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 CaliforniaLos 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 07750 10 11 12750 7 8 9 10 11 12

1500 4 5 6 7 8 9 10 11 121500 4 5 6 7 8 9 10 11 12

N 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07750 10 11 12750 7 8 9 10 11 12

1500 4 5 6 7 8 9 10 11 121500 4 5 6 7 8 9 10 11 126000 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!)

FundingNIEHS, NHLBI, Hastings FoundationCARB, 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