities, then estimated J'awNO and CalvNO from linear and nonlinear regressions of NO output vs. flow. J'awNO, as well as FeNO at all flows, showed influences of asthma, allergy, Asian or African ancestry, age, and height (positive), and of weight (negative), generally corroborating past findings. By contrast, CalvNO results were inconsistent across different extended NO regression models, and appeared more sensitive to small measurement artifacts. Conclusions: Extended NO testing is feasible in field surveys of young populations. In interpreting results, size, age, and ethnicity require attention, as well as instrumental and environmental artifacts. J'awNO and conventional FeNO provide similar information, probably reflecting proximal-airway inflammation. CalvNO may give additional information relevant to peripheral-airway, alveolar, or systemic pathology. However, it needs additional research, including testing of populations with independently verifiable peripheral or systemic pathology, to optimize measurement technique and interpretation.
doi:10.1002/ppul.22708
PMCID: PMC3748140  PMID: 23687084
exhaled nitric oxide; airway inflammation; airways; asthma; allergy; epidemiology; public health; population survey
8.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
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.
doi:10.1186/1755-8794-7-48
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
9.  Joint Analysis for Integrating Two Related Studies of Different Data Types and Different Study Designs Using Hierarchical Modeling Approaches 
Human heredity  2013;74(2):83-96.
Background
A chronic disease such as asthma is the result of a complex sequence of biological interactions involving multiple genes and pathways in response to a multitude of environmental exposures. However, methods to model jointly all factors are still evolving. Some of the current challenges include how to integrate knowledge from different data types and different disciplines, as well as how to utilize relevant external information such as gene annotation to identify novel disease genes and gene-environment interactions.
Methods
Using a Bayesian hierarchical modeling framework, we developed two alternative methods for joint analysis of an epidemiologic study of a disease endpoint and an experimental study of intermediate phenotypes, while incorporating external information.
Results
Our simulation studies demonstrated superior performance of the proposed hierarchical models compared to separate analysis with the standard single-level regression modeling approach. The combined analyses of the Southern California Children's Health Study and challenge study data suggest that these joint analytical methods detected more significant genetic main and gene-environment interaction effects than the conventional analysis.
Conclusion
The proposed prior framework is very flexible and can be generalized for an integrative analysis of diverse sources of relevant biological data.
doi:10.1159/000345181
PMCID: PMC4106669  PMID: 23343600
Bayesian hierarchical modeling; Biological related studies; Data integration; Gene-environment interaction; Joint analysis; Markov-chain Monte Carlo (MCMC) methods; Prior knowledge
10.  Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation 
PLoS ONE  2014;9(6):e99716.
Background
Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail.
Objectives
To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children.
Methods
Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5–12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR.
Results
Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group.
Conclusions
These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.
doi:10.1371/journal.pone.0099716
PMCID: PMC4070909  PMID: 24964093
11.  Traffic-related air pollution and obesity formation in children: a longitudinal, multilevel analysis 
Environmental Health  2014;13:49.
Background
Biologically plausible mechanisms link traffic-related air pollution to metabolic disorders and potentially to obesity. Here we sought to determine whether traffic density and traffic-related air pollution were positively associated with growth in body mass index (BMI = kg/m2) in children aged 5–11 years.
Methods
Participants were drawn from a prospective cohort of children who lived in 13 communities across Southern California (N = 4550). Children were enrolled while attending kindergarten and first grade and followed for 4 years, with height and weight measured annually. Dispersion models were used to estimate exposure to traffic-related air pollution. Multilevel models were used to estimate and test traffic density and traffic pollution related to BMI growth. Data were collected between 2002–2010 and analyzed in 2011–12.
Results
Traffic pollution was positively associated with growth in BMI and was robust to adjustment for many confounders. The effect size in the adjusted model indicated about a 13.6% increase in annual BMI growth when comparing the lowest to the highest tenth percentile of air pollution exposure, which resulted in an increase of nearly 0.4 BMI units on attained BMI at age 10. Traffic density also had a positive association with BMI growth, but this effect was less robust in multivariate models.
