What is the role of genetic factors in the etiology of alpha1-antitrypsin deficiency (AATD)?

Updated: Sep 11, 2020
  • Author: Dora E Izaguirre Anariba, MD, MPH; Chief Editor: John J Oppenheimer, MD  more...
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The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants (denoted by letters). [1] The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M, and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 µmol/L or 150-350 mg/dL).

The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 µmol/L, 10-15% of normal serum levels. Serum levels greater than 11 µmol/L appear to be protective. [1, 4] Emphysema develops in most (but not all) individuals with serum levels less than 9 µmol/L.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.

Patients with the PiSZ phenotype are 20-50% more likely to develop emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.

Patients with the null gene for alpha1-antitrypsin do not produce any alpha1-antitrypsin and are at high risk for emphysema (100% by age 30 years). None with the null gene develops liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes.

Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease, owing to the decreased protease levels being enough to prevent destruction.

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