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

Abstract

BACKGROUND AND OBJECTIVE: Alpha-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. METHODS: AATD 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. RESULTS: The 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. CONCLUSIONS: AATD 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).