Genetics

COPD is a complex human disease influenced by multiple genes, environmental factors, and gene-by-environment interactions. Although cigarette smoking is known to be the most important factor influencing the development of the disease, little is known about the genes involved in the pathogenesis of COPD. DeMeo and coworkers performed an autosomal whole genomewide linkage scan in 72 pedigrees ascertained through a proband with severe, early-onset COPD, focusing the analysis on forced midexpiratory flow, in particular on FEF_25–75 and FEF_25–75/FVC spirometric phenotypes. A linkage was found between chromosome 2 and 12, and FEF_25–75 and FEF_25–75/FVC. Interestingly, when the analysis was stratified by cigarette smoking, the logarithm of the odds score on chromosomes 2 and 12 increased and new unreported regions on chromosomes 16, 20, and 22 were identified. These results suggest that genes in these regions may be involved in gene–smoking interactions potentially relevant to COPD susceptibility.

Skeletal muscle dysfunction is an important complication of COPD associated with reduced quality of life, increased utilization of health care resources, and increased mortality. Angiotensin II is involved in the regulation of production of cytokines, growth factors, and hormones, such as insulin, which might be involved in the development of skeletal muscle dysfunction and cachexia, and a polymorphism in the angiotensin-converting enzyme (ACE) gene has been shown to be associated with skeletal muscle dysfunction in normal subjects. Hopkinson and colleagues found that the D allele of the ACE gene was associated with greater quadriceps strength in patients with COPD, and that this effect was independent of the severity of the disease. The authors also found that skeletal muscle weakness was indeed related to ACE genotype in patients with COPD, providing an interesting insight into the mechanisms of skeletal muscle dysfunction in COPD.

COPD is a heterogeneous disorder with variable morphologic, physiologic, and clinical phenotypes. To identify potential genetic factors of susceptibility to COPD, Guerassimov and colleagues examined five different strains of mice after 6 months of exposure to cigarette smoke. Elastance, extent of emphysema, and the inflammatory cell and cytokine profile were measured in each animal. The results of the study show a remarkably different susceptibility of the five strains to the development of smoking-induced emphysema, with the AKR/J strain being highly susceptible, the C57BL/6/j and SJ/l strains mildly susceptible, and the NZWLac/j strain resistant. The degree of susceptibility was determined not only by the increase in airspace enlargement but also by the decrease of elastance and the pattern of inflammatory cells. T cells and a Th1 cytokine profile were present only in the lungs of highly susceptible animals, suggesting that the inflammatory cell and cytokine profile may be an important determinant of the phenotype in response to cigarette smoke exposure. These results suggest that identification of resistant and susceptible strains for the development of emphysema could be useful for genomic studies of emphysema susceptibility in mice and eventually in humans.

To investigate the role of placenta growth factor (PlGF) in the pathogenesis of pulmonary emphysema, Tsao and coworkers generated PlGF transgenic mice resulting in constitutive overexpression of PlGF. The authors demonstrated that overexpression of PlGF in mice causes structural and functional alterations similar to human emphysema, with enlarged air spaces and enhanced pulmonary compliance, not associated with pulmonary inflammation. Overexpression of PlGF resulted in increased apoptosis of type II pneumocytes in the alveolar septa, a finding that was confirmed by in vitro analysis, showing that exogenous PlGF inhibited proliferation and promoted cell death of type II pneumocytes. Furthermore, PlGF transgenic mice showed decreased production of VEGF (a driver of vascular formation), suggesting that epithelial cell death affects endothelial cell fate. These results suggest that PlGF may play an important role in pulmonary emphysema through its action on type II pneumocytes and on endothelial cells via VEGF. The authors concluded that this mouse model has revealed a novel noninflammatory pathway in pulmonary emphysema.

Citations 1-4 of 4 total displayed.

Genome-wide Linkage of Forced Mid-expiratory Flow in Chronic Obstructive Pulmonary Disease

Dawn L. DeMeo, Juan C. Celedón, Christoph Lange, John J. Reilly, Harold A. Chapman, Jody S. Sylvia, Frank E. Speizer, Scott T. Weiss, and Edwin K. Silverman
Am. J. Respir. Crit. Care Med. 170: 1294 -1301. First published online as doi:10.1164/rccm.200404-524OC [Abstract] [Full text]

The Development of Emphysema in Cigarette Smoke-exposed Mice Is Strain Dependent

Alexei Guerassimov, Yuma Hoshino, Yasutaka Takubo, Antony Turcotte, Midori Yamamoto, Heberto Ghezzo, Alexandra Triantafillopoulos, Kevin Whittaker, John R. Hoidal, and Manuel G. Cosio
Am. J. Respir. Crit. Care Med. 170: 974 -980. First published online as doi:10.1164/rccm.200309-1270OC [Abstract] [Full text]

Angiotensin Converting Enzyme Genotype and Strength in Chronic Obstructive Pulmonary Disease

Nicholas S. Hopkinson, Annabel H. Nickol, John Payne, Emma Hawe, William D.-C. Man, John Moxham, Hugh Montgomery, and Michael I. Polkey
Am. J. Respir. Crit. Care Med. 170: 395 -399. First published online as doi:10.1164/rccm.200304-578OC [Abstract] [Full text]

Overexpression of Placenta Growth Factor Contributes to the Pathogenesis of Pulmonary Emphysema

Po-Nien Tsao, Yi-Ning Su, Hung Li, Pei-Hsin Huang, Chiang-Ting Chien, Yih-Loong Lai, Chien-Nan Lee, Chi-An Chen, Wen-Fang Cheng, Shu-Chen Wei, Chong-Jen Yu, Fon-Jou Hsieh, and Su-Ming Hsu
Am. J. Respir. Crit. Care Med. 169: 505 -511. First published online as doi:10.1164/rccm.200306-774OC [Abstract] [Full text]

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