α1-Antitrypsin (α1AT) deficiency is an important autosomal recessive condition associated with a substantial risk for chronic obstructive lung disease (emphysema) (Fig. 2) and cirrhosis of the liver. The α1AT protein belongs to a major family of protease inhibitors, the serine protease inhibitors or serpins; SERPINA1 is the formal gene name. Notwithstanding the specificity suggested by its name, α1AT actually inhibits a wide spectrum of proteases, particularly elastase released from neutrophils in the lower respiratory tract.

Fig2. The effect of smoking on the survival of patients with α1-antitrypsin deficiency. The curves show the cumulative probability of survival to specified ages of smokers, with or without α1-antitrypsin deficiency. (Redrawn from larson C: Natural history and life expectancy in severe α1-antitrypsin deficiency, Pi Z, Acta Med Scand 204:345–351, 1978.)

In populations of European descent, α1AT deficiency affects ~1 in 6700 persons, and ~4% are carriers. A dozen or so α1AT alleles are associated with an increased risk for lung or liver disease, but only the Z allele (p.Glu342lys) is relatively common. The reason for the relatively high frequency of the Z allele in European populations is unknown, but analysis of DNA haplotypes suggests a single origin with subsequent spread throughout northern Europe. Given the increased risk for emphysema, α1AT deficiency is an important public health problem, affecting an estimated 60,000 persons in the United States alone.

The α1AT gene is expressed principally in the liver, which normally secretes α1AT into plasma. Approximately 17% of Z/Z homozygotes present with neonatal jaundice, and ~20% of this group subsequently develop cirrhosis. The liver disease associated with the Z allele is thought to result from a novel property of the mutant protein – its tendency to aggregate, trapping it within the rough endoplasmic reticulum (ER) of hepatocytes. The molecular basis of the Z protein aggregation is a consequence of structural changes in the protein that predispose to the formation of long beadlike neck laces of mutant α1AT polymers. Thus, like the sickle cell disease variant in β-globin, the Z allele of α1AT is a clear example of a variant that confers a novel property on the protein (in both of these examples, a tendency to aggregate).

Both sickle cell disease and the α1AT deficiency associated with homozygosity for the Z allele are examples of inherited conformational diseases. These disorders occur when a variant causes the shape or size of a protein to change in a way that predisposes it to self-association and tissue deposition. Notably, some fraction of the mutant protein is invariably correctly folded in these disorders, including α1AT deficiency. Note that not all conformational diseases are single-gene disorders, as illustrated, for example, by nonfamilial AD and prion diseases.

The lung disease associated with the Z allele of α1AT deficiency is due to the alteration of the normal balance between elastase and α1AT, which allows progressive degradation of the elastin of alveolar walls (Fig. 3). Two mechanisms contribute to the elastase α1AT imbalance. First, the block in the hepatic secretion of the Z protein, although not complete, is severe, and Z/Z patients have only ~15% of the normal plasma concentration of α1AT. Second, the Z protein has only ~20% of the ability of the normal α1AT protein to inhibit neutrophil elastase. The infusion of normal α1AT is used in some patients to augment the level of α1AT in the plasma, to rectify the elastase:α1AT imbalance. Although difficult to prove definitively, there is evidence that the progression of the lung disease is slowed by α1AT augmentation.

Fig3. A posteroanterior chest radiograph of an individual carrying two Z alleles of the α1AT gene, showing the hyperinflation and basal hyperlucency characteristic of emphysema. (From Stoller JK, Aboussouan lS: α1-Antitrypsin deficiency, Lancet 365: 2225–2236, 2005.)

α1-Antitrypsin Deficiency

as an Ecogenetic Disease The development of lung or liver disease in subjects with α1AT deficiency is highly variable, and although no modifier genes have yet been identified, a major environmental factor, cigarette smoke, dramatically influences the likelihood of emphysema. The impact of smoking on the progression of the emphysema is a powerful example of the effect that environmental factors may have on the phenotype of a monogenic disease. Thus, for persons with the Z/Z genotype, survival after 60 years of age is ~60% in nonsmokers but only ~10% in smokers (see Fig. 2). One molecular explanation for the effect of smoking is that the active site of α1AT, at methionine 358, is oxidized by both cigarette smoke and inflammatory cells, thus reducing its affinity for elastase by 2000-fold.

The field of ecogenetics, illustrated by α1AT deficiency, is concerned with the interaction between environmental factors and different human genotypes. This area of medical genetics is one of increasing importance as genotypes are identified that entail an increased risk for disease on exposure to certain environmental agents (e.g., drugs, foods, industrial chemicals, and viruses). At present, the most highly developed area of ecogenetics is that of pharmacogenetics.

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