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Rationale: Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered., Objectives: To identify additional genetic susceptibility factors of asthma in European American and African American populations., Methods: A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status., Measurements and Main Results: The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E 2 synthesis has been associated with airway remodeling., Conclusions: This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.

Rationale: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways., Objectives: To investigate the genetic component of AWT., Methods: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated., Measurements and Main Results: Three significant loci on chromosomes 2q (rs734556; P =  6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41))., Conclusions: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.

Rationale: The development of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) is associated with increased morbidity., Objectives: To elucidate whether vascular remodeling in a well-characterized PH-COPD and PH-IPF patient cohort results from similar or divergent molecular changes., Methods: Vascular remodeling of donor, PH-COPD, and PH-IPF pulmonary arteries was assessed. Laser capture microdissected pulmonary artery profiles in combination with whole genome microarrays were performed., Measurements and Main Results: Pulmonary arteries from patients with COPD and IPF with PH exhibited remodeling of vascular layers and reduction of lumen area. Pathway analyses comparing normalized gene expression profiles obtained from patients with PH-IPF or PH-COPD revealed the retinol and extracellular matrix (ECM) receptor interaction to be the most perturbed processes. Within the ECM-receptor pathway, differential regulation of 5 out of the top 10 results (collagen, type III, α-1; tenascin C; collagen, type VI, α-3; thrombospondin 2; and von Willebrand factor) were verified by real-time polymerase chain reaction and immunohistochemical staining., Conclusions: Despite clinical and histologic vascular remodeling in all patients with PH-COPD and PH-IPF, differential gene expression pattern was present in pulmonary artery profiles. Several genes involved in retinol metabolism and ECM receptor interaction enable discrimination of vascular remodeling in PH-IPF or PH-COPD. This suggests that pulmonary arterial remodeling in PH-COPD and PH-IPF is caused by different molecular mechanisms and may require specific therapeutic options.

Rationale: The airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction., Objectives: To examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair., Methods: The expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV(1) by linear regression analysis., Measurements and Main Results: After corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-alpha1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3alpha1) decreased in small airways in association with FEV(1). In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1alpha1, and transforming growth factor-beta3) decreased in the surrounding lung tissue in association with progression of COPD., Conclusions: The progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.