Conclusions
Traffic pollution was positively associated with growth in BMI in children aged 5–11 years. Traffic pollution may be controlled via emission restrictions; changes in land use that promote jobs-housing balance and use of public transit and hence reduce vehicle miles traveled; promotion of zero emissions vehicles; transit and car-sharing programs; or by limiting high pollution traffic, such as diesel trucks, from residential areas or places where children play outdoors, such as schools and parks. These measures may have beneficial effects in terms of reduced obesity formation in children.
doi:10.1186/1476-069X-13-49
PMCID: PMC4106205  PMID: 24913018
Childhood obesity; Air pollution; Traffic; California
12.  Environmental pollution in Mongolia: Effects across the lifespan 
Environmental research  2013;124:65-66.
doi:10.1016/j.envres.2013.04.002
PMCID: PMC4043223  PMID: 23673312
13.  Birth Weight and Carotid Artery Intima-Media Thickness 
The Journal of pediatrics  2012;162(5):906-11.e1-2.
Objectives
To determine the association between birth weight and carotid artery intima-media thickness (CIMT), a measure of atherogenesis, in a population of 11-year-old children.
Study design
CIMT measured by high-resolution ultrasound, and birth registry data were available for 670 children of the Southern California Children’s Health Study. Multivariate regression analyses were performed to investigate the association between birth weight and CIMT, with adjustment for child’s health status and lifestyle, pregnancy information, and parental health.
Results
Mean CIMT was 0.57 mm (SD 0.04). We found a nonlinear association between birth weight and CIMT, with an increase in CIMT of 0.014 mm in the fifth (P value .01) compared with the third birth weight quintile. These associations were robust in subsample analyses in children considered normal-weight by gestational age or in term-born children. No significant association with CIMT was found for the lowest quintile.
Conclusions
Greater birth weight was significantly associated with increased CIMT at age 11 years. No evidence for an impact of lower birth weight was found. The predictive value of childhood CIMT on future cardiovascular outcomes is largely unknown, but strong associations between childhood cardiovascular disease risk factors and adult vascular disease suggest that increased CIMT in childhood may be clinically important.
doi:10.1016/j.jpeds.2012.10.060
PMCID: PMC4030536  PMID: 23260106
14.  Development of a regional-scale pollen emission and transport modeling framework for investigating the impact of climate change on allergic airway disease 
Biogeosciences (Online)  2013;10(3):3977-4023.
Exposure to bioaerosol allergens such as pollen can cause exacerbations of allergenic airway disease (AAD) in sensitive populations, and thus cause serious public health problems. Assessing these health impacts by linking the airborne pollen levels, concentrations of respirable allergenic material, and human allergenic response under current and future climate conditions is a key step toward developing preventive and adaptive actions. To that end, a regional-scale pollen emission and transport modeling framework was developed that treats allergenic pollens as non-reactive tracers within the WRF/CMAQ air-quality modeling system. The Simulator of the Timing and Magnitude of Pollen Season (STaMPS) model was used to generate a daily pollen pool that can then be emitted into the atmosphere by wind. The STaMPS is driven by species-specific meteorological (temperature and/or precipitation) threshold conditions and is designed to be flexible with respect to its representation of vegetation species and plant functional types (PFTs). The hourly pollen emission flux was parameterized by considering the pollen pool, friction velocity, and wind threshold values. The dry deposition velocity of each species of pollen was estimated based on pollen grain size and density. An evaluation of the pollen modeling framework was conducted for southern California for the period from March to June 2010. This period coincided with observations by the University of Southern California's Children's Health Study (CHS), which included O3, PM2.5, and pollen count, as well as measurements of exhaled nitric oxide in study participants. Two nesting domains with horizontal resolutions of 12 km and 4 km were constructed, and six representative allergenic pollen genera were included: birch tree, walnut tree, mulberry tree, olive tree, oak tree, and brome grasses. Under the current parameterization scheme, the modeling framework tends to underestimate walnut and peak oak pollen concentrations, and tends to overestimate grass pollen concentrations. The model shows reasonable agreement with observed birch, olive, and mulberry tree pollen concentrations. Sensitivity studies suggest that the estimation of the pollen pool is a major source of uncertainty for simulated pollen concentrations. Achieving agreement between emission modeling and observed pattern of pollen releases is the key for successful pollen concentration simulations.
doi:10.5194/bgd-10-3977-2013
PMCID: PMC4021721  PMID: 24839448
15.  Exhaled Nitric Oxide, Susceptibility and New-Onset Asthma in the Children’s Health Study 
The European respiratory journal  2010;37(3):523-531.
