Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency.

Background: Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the 'Z' and 'S' variants - single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V.

Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations.

Rationale: Individuals with a single Z mutation in the gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown.

Objectives: To determine whether additional variants impact COPD development in a previously identified MZ (carrier) cohort.