Alpha-1 Antitrypsin Gene, Genetic Heritage, Phenotypes, and Genotypes

Human alpha-1 antitrypsin (AAT) is codified by the SERPINA1 (serine peptidase inhibitor, clade A, member 1) gene, located on chromosome 14q32. This gene is organized into three noncoding exons (1A, 1B, and 1C), four coding exons (II–V), and six introns, and it is transmitted from parents to children by simple Mendelian inheritance by two alleles (one from each parent) that express at 50% in each child. Approximately 125 genetic variants have been described in humans so far, and for clinical purposes they have been classified into four major categories, namely normal, deficiency, null, and dysfunctional variants. Most genotypes are resulting from the combination of the normal allele M and the S and Z deficiency alleles, that is, Pi*MM, Pi*MS, Pi*SS, Pi*MZ, PI*SZ, and Pi*ZZ, with a mean frequency in the general population worldwide of 95.8% for Pi*MM, 2.8% for Pi*MS, 0.6% for Pi*MZ, 0.6% for Pi*SS, 0.2% for Pi*SZ, and 0.004% for Pi*ZZ, but with large differences in these percentages between races and ethnic groups due to a much higher prevalence of the S and Z alleles in Caucasians than in African, Asian, or Native Americans subjects. Reduced serum levels of the AAT protein are commonly associated with the deficient S and Z alleles, but there are also approximately 25 rare deficiency alleles that produce very small amounts of AAT, as well as approximately other 25 null alleles that virtually do not express AAT.