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Muhammad Towhid Salam University of Southern California Los Angeles, USA

Overview of the Southern California Children’s Health Study Genes and the Environment: The Genesis of Asthma and Allergy Workshop. Muhammad Towhid Salam University of Southern California Los Angeles, USA. Southern California Children’s Health Study.

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Muhammad Towhid Salam University of Southern California Los Angeles, USA

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  1. Overview of the Southern CaliforniaChildren’s Health StudyGenes and the Environment: The Genesis of Asthma and Allergy Workshop Muhammad Towhid Salam University of Southern California Los Angeles, USA

  2. Southern California Children’s Health Study • 15+ year cohort study of respiratory health effects of air pollution school children • Children recruited from public school classrooms • 12-13 communities selected to represent range of exposures to O3, NO2, PM, and acids • Baseline questionnaire for host risk factors, exposures, prevalent health endpoints • Buccal samples for genotyping

  3. Enrollment and Follow-up of CHS Cohorts Sub-sample of the initial cohort was traced and enrolled during 1998-2004 (N ~ 1700) Plans for tracking and enrolling earlier cohorts

  4. LLLL LLLL LMLH LLLL HMLM HHHH HHHH HMHL HHHL O3, PM10, NO2, H+: L = low M = Medium H = High LHMH MMMM MLLL

  5. Respiratory Health Outcomes Lung function level and growth (10-18 years) Asthma Prevalent (by cohort entry) Incident (during annual follow-ups) Asthma symptoms (cough/phlegm) Illness-related school absences (Jan-June 1996) Exhaled nitric oxide (2004-07)

  6. Exposure Assessment: Air Pollution • Ambient levels (continuous or two-week) • Lifetime residential history • Time-activity and household characteristics • Sample measurements (personal & area) • GIS-based assessments of traffic density and pollutant dispersion modeling • Local variability in ambient pollution levels

  7. Spatial Variability of Measured Pollution and Traffic Density Within Communities Regionally Modeled Exposure

  8. Other Exposures of Interest Maternal smoking during pregnancy Exposure to secondhand smoke Exposure to surrogates for allergen/endotoxin exposures (e.g., pets, pests) Sun exposure (UVR)

  9. Methodological Papers From CHS Air pollution estimation Lung function growth Two-stage modeling for time-series data of illness-related school absences GxE using Candidate gene approach GxE using GWAS

  10. Hypotheses For Genetic and GxE Studies Oxidative stress is central to respiratory system pathobiology Genes and exposures that modulate levels and responses to oxidative stress are determinants of respiratory health Gilliland et al. EHP 1999;107:403-7

  11. Conceptual Model for Oxidative Stress Mediated Health Effects Oxidative production & detoxification Xenobiotic metabolism Physical Activity Oxidative Stress Oxidant Exposure Health Effects Dose Molecular & enzymatic antioxidants Inflammation ROS metabolism Gilliland et al. EHP 1999;107:403-7

  12. HOCI MPO TNF, ICAM1 Metabolic Production Catalase H2O+ O2 Perioxidases - GPX1-4 - GSTM1-5, T1, P1 Physical Activity Vit C, E, A GSH, Bilirubin W3 Fatty Acids GPX GST NQO1 P450 Oxidase AhR O2, O3 PM PAHs Genes in The Oxidative Stress Pathways SODs O2-1 H2O2 Fe NQO1 GSTs EPHX1 OH–, . OH Oxidant Targets - Lipids - Protein - DNA Gilliland et al. EHP 1999;107:403-7

  13. GWAS in CHS • Goals • Find genes with direct effects • Find genes that interact with: • Air pollution • in utero and second-hand smoke exposure • GSTM1, GSTP1 • Replication of GWAS findings

  14. GWAS in the CHS • Proposed sample size: ~3,000 • 1,000 asthmatics, 2,000 controls • 2,000 informative for lung function growth • Genotyping: • Illumina HumanHap550: 550K Tagging SNPs • N=2,174 genotyped so far…~800 still to do

  15. Hispanic Q-Q Plots, No Adjustments Non-Hispanic White λ=1.62 λ=1.01

  16. Children’s Health Study: Individual Admixture Af. American Asian Hispanic Caucasian MEC: K=4 Groups (Reference sample) CHS: K=4 Groups Non-Hispanic Whites Hispanic Whites

  17. Hispanic Q-Q Plots, Adjusted Non-Hispanic White λ=1.05 λ=1.02

  18. Preliminary CHS GWAS Results

  19. Collaborative Work • With SAGE and other research groups : AMCase and Asthma (submitted) • With CAMP and other research groups: TSLP and Asthma (submitted) • Main effects were replicated in the CHS

  20. CHS Team • Biostatistics • Duncan Thomas • James Gauderman • Kiros Berhane • Bryan Langholz • David Conti • Dan Stram • Mike Jerrett • Bill Navidi • Exposure Assessment • Ed Avol • Scott Fruin • Fred Lurmann • Field Team (many!) Epidemiology John Peters Frank Gilliland Rob McConnell Talat Islam Nino Kuenzli Stephanie London • Genetics • Louis Dubeau • David Van Den Berg • Pi-Chu Lin • Wendy Manuel Respiratory Medicine Bill Linn • Data Management & Analysis • Ed Rappaport Hita Vora • Towhid Salam John Morrison • Carrie Breton Feifei Liu • Cassandra Murcray Xia Li • Josh Millstein Yu-Fen Li • John Molitor Jassy Molitor • Ketan Shankardass Sylvia Tan • Made Wenten • Funding • NIEHS, NHLBI, • Hastings Foundation • CARB, EPA

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