For diseases that have a clear underlying genetic cause, scientists have proven eager to explore precision medicine approaches in order to eliminate or decrease the phenotype of the disease.

First, let’s briefly recap the evolution of genetic medicine over the last few decades. Genetic testing and treatment have attracted exponential interest in recent years. The 2004 Human Genome Project allowed medical researchers to access genetic information in ways that were previously unthinkable. Geneticist Richard A. Gibbs, PhD, from the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas, wrote “it is simply inconceivable today that we would not have the genome at our fingertips—as unimaginable, perhaps, as not having computers or the internet.” 

So how does genetic testing factor into day-to-day medicine? Certainly, it is not feasible to provide genetic testing for any group of signs and symptoms, even if a genetic cause is plausible. Since genetic diseases often run in the family, a detailed clerking of the patient’s family medical history is an excellent method for physicians to decide whether genetic testing is necessary. 

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In a published review article, Horton and Lucassen highlighted the sometimes ironic difficulties of employing genetic testing in cases that warrant suspicion. For example, many genetic conditions have a wide spectrum of clinical features, making it challenging for physicians to pin them down to a genetic cause. On the flip side, physicians may become overly concerned about finding a genetic cause for a group of symptoms (whether one exists or otherwise). 

“There is some evidence that people find receiving a variant of uncertain significance surprising and disturbing, and some people misinterpret it as being definitely pathogenic or definitely benign,“ they wrote. “However, there is also evidence that many people have a strong desire to receive a broad range of results from genetic testing, including uncertain results, and are uncomfortable with the idea that decisions about non-disclosure might be made without involving them.”

The Genetic Basis of AATD

Alpha-1 antitrypsin deficiency (AATD) is one disease that is clearly rooted in genetics. It “can arise in individuals who either have two copies of a single deleterious allele (homozygous) or a copy of two different deleterious alleles (compound heterozygous) in the SERPINA1 gene encoding AAT,” Ghosh and Hobbs wrote in a recently published review article.

“While the genetic basis for AATD has been known for decades, there has been significant advancement in our understanding of the gene variation and regulation that leads to clinical heterogeneity (ie, the incomplete penetrance of lung disease), opening the door to future precision medicine approaches,” the pair wrote. 

Read more about AATD diagnosis 

Physicians familiar with AATD will be familiar with some of the key genetic facts about the disease: 

  • The SERPINA1 gene encodes for AAT. 
  • The Z and S alleles are the most common pathological genetic variants in SERPINA1. 
  • The variable penetrance of lung disease among AATD patients remains a subject of continuous research. 

AATD is closely associated with chronic obstructive pulmonary disease (COPD), but since COPD patients are often smokers, physicians often assume their smoking habit is the cause of COPD. This is a valid point, but if AATD is diagnosed accurately in a patient with COPD, physicians have a broader perspective of what needs to be treated. For this reason, the American Thoracic Society and the European Respiratory Society recommend SERPINA1 genotype testing for symptomatic adults diagnosed with COPD. 

Advancing Therapeutic Approaches

Given that intravenous AAT augmentation therapy remains the main (and sometimes only) therapeutic option for AATD patients, medical researchers are racing to develop alternative therapies that are more effective and less burdensome. AAT augmentation therapy requires time, commitment, and the repeated injection of needles. Studies have demonstrated that patients find the entire process to be uncomfortable and that it compromises their quality of life. 

Since we have a relatively firm grasp of the genetics underlying AATD, scientists are increasingly looking to develop genetic-based therapies.

“With the limited scope of eligible individuals and shortcomings in treatment effectiveness, there has been significant interest in developing additional therapies for AATD,“ Ghosh and Hobbs wrote. “Several avenues are currently under development, inducing gene therapy, gene-editing cell-based therapy, and small-molecule therapies.”

Read more about AATD treatment 

The goal is clear: to work toward a cure for AATD. Setting aside the fact that studies have demonstrated that AAT augmentation therapy is not as effective as previously imagined, scientists are hoping to use genetic medicine to get to the root of the issue. “Gene therapy may one day progress to the point of addressing AATD-associated lung disease related to uninhibited neutrophil elastase activity, but the single target of gene therapy does not affect any non-SERPINA1 genetic modifiers of disease,” Ghosh and Hobbs wrote. 

Even if genetic medicine is unable to go the full distance just yet, it can still be used as an adjunct to current treatment strategies to improve the efficacy of existing interventions. Advancements in precision medicine will “pave the way for further personalization in the diagnosis, prognosis, and treatment of AATD-associated lung disease,” Ghosh and Hobbs concluded.


Gibbs RA. The Human Genome Project changed everything. Nat Rev Genet. 2020;21(10):575-576. doi:10.1038/s41576-020-0275-3

Horton RH, Lucassen AM. Recent developments in genetic/genomic medicine. Clin Sci (Lond). 2019;133(5):697-708. doi: 10.1042/CS20180436

Ghosh AJ, Hobbs BD. Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches. Expert Rev Respir Med. 2022;1-10. doi:10.1080/17476348.2022.2027755