Efficient and Accurate Approaches to the Laboratory Diagnosis of α1-Antitrypsin Deficiency: The Promise of Early Diagnosis and Intervention

Abstract

Abnormal human genes are rarely absolute predictors of the development of disease. With a few notable exceptions, abnormal genes predict risk of disease, and this risk is modified by environmental factors. When these environmental risk factors are known and minimized, early identification may translate into substantial health benefits. One of the best examples of the potential of this paradigm is α1-antitrypsin deficiency. α1-Antitrypsin (AAT) deficiency is most often caused by inheritance of the so-called PI*Z allele (1)(2). “PI” is the former nomenclature for the SERPINA1 [serpin peptidase inhibitor, clade A (α1 antiproteinase, antitrypsin), member 1] gene locus and stands for protease inhibitor. While the number of AAT variants is >100, ∼95% of all AAT-deficient individuals are homozygous for the Z allele. The PI*Z allele is the result of a guanine-to-adenine base substitution, which in turn changes glutamic acid to lysine at position 342 of the mature AAT protein. This amino acid change alters the net charge of the protein and is the basis of its identification in isoelectric focusing gels. Inheritance of this allele increases the risk of developing chronic obstructive lung disease (COPD) and liver disease (1)(2). The diagnosis of AAT deficiency is based exclusively on laboratory assays (3). Risk ratios for COPD range from 1.5–12-fold, depending on whether the Z allele is present in heterozygous or homozygous combinations (4)(5)(6)(7)(8). Among normal …