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With rapid advances in our knowledge of the human genome and increasing availability of high-throughput investigative technology, genome-wide association (GWA) studies have recently gained marked popularity. As an unbiased approach to identifying genomic regions of importance in complex human disease, the results of such studies have the potential to illuminate novel causal pathways, guide mechanistic research, and aid in prediction of disease risk. The use of a genome-wide approach presents considerable methodological and statistical challenges, and properly conducted studies are essential to avoid false-positive results. A total of 22 GWA studies have been published in pulmonary medicine thus far, implicating several intriguing genomic regions in the determination of pulmonary function measures, onset of asthma, and susceptibility to chronic obstructive pulmonary disease. Many questions remain, however, as most identified genetic variants contribute only nominally to overall disease risk, genetic disease mechanisms remain uncertain, and disease-associated variants are not consistent across studies. Perhaps most fundamentally, the association signals identified have not yet been traced to causal variants. This perspective will review the current state of GWA studies in pulmonary disease. We begin with an introduction to the hypothesis, principles, and limitations of this type of genome-wide approach, highlight key points from available studies, and conclude by addressing future approaches to better understand the genetics of complex pulmonary disease.

Intrauterine growth restriction is associated with impaired lung function in adulthood. It is unknown whether such impairment of lung function is linked to the transforming growth factor (TGF)-β system in the lung. Therefore, we investigated the effects of IUGR on lung function, expression of extracellular matrix (ECM) components and TGF-β signaling in rats. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 70. Pulmonary activity of the TGF-β system was determined at P1 and P70. TGF-β signaling was blocked in vitro using adenovirus-delivered Smad7. At P70, respiratory airway compliance was significantly impaired after IUGR. These changes were accompanied by decreased expression of TGF-β1 at P1 and P70 and a consistently dampened phosphorylation of Smad2 and Smad3. Furthermore, the mRNA expression levels of inhibitors of TGF-β signaling (Smad7 and Smurf2) were reduced, and the expression of TGF-β-regulated ECM components (e.g. collagen I) was decreased in the lungs of IUGR animals at P1; whereas elastin and tenascin N expression was significantly upregulated. In vitro inhibition of TGF-β signaling in NIH/3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Taken together, these data demonstrate a significant impact of IUGR on lung development and function and suggest that attenuated TGF-β signaling may contribute to the pathological processes of IUGR-associated lung disease.

To identify the genetic etiology of a disease of interest, disease-related characteristics (phenotypes) are often tested for association with genetic variants (genotypes). Although genetic association studies of single genetic variants have been widely performed, there has been increasing interest in studies of multiple adjacent genetic variants on one chromosome, known as a haplotype. In this review, we will provide background about the origin of haplotypes and why they can be useful in genetic studies; we will discuss approaches to determining haplotypes and performing haplotype-based genetic association studies; and we will compare single variant and haplotype-based approaches.

This paper is the fourth in a series of reviews that will summarize available data and critically discuss the potential role of lung-function testing in infants with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses information derived from tidal breathing measurements within the framework outlined in the introductory paper of this series, with particular reference to how these measurements inform on control of breathing. Infants with acute and chronic respiratory illness demonstrate differences in tidal breathing and its control that are of clinical consequence and can be measured objectively. The increased incidence of significant apnea in preterm infants and infants with chronic lung disease, together with the reportedly increased risk of sudden unexplained death within the latter group, suggests that control of breathing is affected by both maturation and disease. Clinical observations are supported by formal comparison of tidal breathing parameters and control of breathing indices in the research setting.