Ecogenetics of lung diseases

Lung Disease and Ecogenetics

Emphysema means, literally, "inflated tissues"' In pulmonary emphysema the lungs become permanently inflated owing to loss of elasticity in the walls of their thin air sacs, the alveoli.  Affected people cannot exhale properly, and the exchange of oxygen and carbon dioxide across alveolar wails is reduced.

As the disease Progresses, damaged alveoli combine to form larger (and even less efficient) air sacs and also become infiltrated with fibrous tissue.

Because of damage to alveolar capillaries, the heart must work much harder to pump blood through the lungs.

Infections also occur more frequently. The patient becomes more and more incapacitated and dependent on extra oxygen. What causes the alveoli to lose their elasticity? Some environmental factors (especially smoking) have been implicated, and the inherited deficiency of enzyme called α1-antitryPsin (AAT) may also be a key element. AAT is a small protein produced in liver cells and secreted into the blood. From there it diffuses into body tissues, mainly the lungs, and functions as a protease inhibitor. It counterbalances the action of certain lysosomal proteases (intracellular enzymes that digest proteins), which in this case are released by infection-fighting white blood cells in the lungs. Proteases are useful in digesting bacteria and other dead cells. But they can also attack elastin fibers in the walls of the alveoli if they are not bound and inactivated by α1-antitrypsin.The AAT gene, called Pi (for protease inhibitor), maps to chromo-some 14q. It has been cloned, and its mutant DNA sequences have been identified. The locus is highly polymorphic, with over 70 known alleles whose frequencies vary among different populations,. The most common of these co dominant variants is the normal one, Pi^M (82-96% in whites,98-100% in non whites). The most clinically significant alleles are Pi^Z, Pi^S ,and pi^QO. The first two are point mutations and fairly common (1-2%) in whites (especially those of Scandinavian, Spanish, and Portuguese origin),but rare or absent in black or Asian populations. They produce defective polypeptides that tend to get hung up in the liver cells, rather than being3M secreted into the bloodstream. The third, a rare "null" mutant, makes no polypeptide at all.

Homozygote’s  for the Pi^z and Pi^QO alleles suffer from severe lung disease, with smokers showing an earlier onset. Indeed, all AAT disease phenotypes develop from an interplay between genotype and environment. Thus, AAT deficiency is an ecogenetic disorder, with cigarette smoking and other chemical irritants being major hazards for people having this inherited tendency to lung disease.