Rare alpha-1-antitrypsin variants: are they really so rare?

Abstract

Alpha-1-antitrypsin (α1-AT) deficiency is mainly evaluated in the diagnostic process of chronic obstructive pulmonary disease (COPD). Around 95% of individuals with severe α1-AT deficiency carry the PI*ZZ genotype. Little is known about the epidemiology of the remaining deficient α1-AT variants, which are called 'rare' due to their low prevalence. The retrospective revision of 3511 α1-AT deficiency determinations performed in Barcelona from 1998 to 2010 detected 1.6% of cases with rare α1-AT alleles, a rate similar to those reported in other European studies. Among these variants, PI*I and PI*Mmalton represented 54% of cases. Hence, the so-called 'rare' α1-AT alleles may not be rare as has been assumed. It would be of interest to implement simple allele-specific molecular biology methods to study the most prevalent rare variants in each region. Augmentation therapy is recommended in patients with emphysema and PI*ZZ genotype, but there is little evidence regarding the implications of rare variants on therapy.

Clinical phenotypes of Italian and Spanish patients with α1-antitrypsin deficiency

“…More awareness campaigns are needed, especially among primary care physicians who care for most patients with COPD, particularly in early stages of the disease [23]. Another interesting difference is the higher prevalence of rare genotypes in Italy compared with Spain, which is in accordance with previous reports [24,25] and could be related to the differences between the two nationwide diagnostic algorithms [19]. A list of the rare genotypes reported in the two registries is available as online supplementary material.…”

Rare α1-antitrypsin genotype in a grass seed worker

“…Based on this information, the prevalence of having any two rare alleles would be less than one in 10 5 . However, there are substantial geographical differences in SERPINA1 polymorphisms [7] and no valid information of rare alleles in Denmark is available. Organic dust is a well-known contributor to the development of COPD.…”

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

“…Little is known about the epidemiology of the remaining deficient AAT variants, which are called 'rare' due to their low prevalence (2-4%). A recent Spanish study found that 1.6% of registered AATD patients had rare AAT alleles with Pi I and Pi Mmalton representing 54% of them [30]. Null variants are variable and a novel one was detected firstly in an Egyptian family in Southern Italy and known as Q0 Cairo.…”