A substantial body of evidence suggests an etiologic role of inflammation and oxidative/nitrosative stress in asthma pathogenesis. Fractional concentration of nitric oxide in exhaled air (FeNO) may provide a non-invasive marker of oxidative/nitrosative stress and aspects of airway inflammation. We examined whether children with elevated FeNO are at increased risk for new-onset asthma.
We prospectively followed 2206 asthma-free children (age 7–10 years) who participated in the Children’s Health Study. We measured FeNO and followed these children for three years to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between FeNO and new-onset asthma.
We found that FeNO was associated with increased risk of new-onset asthma. Children with the highest quartile of FeNO had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio: 2.1; 95% confidence interval: 1.3–3.5). This effect did not vary by child’s history of respiratory allergic symptoms. However, the effect of elevated FeNO on new-onset asthma was most apparent among those without a parental history of asthma.
Our results indicate that children with elevated FeNO are at increased risk for new-onset asthma, especially if they have no parental history of asthma.
doi:10.1183/09031936.00021210
PMCID: PMC4020940  PMID: 20634264
Incident Asthma; Exhaled Nitric Oxide; Airway Inflammation
16.  Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau 
Carcinogenesis  2013;34(5):1044-1050.
Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
doi:10.1093/carcin/bgt024
PMCID: PMC3643420  PMID: 23354305
17.  A Meta-analysis of Genome-wide Association Studies for Serum Total IgE in Diverse Study Populations 
Background
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
Objective
To identify the genetic predictors of serum total IgE levels.
Methods
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
Results
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
Conclusion
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
doi:10.1016/j.jaci.2012.10.002
PMCID: PMC3596497  PMID: 23146381
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
18.  Breast cancer survivors who use estrogenic botanical supplements have lower serum estrogen levels than non users 
Objective
To measure the association between use of estrogenic botanical supplements and serum sex hormones in postmenopausal breast cancer survivors.
Methods
502 postmenopausal women were queried 2-3 years after breast cancer diagnosis about their use of botanical supplements, and supplements were categorized according to their estrogenic properties. Concurrently, a fasting blood sample was obtained for assay of estrone, estradiol, free estradiol, testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin. Adjusted means of the serum hormones were calculated by use of estrogenic supplements.
Results
Women reporting use of any estrogenic botanical supplement had significantly lower levels of estrone (20.8 v 23.6 pg/mL), estradiol (12.8 v 14.7 pg/mL), free estradiol (0.29 v 0.35 pg/mL), and DHEAS (47.7 v 56.2 ug/dL) compared to women reporting no use.
Conclusion
Data from this cross-sectional study suggest the use of estrogenic botanical supplements may be associated with sex hormone concentrations in breast cancer survivors. Considering the high use of these supplements among breast cancer patients, further research is needed to clarify the relative estrogenicity/antiestrogenicity of these compounds and their relation with prognosis.
doi:10.1007/s10549-008-0224-x
PMCID: PMC3935483  PMID: 18931907
19.  Confounding and Heterogeneity in Genetic Association Studies with Admixed Populations 
American Journal of Epidemiology  2013;177(4):351-360.
Association studies among admixed populations pose many challenges including confounding of genetic effects due to population substructure and heterogeneity due to different patterns of linkage disequilibrium (LD). We use simulations to investigate controlling for confounding by indicators of global ancestry and the impact of including a covariate for local ancestry. In addition, we investigate the use of an interaction term between a single-nucleotide polymorphism (SNP) and local ancestry to capture heterogeneity in SNP effects. Although adjustment for global ancestry can control for confounding, additional adjustment for local ancestry may increase power when the induced admixture LD is in the opposite direction as the LD in the ancestral population. However, if the induced LD is in the same direction, there is the potential for reduced power because of overadjustment. Furthermore, the inclusion of a SNP by local ancestry interaction term can increase power when there is substantial differential LD between ancestry populations. We examine these approaches in genome-wide data using the University of Southern California's Children's Health Study investigating asthma risk. The analysis highlights rs10519951 (P = 8.5 × 10−7), a SNP lacking any evidence of association from a conventional analysis (P = 0.5).
doi:10.1093/aje/kws234
PMCID: PMC3626055  PMID: 23334005
confounding; genetic association studies; genome-wide association studies; heterogeneity; linkage disequilibrium; population stratification
20.  Estimation of Parameters in the Two-Compartment Model for Exhaled Nitric Oxide 
PLoS ONE  2014;9(1):e85471.
