A Step Toward Simplicity for a Complex Analyte

Abstract

α1-Antitrypsin (A1AT)2 deficiency is a serious, life-threatening disorder driven by abnormally low circulating concentrations of A1AT, which lead to protease–antiprotease imbalance. This imbalance accentuates protease activity and can lead to tissue damage, the most important of which leads to impairment of lung function (1). The apparent simplicity of diagnosing this disorder by a single measurement of the A1AT concentration is belied by the variety of A1AT tests offered by every reference laboratory. Physicians frequently evaluate genotyping, phenotyping, and concentration measurements in toto or through results produced via an algorithm that involves reflexing from one test to another (2). The need for this complex approach reflects the intricate relationships between genotype, phenotype, protein function, and concentration. The challenge in arriving at appropriate diagnosis and treatment comes from the variable penetrance of A1AT genetic defects and the limitations of each test. Typical genotyping tests detect only the most common disease alleles, S and Z, unless full exon sequencing is used. Phenotyping by isoelectric focusing can detect known and unknown polymorphs, but only in cases in which the amino acid substitution leads to a change in the protein's isoelectric point. Finally, A1AT is an acute-phase protein, and circulating concentrations …