Overview of the Southern California Children’s Health Study Genes and the Environment: The Genesis...
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Overview of the Southern CaliforniaChildren’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
• 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
Enrollment and Follow-up of CHS Cohorts
N 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
750 10 11 12
750 7 8 9 10 11 12
1500 4 5 6 7 8 9 10 11 12
1500 4 5 6 7 8 9 10 11 12
N 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
750 10 11 12
750 7 8 9 10 11 12
1500 4 5 6 7 8 9 10 11 12
1500 4 5 6 7 8 9 10 11 12
6000 K 1 2 3 4 5 6 7 8
Sub-sample of the initial cohort was traced and enrolled during 1998-2004 (N ~ 1700)
Plans for tracking and enrolling earlier cohorts
LLLL
LLLL
LLLL
LMLH
HMLM
HHHH
HHHH
LHMH
HHHL HMHL
MMMM
MLLL
O3, PM10, NO2, H+: L = low M = Medium H = High
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)
Exposure Assessment: Air Pollution 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
Spatial Variability of Measured Pollution Spatial Variability of Measured Pollution and Traffic Densityand Traffic Density
Regionally
Within Within CommunitiesCommunities
Modeled ExposureModeled Exposure
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)
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
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
Conceptual Model for Oxidative Stress Mediated Health Effects
Oxidant Oxidant Exposure Exposure
Oxidative Oxidative Stress Stress
Health Health EffectsEffects
Molecular & Molecular & enzymatic enzymatic antioxidantsantioxidants
DoseDose
Physical Physical ActivityActivity
ROS ROS metabolismmetabolism
Xenobiotic Xenobiotic metabolismmetabolism
Oxidative Oxidative production & production & detoxificationdetoxification
InflammationInflammation
Gilliland et al. EHP 1999;107:403-7
SODs
O2-1 H2O2
Fe
OH–, . OH
Oxidant Targets - Lipids - Protein - DNA
O2, O3
PM
Physical Activity
Metabolic Production
HOCI
MPO TNF, ICAM1
CatalaseH2O + O2
PerioxidasesPerioxidases- GPX1-4- GSTM1-5, T1, P1NQO1
GSTsEPHX1
GPXGSTNQO1
Vit C, E, AGSH, BilirubinW3 Fatty Acids
Genes in The Oxidative Stress Pathways
PAHs
P450 OxidaseAhR
Gilliland et al. EHP 1999;107:403-7
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
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
Hispanic
λ=1.62λ=1.01
Non-Hispanic White
Q-Q Plots, No Adjustments
Children’s Health Study: Individual Admixture
CHS: K=4 Groups
MEC: K=4 Groups (Reference sample)
Non-Hispanic Whites Hispanic Whites
Af. American Asian Hispanic Caucasian
Hispanic
λ=1.05λ=1.02
Q-Q Plots, AdjustedQ-Q Plots, Adjusted
Non-Hispanic White
Preliminary CHS GWAS Results
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
CHS TeamEpidemiology
John PetersFrank GillilandRob McConnellTalat IslamNino KuenzliStephanie London
BiostatisticsDuncan ThomasJames GaudermanKiros BerhaneBryan LangholzDavid ContiDan StramMike JerrettBill Navidi
Exposure AssessmentEd AvolScott FruinFred LurmannField Team (many!)
Funding
NIEHS, NHLBI,
Hastings Foundation
CARB, EPA
Data Management & AnalysisEd Rappaport Hita VoraTowhid Salam John MorrisonCarrie Breton Feifei LiuCassandra Murcray Xia LiJosh Millstein Yu-Fen Li John Molitor Jassy Molitor Ketan Shankardass Sylvia Tan Made Wenten
GeneticsLouis DubeauDavid Van Den BergPi-Chu LinWendy Manuel
Respiratory MedicineBill Linn