The selective advantage of α1-antitrypsin deficiency

The S- and Z-deficiency alleles of alpha(1)-antitrypsin are found in more than 20% of some white populations. This high gene frequency suggests that these mutations confer a selective advantage, but the biologic mechanism of this has remained obscure. It is now well recognized that the S and Z alleles result in a conformational transition within the oil-antitrypsin molecule and the formation of polymers that are retained within the endoplasmic reticulum of hepatocytes. Polymers of mutant alpha(1)-antitrypsin can also form within the alveoli and small airways of the lung where they may drive the inflammation that underlies emphysema in individuals with a,antitrypsin deficiency. This local production of polymers by mutant S and Z alpha(1)-antitrypsin may have also provided protection against infectious disease in the preantibiotic era by focusing and amplifying the inflammatory response to limit invasive respiratory and gastrointestinal infection. It is only since the discovery of antibiotics, the widespread adoption of smoking, and increased longevity that these protective, proinflammatory properties of alpha(1)-antitrypsin mutants have become detrimental to cause the emphysema and systemic inflammatory diseases associated with of alpha(1)-antitrypsin deficiency.