Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive inherited disease characterized by pulmonary emphysema and liver cirrhosis with variable clinical manifestations. Serum concentrations of alpha-1-AT are decreased. Alpha-1-AT is encoded by the SERPINA1 (PI) gene and is an important protease inhibitor whose deficiency leads to enhanced elastase-mediated lysis processes, especially in pulmonary infections.
The polymorphic SERPINA1 gene is divided into 3 allele types: normal (M), deficiency (Z, S), and null. The PI*Z allele (Glu342Lys) is the most common in Europe with a prevalence of 1-5%, highest frequency in Scandinavia. Homozygous ZZ carriers (prevalence 1:2,000-1:7,000) have a 10-15% decreased serum concentration of alpha-1-AT with a significantly increased risk of chronic obstructive pulmonary disease (COPD). In addition, a high level of the protein accumulates in hepatocytes which can lead to cell damage and liver cirrhosis. In about 10%, neonatal hepatic syndrome with jaundice develops in infancy. Heterozygous MZ carriers also have decreased serum alpha-1-AT concentrations and an increased risk of COPD. The prevalence of the PI*S allele (Glu264Val) is 2-4% in Europe with the highest frequency in the Iberian Peninsula. The risk of COPD in heterozygous SZ carriers is intermediate, ranging between MZ and ZZ carriers. Homozygous and heterozygous carriers of the S allele are not likely to have an increased risk of lung or liver disease. Cigarette smoke is considered a major risk factor for COPD in carriers of a PI* risk allele. Null alleles are very rare and are caused by stop or splice mutations and deletions in the SERPINA1 gene.
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