REVIEW SERIES a1-Antitrypsin deficiency ? 2: Genetic aspects of a1- antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk

Correspondence to: Dr D L DeMeo, Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02446, USA; dawn. [email protected]. edu . . . . . . . . . . . . . . . . . . . . . . . T he susceptibility to develop chronic obstructive pulmonary disease (COPD) results from a combination of genetic and environmental factors. The most important environmental risk factor for COPD is cigarette smoking, but individuals vary in their susceptibility to the effects of cigarette smoke and only a minority of smokers will develop COPD. Severe a1-antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD. However, this genetic predisposition is present in only 1–2% of COPD patients, suggesting that most COPD in the general population probably represents a complex genetic disease with multiple genetic and environmental contributions. Even in individuals with severe AAT deficiency, the development and manifestations of COPD are highly variable, which suggests that modifier genes, environmental exposures, and gene 6 environment interactions may be relevant to disease expression. Because of the potential role of modifier genes in COPD associated with AAT deficiency, AAT deficiency provides a useful paradigm for understanding genetic and environmental effects, and their interactions in more common forms of COPD. This review will focus on the genetic aspects of AAT deficiency and the variable manifestations of lung disease in PI Z individuals. The risk of lung disease in heterozygous individuals will also be discussed, as will directions for future research.