Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: Revelations about underdiagnosis

Abstract

Background and objectiveAlpha-1 antitrypsin deficiency (AATD) is an underdiagnosed hereditary condition that promotes the development of lung and liver diseases, and the most common potentially life-threatening genetic condition in Caucasian adults. In this study, the clinical and genetic profile of pulmonary patients from a single center in La Palma Island (Canary Islands, Spain) was assessed to predict how to increase AATD diagnosis. MethodsAATD was tested in 1,493 pulmonary outpatients without regard to respiratory symptoms and 465 newborns. Variants of the SERPINA1 gene were characterised by real-time PCR, DNA sequencing, molecular haplotyping and phenotyping (AAT isoelectric focusing). Different respiratory pathologies were diagnosed in patients and their levels of serum AAT were measured by nephelometry. ResultsThe prevalence of pneumological patients with AATD alleles was 30.5%, including PI*S, PI*Z and 6 rare genetic variants. Certain deficiency genotypes were unevenly distributed among patients diagnosed with respiratory diseases: PI*ZZ (71.4%) and PI*SS (34.8%) genotypes were more represented in patients with chronic obstructive pulmonary disease (COPD), whereas PI*MZ (27.7%) and PI*SZ (34.5%) genotypes were more abundant in patients with bronchial asthma. The estimated frequency of PI*S and PI*Z alleles in the general population was 8.2% and 2.1%, respectively. A very significant enrichment (p< 0.01) of PI*S allele, independent of the PI*Z allele, was detected in the clinical population. ConclusionsAATD diagnosis would improve if both the COPD and the asthmatic patients were included to screening programs. The prevalence of PI*ZZ genotype in La Palma (1/2,162) was relatively high within Spain (average 1/3,344).