Alpha-1 Antitrypsin Mutations: Is One Too Many?

The association between severe deficiency of alpha-1 antitrypsin and early-onset pulmonary emphysema has been known for several decades. Alpha-1 antitrypsin is encoded by the SERPINA1 gene, and the most common genetic variants causing deficiency are termed S and Z. The molecular basis of the deficiency is the abnormal folding, polymerization, and retention of the variant proteins in the endoplasmic reticulum of hepatocytes. Here, Sandford discusses a study by Ortega et al in this issue of American Journal of Respiratory and Critical Care Medicine which presents a comprehensive survey of all genetic variants in the SERPINA1 gene in a large study sample. This study illustrates the difficulty in analyzing rare genetic variants: Although there may be significant associations when considered in aggregate, there are often too few individuals with each variant to test individually with sufficient power. Nevertheless, rare variants are potentially important for the individual patient, and therefore additional large-scale studies such as this are warranted.