Screening and Familial Testing of Patients for α1-Antitrypsin Deficiency: Genetics of AATD

The AAT protein is encoded by the protease inhibitor (PI) locus located on chromosome 14q32.1. Normal levels of AAT protein protect the tissues against enzymatic degradation by neutrophil elastase. The PI locus is highly polymorphic, and approximately 100 variants have been identified. Normal serum levels of AAT are associated with the M allele, and reduced levels are commonly associated with the S and Z alleles. The Z mutation leads to misfolding of the protein, with accumulation in liver cells and severely reduced plasma AAT levels. There are also rare dysfunctional forms of AAT, and in some cases no protein is secreted (the null allele). The Z allele is usually associated with a severe form of AATD and is the phenotype most often associated with disease (Table 1). Liver disease occurs as a consequence of the misfolding, polymerization, and hepatic retention of the abnormal ZZ phenotype a-protein. Emphysema occurs secondary to reduced levels of circulating antiprotease protein ordered via My Canadian Pharmacy.

The inheritance of the PI phenotype is autosomal codominant. If both parents are carriers of the Z allele, there is a one in four chance of their child being PI ZZ homozygous. If one parent is PI ZZ homozygous and the other is heterozygous, all offspring either are carriers or are affected. Typically, ZZ patients are the offspring of two unknown heterozygotes (eg, two people with the MZ genotype). Given the frequency of carrier rates in the United States, the probability of having ZZ offspring is quite evident. AATD is not a rare disease, but is a rarely diagnosed disease. This high frequency of carriers reinforces the importance of testing the family members of individuals affected by AATD. The S allele may be more predominant in some populations.

Disease-Modifying Factors

Risk factors for disease severity and progression include smoking, exposure to environmental respiratory irritants, kerosene heaters, and employment in agriculture. There are other undefined genetic modifiers of lung disease, as evidenced by the wide variety of clinical presentations of AATD, even in patients with similar phenotypes and risk factors. The high prevalence of abnormal phenotypes hypothetically exists as a consequence of a selective advantage in protecting against invading pathogens, resulting in a heightened, less regulated inflammatory response.

It is important that affected individuals are identified as early as possible, and preventive measures taken, disease progression minimized, and appropriate treatment given. The counseling of patients before and after testing is also vital. Early knowledge of AATD encourages wiser choices among young patients and reinforces the importance of tobacco avoidance. This has been demonstrated by the largest long-term cohort, the original patients from the 1970s AATD-screening program in Sweden, who are now 30 years of age. The results from these individuals, who received guidance on the dangers of smoking, show that smoking is less common in them than in control subjects. AATD individuals who reported smoking also reported more respiratory symptoms than smokers without AATD. Predispositional testing of affected children and adolescents is valued by their parents. However, persistent smoking, even after diagnosis, is still a problem in some individuals, as demonstrated in the a Coded Testing (ACT) study in which 12 of 54 PI SZ individuals (22.2%) and 6 of 81 PI ZZ individuals (7.4%) continued to smoke 1 year after the diagnosis of AATD. The ACT study assesses outcomes of home-administered tests for AATD, supported by a specialty call center.

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Table 1—The Most Common PI Phenotypes and the Likely Clinical Consequences