1. University of Southern California
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

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 Cohorts93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
750 10 11 12 7 8 9
1500 4 5 6
6000 K 1 2 3 N 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
750 10 11 12 7 8 9
1500 4 5 6
Sub-sample of the initial cohort was traced and enrolled during (N ~ 1700)
Plans for tracking and enrolling earlier cohorts

4. O3, PM10, NO2, H+: L = low 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 )
Exhaled nitric oxide ( )

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)

10. 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

11. 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

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

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

14. GSTM1 null, Maternal Smoking, and Asthma/Wheeze
Models are adjusted for towns, age, grade, race, family history of asthma and atopy, gestational age, and current ETS exposure. All outcomes are for the previous 12 months except ever and early onset asthma, and ever wheezing.
*Statistically significant interaction (p < 0.05).
Gilliland et al, Am J Respir Crit Care Med, 2002

15. GSTP1 Ile105Val, Participation in Team Sports and Incident Asthma
Number of Sports played
Hazard ratio (95% CI)
Interaction p-value
Ile/Ile
Ile/Val or Val/Val
None
(Ref)
0.90 (0.5–1.6)
0.02
1-2
1.42 (0.8–2.5)
0.73 (0.4–1.3) 3+
2.66 (1.2–5.9)
0.68 (0.2–1.9)
Trend p-value
0.03
0.41
Islam et al. Thorax 2009

16. GSTM2, Maternal Smoking, and FEV1 Growth (10-18 years)
The model allowed for separate growth curves for each sex, race, ethnicity, cohort, and asthma status at baseline. The model was adjusted for height, height2, body mass index (BMI), BMI2, current asthma, exercise/ respiratory illness on test day, active smoking in the last year, ancestry, and indicator variables for field technician.
Breton et al, Am J Respir Crit Care Med, In Press, 2009

17. TNF A-308G, Secondhand Tobacco Smoke, and Respiratory Illness-related School Absences
Models are adjusted for community, age, race, sex, income, insurance, asthma, and body mass index.
Wenten et al, Am J Respir Crit Care Med, 2005

18. NOS2A Promoter Haplotype, Secondhand Smoke, and FENO
* Estimates ( coefficients for log FENO). Models are adjusted for age, race/ethnicity, indices of genetic population stratification, maternal smoking during pregnancy, asthma, atopy, asthma medication use, community of residence, respondent education, and hour and month of FENO collection.
Salam et al, to be submitted

19. 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

20. GWAS in the CHS Proposed sample size: ~3,000 Genotyping:
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

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

22. Children’s Health Study: Individual Admixture
MEC: K=4 Groups (Reference sample)
Af. American
Asian
Hispanic
Caucasian
CHS: K=4 Groups
Non-Hispanic Whites
Hispanic Whites 22

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

24. Preliminary CHS GWAS Results

25. 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

26. CHS Team Epidemiology Biostatistics Exposure Assessment Genetics
John Peters
Frank Gilliland
Rob McConnell
Talat Islam
Nino Kuenzli
Stephanie London
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!)
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