Genetics of Pulmonary Disorders

The progress made in discovering the genetic basis of pulmonary disease is astounding. This issue, while focusing on a just a few disorders, illustrates how the tools of genetic epidemiology are being applied to a variety of complex pulmonary disorders. We will soon understand why it is that some individuals who smoke develop chronic obstructive pulmonary disease (COPD) and lung cancer, whereas others do not; why after the same exposure to Mycobacterium tuberculosis or beryllium individuals may or may not develop disease, why sarcoidosis affects certain ethnic groups more commonly and severely, and even why patients at risk go on to develop acute respiratory distress syndrome (ARDS).

The article by Dr. Rybicki provides an excellent overview for applying genetic epidemiology to lung disease. The reader will agree that the scientific path to identifying disease genes in complex disorders, those disorders that result from an interplay of environmental and genetic factors, is more difficult than that taken for single-gene, Mendelian disorders. Association studies used to detect genetic risk must be carefully designed to minimize potential pitfalls, such as population stratification. Dr. Rybicki also introduces us to the application of microarray technology for mining the genome and for dissecting gene expression in complex systems.

Drs. DeMeo and Silverman illustrate the power of using family studies in complex diseases and how using individuals with extreme phenotypes, such as severe, early-onset COPD, stacks the deck in favor of disease gene identification. We also learn about progress made using both association and linkage studies in COPD.

Drs. Floros and Pavlovic review for us the genetics of ARDS, perhaps the most difficult topic in this issue. These authors point out that the need to identify homogeneous subgroups is essential to genetic epidemiological study design in pulmonary fibrosis. Further, Drs. Floros and Pavlovic evaluate the role of the surfactant proteins as candidate genes in ARDS. These genes are particularly attractive candidates because ARDS has been associated with derangements in surfactant composition and biophysical activity.

Discussions of the genetics of beryllium disease by Drs. Tinkle, Weston, and Flint; of sarcoidosis by Dr. Schürmann; and of tuberculosis by Drs. Maliarik and Iannuzzi provide us with updates on three diseases that likely exist on the same continuum of granulomatous diseases. Each offers insight to the other. Human leukocyte antigen, T cell receptor genes, and cytokine dysregulation play a role in all three disease entities, and association and linkage studies have been successfully applied.

Drs. Luisetti and Pignatti report on evaluating the cystic fibrosis transmembrane regulator gene (CFTR) as a candidate gene for idiopathic disseminated bronchiectasis. With over 1000 mutations in CFTR identified in patients with cystic fibrosis, it makes good sense to scrutinize this gene in patients with bronchiectasis. These authors argue that perhaps bronchiectasis should be considered one of the "CFTR-opathies."

Although many excellent reviews on asthma genetics have been written, Drs. Zaas and Schwartz reinforce the need to study gene-environment interactions in asthma.

Lung cancer remains the leading cause of cancer death, with treatment advances only modest at best. Several promising markers of lung cancer susceptibility have been identified, and Drs. Miller and Fain review for us progress made in the molecular and genetic epidemiology of lung cancer. Genetic research, until recently, focused on single-gene disorders such as cystic fibrosis. Advances in high throughput molecular analysis and statistical methods now allow us to approach the genetics of complex disorders.

Drs. du Bois and Veeraraghavan present the three key aspects to elucidating genetic factors in the pathogenesis of pulmonary fibrosis-defining phenotype, assessing disease severity, and using family and association studies. These factors must be considered in the study design for complex disorders; readers will find this update useful in evaluating future publications. These authors also review for us the exciting discovery of the importance of surfactant protein genes in interstitial lung disease.

The topics covered in this issue provide an update on advances in molecular analysis and statistical methods, particularly as applied to pulmonary diseases. As we read the articles in this issue and come to understand how nearly all disease can be thought of as occurring from some balance of environmental and genetic factors, it becomes easy to agree with Mark Twain's observation that "[w]e're nothing but a ragbag of disappeared ancestors."

Finally, I am sincerely grateful to the authors contributing to this issue. Their succinct reviews serve us well.