The hypothesis that a disturbed early development of the lungs may underlie the susceptibility to COPD is well accepted. There is sparse epidemiological evidence that early life events, including antenatal influences on lung growth, program a child to be at increased risk for future COPD.COPD may not only have its origins, but also its first symptoms in early childhood. In a report based on the Tucson Children's Respiratory Study, Martinez et al. proposed three patterns of wheezing during the first six years of life, i.e. transient early wheezing in the first three years of life, non-atopic wheezing in preschool years and IgE-mediated wheeze or asthma. Children with transient early wheezing who do not develop asthma, usually wheeze in the first years in response to environmental exposures such as maternal smoking or viral infections. We put forward the hypothesis that these symptoms constitute the first signs of disturbed early lung development and lung growth and as a corollary hypothesis that this may reflect later development of COPD. This is supported by the replicated findings that transient early wheeze is associated with lower lung function levels up to age 16, even when the symptoms of wheeze have disappeared. Since the level of lung function, expressed as FEV1, has been shown to track over time, it is plausible that infants with lower lung function levels have an increased risk to develop COPD later in life. A limiting factor in research on this hypothesis is the huge logistic difficulty of studying the effect of early life events with respect to a disorder that only becomes apparent 50-60 years later. Therefore research must rely on indirect evidence and one such a feasible type of research is the investigation of common underlying genes. The aim of our study is to investigate whether replicated genes of COPD are associated with transient early wheeze and the level of lung function in children. The current birth cohorts under study (PIAMA and KOALA) allow us to analyze data from 2500 children and take into account important environmental stimuli like in utero and early childhood smoke exposure and air pollution. Moreover, a birth cohort in England will provide data to replicate our positive findings.There is increasing evidence from studies in adults that genes involved in the response to oxidative stress are associated with COPD development. The strongest and most consistent effects on COPD have been found in the genes of glutamate-cysteine ligases (GCL), glutathione S-tranferases M1 (GSTM1) and P1 (GSTP1), and superoxide dismutase 3 (SOD3). Other replicated genes of COPD are involved in the balance between proteases and antiproteases in the lungs, such as alpha1-antitrypsin (AAT) deficiency (AAT), Tissue Inhibitors of MMPs (TIMP)-1, transforming growth factor (TGF)-b1, Tumor necrosis factor (TNF)-a and Serpine2. In addition, we aim to use the positive findings of a currently performed genome wide association study (GWA) on COPD in adults (COPACETIC). This allows us to verify if genes that are found by GWA in a COPD cohort and replicated in other cohorts of adults are also associated with low lung function and wheezing phenotypes in childhood.This study aims to provide more insight in the natural history and pathogenesis of COPD. In addition, it may offer opportunities to identify susceptible individuals at the earliest stages of the disease, when preventive strategies are most effective.

The data required will be early wheezing phenotypes and lung function measurements, tobacco smoke exposure and usual confounding variables for early life asthma studies (already compiled).