Alpha-1-antitrypsin variants in New Zealand and their clinical implications

Abstract

Synthesis of alpha-1-antitrypsin (A-1-AT), the main anti-protease in serum, is controlled by a pair of codominant autosomal alleles. Many genetic variants of A-1-AT have now been recognized, however only alleles which result in a deficiency of A-1-AT seem to be of clinical significance. 1303 samples from New Zealand European male blood donors were phenotyped using acid starch gel electrophoresis. Unusual phenotypes were confirmed by crossed antigen antibody electrophoresis and in some cases by family studies. 12.1% of the subjects had A-1-AT variants including MS in 7.0% and MZ in 3.9%. The rarer phenotypes FM, SS, IM, SZ, FS and ZZ were also found. A more recent study using isoelectric focusing techniques has confirmed these findings. From the gene frequencies calculated, the incidence of the ZZ phenotype (in which A-1-AT levels are 10% of normal) is 1 in 2000. ZZ homozygotes usually develop emphysema with onset of symptoms by age 30. In our study of 38 homozygotes it was found that in women and non-smokers the onset of respiratory disease may be delayed. Less commonly ZZ homozygotes developed cirrhosis, usually in childhood (2 cases), but sometimes in adult life (1 case). The MZ heterozygous state with A-1-AT levels at 60% of normal was found in 14.2% of 190 patients with emphysema, all smokers, indicating a predisposition to emphysema in the 3.9% of the population carrying this genetic abnormality. There is also some evidence to suggest predisposition of heterozygotes to liver disease. Patients carrying the Z allele deposit A-1-AT in the liver cells and fail to secrete adequate serum levels of A-1-AT leaving the alveoli vulnerable to attack by proteases in inflammatory exudates.