Early Life Exposures as “Causes” of Asthma/Atopic Phenotypes: Key Questions Anita L Kozyrskyj, PhD, Research Chair & Associate Professor Dept Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada The Genesis of Allergy and Asthma Workshop Vancouver, March 2009 Total = No AsthmaPhysician Diagnosis Overweight Asthma Normal Weight Body Weight %N

Innovation from cell to society Objectives  List key questions/issues  Identify opportunities for investigation

Innovation from cell to society Key Questions/Issues in Early Life Exposure Measurement Timing of exposure  Is there a critical window: early pregnancy, late pregnancy, first year of life, first 3 years? Persistence of exposure  All or nothing phenomenon during a critical time period or first exposure followed by continued exposure? Accumulation of exposure  One key exposure or a combination of exposures?  Is there an additive risk in high risk children? Validity of exposure measurement  Are we measuring what we think we are (and does it matter)?

Innovation from cell to society `` Social and Economic Policies Neighborhoods/Communities Institutions Living Conditions Social Relationships Nutrition/care Environment Child at birth Lifecourse Genetic Factors

Innovation from cell to society SAGE: Maternal distress measure  postpartum time period only  one and 1-5 years (short-term)  persistent over 1-7 years of child’s life  late onset (after postpartum period) Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma. Kozyrskyj AL, Mai XM, McGrath P, HayGlass KT, Becker AB, MacNeil B. Am J Respir Crit Care Med 2008; 177:142-7.

Innovation from cell to society Risk of asthma following adjustment for additional confounding factors Child sex, maternal asthma, urban/rural, health care visits, number siblings, lower respiratory and non-respiratory tract infections, antibiotic use in 1 st yr

Innovation from cell to society Maternal Distress: Phenomena in the 1 st year of life or persistent exposure

Innovation from cell to society The Complexity of the Association between Socioeconomic Status and the Development of Childhood Asthma “as revealed by trajectory analyses” Kozyrskyj AL, Kendall GE, Jacoby P, Sly PD, Zubrick SR. Am J Pub Health 2009 in press

Innovation from cell to society Family Income Trajectories Rather than pre-determined categories, maximum- likelihood longitudinal (latent class) modeling techniques classified children on the basis of their family’s movements in and out of low income over the child’s lifetime (timing, duration, sequence of family low income) SAS ‘PROC TRAJ’ program was used to create family income trajectories from birth until child age 6 or 14 years. PROC TRAJ uses Bayes’s theorem to assign children to the income trajectory group for which they had the highest probability of belonging.

Innovation from cell to society The Complexity of the Association between Socioeconomic Status and the Development of Childhood Asthma “as revealed by trajectory analyses” Kozyrskyj AL, Kendall GE, Jacoby P, Sly PD, Zubrick SR. Am J Pub Health 2009 in press

Innovation from cell to society

Odds ratio for asthma subsequent to chronic low income vs not, by age

Innovation from cell to society Are the results biologically plausible? Stress hypothesis Pregnancy, early life stress and chronic family stress were independently associated with asthma at age 6 and diminished the SES association with asthma –Caregiver stress in early life has been associated with increased levels of pro-inflammatory cytokines in asthma. Infants (esp male) born into low income households are more likely to have an atopic profile at birth. By age 14, chronic life stress was associated with a two-fold increase in asthma. –Children with asthma who experience both acute and chronic stress show a reduction in the expression of the glucocorticoid receptor, which can increase the airway inflammatory response to allergens.

Innovation from cell to society Are the results biologically plausible? Hygiene hypothesis Children born to single-parents live in a SES environment that protects against asthma development. Single-parents made up 44% of households that “moved out of poverty.” Single-parent status diminished the inverse association between increasing income and asthma. When the increasing income trajectory was compared to chronic low income, asthma risk ↓’d by more than 60%. –Chen et al reported that asthma likelihood was lower in children whose families had moved up in income, than in children who continued to live in a low income family. Children living in increasing income families may experience higher rates of exposure to endotoxin and infections during early infancy, which may protect against asthma development. These exposures continue in chronic low income families and increase risk of asthma, as Celedon et al have found.

Innovation from cell to society SAGE: Absence of additive risk? Increased risk of childhood asthma from antibiotic use in early life. Kozyrskyj AL, Ernst P, Becker AB. Chest 2007: 131: 1-7.

Innovation from cell to society Key Questions/Issues in Early Life Exposure Assessment Indoor environment  Is endotoxin exposure in later life a valid exposure for early life?  What are the important questions to ask: living on a farm or exposure to farm animals?  How do you disentangle reverse causation for antibiotic use? Psychosocial environment  What is it about socioeconomic status that is associated with asthma?  What types of exposures are important, ie. depression vs anxiety?  How do you disentangle reverse causation for exposure maternal distress (“living” exposure which can change in response to the child)? Outdoor environment  Why measure outdoor environmental exposures when the infant/toddler spends most of her/his time indoors?  Do exposures during pregnancy matter and how can they be measured?

Innovation from cell to society Key Questions/Issues in Early Life Exposure Assessment Indoor environment Psychosocial environment

Innovation from cell to society Key Questions/Issues in Gene- Environment Interactions Indoor environment Psychosocial environment