Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches

ABSTRACT

Introduction

Alpha-1 antitrypsin deficiency occurs in individuals with deleterious genetic mutations on both chromosomes (maternal and paternal) in SERPINA1, the gene encoding the alpha-1 antitrypsin protein. There has been substantial progress in understanding the genetic variation that underlies the heterogeneous penetrance of lung disease in alpha-1 antitrypsin deficiency.

Areas covered

This review will cover SERPINA1 gene structure and genetic variation, population genetics, genome-wide genetic modifiers of lung disease, alternative mechanisms of disease, and emerging therapeutics – including gene and cell therapy – related to alpha-1 antitrypsin deficiency-associated lung disease.

Expert opinion

There remains ample opportunity to employ precision medicine in the diagnosis, prognosis, and therapy of alpha-1 antitrypsin deficiency-associated lung disease. In particular, a genome-wide association study and subsequent polygenic risk score is an important first step in identifying genome-wide genetic modifiers contributing to the variability of lung disease in severe alpha-1 antitrypsin deficiency.

KEYWORDS:

• Alpha-1 antitrypsin deficiency
• COPD
• genetic modifiers
• polygenic risk score
• precision medicine

Article highlights

• AATD-associated lung disease is a subtype of chronic obstructive pulmonary disease (COPD).

• Alpha-1 antitrypsin deficiency (AATD) is caused by genetic mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin protein.

• SERPINA1 is one of the most transcriptionally complex genes in the human genome

• The most common pathologic genetic variants in SERPINA1 are the Z and S alleles, which are common in Northern European and Iberian populations, respectively.

• The variable penetrance of lung disease due to pathologic variants in SERPINA1 remains unexplained, but smoking burden and biological sex may play a role.

• Genome-wide association studies (GWAS) have successfully identified many COPD-associated SNPs, which have been aggregated to develop polygenic risk scores. Similar studies have yet to be performed in AATD-associated lung disease.

• In addition to the known disinhibition of neutrophil elastase, there may be a role of dysregulated inflammation that contributes to development of AATD-associated lung disease.

• There are several emerging therapeutics at various stages of development, though alpha-1 antitrypsin augmentation remains the mainstay of therapy.

Declaration of interest

The authors have nothing to declare.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Dr. Ghosh has no funding to report. Dr. Hobbs reports funding from the NIH-NHLBI: K08 HL136928.