DNA polymorphisms of the alpha 1-antitrypsin gene region in patients with chronic obstructive pulmonary disease.

Alpha 1-antitrypsin (AAT) is an important part of the defence mechanism of the lung against proteolytic attack. The Z and Null mutants of the AAT gene are associated with very low or missing serum concentrations of AAT, so that for individuals with genotypes ZZ or Null there is a very high risk of developing chronic obstructive pulmonary disease (COPD). In more than 90% of the patients suffering from COPD, however, the common MM phenotype of AAT is expressed at normal AAT serum levels. The MM phenotype has a heterogeneous constitution and the alleles M1, M2 and M3 are distinguished by isoelectric focusing. At the DNA level many mutants of the AAT gene may exist that cannot be recognized by IEF. In this paper we report DNA sequence heterogeneity of the AAT gene region among 137 patients with COPD and 130 healthy control subjects. All 267 individuals studied were MM phenotype. Several restriction fragment length polymorphisms (RFLPs) were observed using genomic probes of the AAT gene. One allele (T2) of a Taq I RFLP located 1 kb downstream of the AAT gene was significantly more frequent in patients (15.3%) than in controls (5.4%) (P less than 0.005). The relative incidence of COPD was 3.3 times higher for subjects carrying at least one T2 allele than for the common T1T1 genotype. The T2 allele may be in linkage disequilibrium with a functionally deficient variant of AAT or some gene in close neighbourhood, e.g. the alpha 1-antichymotrypsin gene. A deletion of 1.8 kb in the alpha 1-antichymotrypsin-like gene (PIL gene) occurs at a frequency of 0.26 in patients and in control subjects as well.