The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that is being increasingly considered in clinical, occupational, and epidemiological applications ranging from asthma management to the detection of air pollution health effects. FeNO depends strongly on exhalation flow rate. This dependency has allowed for the development of mathematical models whose parameters quantify airway and alveolar compartment contributions to FeNO. Numerous methods have been proposed to estimate these parameters using FeNO measured at multiple flow rates. These methods—which allow for non-invasive assessment of localized airway inflammation—have the potential to provide important insights on inflammatory mechanisms. However, different estimation methods produce different results and a serious barrier to progress in this field is the lack of a single recommended method. With the goal of resolving this methodological problem, we have developed a unifying framework in which to present a comprehensive set of existing and novel statistical methods for estimating parameters in the simple two-compartment model. We compared statistical properties of the estimators in simulation studies and investigated model fit and parameter estimate sensitivity across methods using data from 1507 schoolchildren from the Southern California Children's Health Study, one of the largest multiple flow FeNO studies to date. We recommend a novel nonlinear least squares model with natural log transformation on both sides that produced estimators with good properties, satisfied model assumptions, and fit the Children's Health Study data well.
doi:10.1371/journal.pone.0085471
PMCID: PMC3894971  PMID: 24465571
21.  Dietary Fat, Tamoxifen Use and Circulating Sex Hormones in Postmenopausal Breast Cancer Survivors 
Nutrition and cancer  2010;62(2):10.1080/01635580903305359.
Evidence is inconsistent regarding whether dietary fat influences sex hormone concentrations. This issue is important for breast cancer survivors since clinical recommendations suggest maintaining low hormone levels primarily via pharmacologic agents. This study examines associations between dietary fat and circulating sex hormones among participants in the HEAL (Health, Eating, Activity and Lifestyle) Study, a cohort of breast cancer survivors (n=511). During a post-diagnosis interview, detailed data were collected on diet, physical activity, lifestyle habits, and medication use (including tamoxifen). Staff measured height and weight and collected fasting bloods. Multivariate linear regression modeled associations of dietary fat with serum sex hormones. Among women using tamoxifen, we observed modest inverse associations of dietary fat with estrone (p< 0.01), estradiol (p< 0.05), testosterone (p< 0.01), free testosterone (p< 0.01), and DHEA (p< 0.01) for higher vs. lower fat intake, but there was no evidence for a trend. Associations were consistent across measures (percent energy from fat, total, saturated and polyunsaturated fat) and modest effect modification was observed between fat intake and tamoxifen in relation to hormones. Among women not using tamoxifen, fat intake was not associated with hormone concentrations. Further work is needed to confirm the findings and to understand the clinical implications of these observations.
doi:10.1080/01635580903305359
PMCID: PMC3846524  PMID: 20099190
Diet; dietary fat; sex steroid hormones; estrogen; testosterone; postmenopausal breast cancer; tamoxifen
22.  Further Replication Studies of the EVE Consortium Meta-Analysis Identifies Two 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 SNPs for replication based on the p-values from the EVE Consortium meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine different studies, totaling to 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 OR = 1.18; 95% CI 1.10 – 1.25) and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not replicate any additional associations in the African American or Latino individuals.
Conclusions
This extended replication study identified two additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latino individuals highlights the difficulty in replicating associations in admixed populations.
doi:10.1016/j.jaci.2012.07.054
PMCID: PMC3666859  PMID: 23040885
Asthma; genetic risk factors; meta-analysis; KLK3
23.  Physical Activity, Body Mass Index and Mammographic Density in Postmenopausal Breast Cancer Survivors 
Purpose
To investigate the association between physical activity, body mass index (BMI) and mammographic density in an ethnically-diverse population-based sample of 522 postmenopausal women diagnosed with stage 0–IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study.
Methods
We collected information on BMI and physical activity during a clinic visit two to three years after diagnosis. Weight and height were measured in a standard manner. Using an interview-administered questionnaire, participants recalled the type, duration, and frequency of physical activities in the past year. We estimated dense area and percent density as a continuous measure using a computer-assisted software program from mammograms imaged approximately one to two years after diagnosis. Analysis of covariance methods were used to obtain mean density across World Health Organization BMI categories and physical activity tertiles adjusted for confounders.
Results
We observed a statistically significant decline in percent density (p for trend = .0001), and mammographic dense area (p for trend = 0.0052), with increasing level of BMI adjusted for potential covariates. We observed a statistically significant decline in mammographic dense area (p for trend = .036) with increasing level of sports/recreational physical activity in women with a BMI ≥ 30 kg/m2. Conversely, in women with a BMI < 25 kg/m2, we observed a nonstatistically significant increase in mammographic dense area and percent density with increasing level of sports/recreational physical activity.
Conclusions
Increasing physical activity among obese postmenopausal breast cancer survivors may be a reasonable intervention approach to reduce mammographic density.
doi:10.1200/JCO.2006.07.3965
PMCID: PMC3839099  PMID: 17261853
breast cancer; body fat; exercise; obesity; weight; breast tissue; breast density
24.  Organized Physical Activity in Young School Children Predicts Subsequent 4-Year Change in Body Mass Index 
Objective
To determine whether participation in organized outdoor team sports and structured indoor non-school activity programs in kindergarten and first grade predicted subsequent 4-year change in Body Mass Index (BMI) across the adiposity rebound period of childhood.
Design
Longitudinal cohort study.
Setting
Forty-five schools in 13 communities across Southern California.
Participants
Largely Hispanic and non-Hispanic white children (N = 4,550; average age at study entry 6.60 years, standard deviation 0.65).
Main Exposures
Parents completed questionnaires assessing physical activity, demographic characteristics and other relevant covariates at baseline. Data on built and social environmental variables were linked to the neighborhood around children’s homes using geographical information systems (GIS).
Main Outcome Measures
Each child’s height and weight were measured annually during 4-years of follow-up.
Results
After adjusting for several confounders, BMI increased at a 0.05 unit per year slower rate for children who participated in outdoor organized team sports at least twice per week as compared to children who did not. For participation in each additional indoor non-school structured activity classes, lessons, and program, BMI increased at a 0.05 unit per year slower rate, and the attained BMI level at age 10 was 0.48 units lower.
Conclusions
Engagement in organized sports and activity programs as early as kindergarten and the first grade may result in smaller increases in BMI during the adiposity rebound period of childhood.
doi:10.1001/archpediatrics.2012.20
PMCID: PMC3415326  PMID: 22869403
25.  The impact of secondhand smoke on asthma control among Black and Latino children 
Background
Among people with asthma, the clinical impact and relative contribution of maternal smoking during pregnancy (in utero smoking) and current secondhand smoke exposure on asthma control is poorly documented, and there is a paucity of research involving minority populations.
Objectives
To examine the association between poor asthma control and in utero smoking and current secondhand smoke exposure among Latino and Black children with asthma.
Methods
Case-only analysis of 2 multi-center case-control studies conducted from 2008–2010 using similar protocols. We recruited 2,481 Latinos and Blacks with asthma (ages 8–17) from the mainland United States and Puerto Rico. Ordinal logistic regression was used to estimate the effect of in utero smoking and current secondhand smoke exposures on National Heart Lung and Blood Institute-defined asthma control.
Results
Poor asthma control among children 8–17 years of age was independently associated with in utero smoking (odds ratio; 95% confidence interval = 1.5; 1.1–2.0). In utero smoking via the mother was also associated with secondary asthma outcomes, including early onset asthma (1.7; 1.1–2.4), daytime symptoms (1.6; 1.1–2.1), and asthma-related limitation of activities (1.6; 1.2–2.2).
Conclusions
Maternal smoking while in utero is associated with poor asthma control in Black and Latino subjects assessed at 8–17 years of age.
doi:10.1016/j.jaci.2012.03.017
PMCID: PMC3367092  PMID: 22552109
Secondhand smoke; prenatal exposure delayed effects; asthma; health status disparities

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