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Genetic testing could correct under-diagnosis of serious respiratory condition
Alpha-1 antitrypsin deficiency (AATD) is among the most common inherited respiratory conditions in people of European descent, and one of the leading causes of serious respiratory diseases. Though AATD is readily detected by a mutation in the SERPINA1 gene, it is significantly under-diagnosed because of insufficient awareness of the disease. By expanding genetic screening for AATD, people could be informed of the preventive measures they could adopt to help avoid serious complications, concludes research conducted at the Lady Davis Institute (LDI) at the Jewish General Hospital and published in the European Respiratory Journal.

Using the UK Biobank, one of the world’s largest repositories of medical data, which included 458,164 European-ancestry participants, 140 had the PI*ZZ genotype of the SERPINA1 gene. Of these, only 9 - or 6.4% - were actually diagnosed with AATD.

“One of the reasons why AATD is poorly diagnosed could be that this disease is so rare that few primary physicians recognize it,” explained Dr. Tomoko Nakanishi, a doctoral candidate at the Centre for Clinical Epidemiology at the LDI and the Department of Human Genetics at McGill University. She is the first author on the paper. AATD affects roughly one in 3,000 individuals of European ancestry. Thus, while the proportion is low, the absolute number is quite substantial. “Genetic screening, however, can identify nearly everybody with the relevant SERPINA1 mutation who is at risk of developing disease.”

People with PI*ZZ have, the researchers discovered, substantially higher odds of COPD (OR: 8.8, 95%CI: 5.8 – 13.3), asthma (OR: 2.0, 95%CI: 1.4 – 3.0), bronchiectasis (OR: 7.3, 95%CI 3.2 - 16.8), pneumonia (OR: 2.7, 95%CI: 1.5 - 4.9), and cirrhosis diagnoses (OR: 7.8, 95%CI 2.5 – 24.6) and a higher hazard of mortality (2.4, 95%CI: 1.2 - 4.6), compared to the PI*MM (wildtype) (n=398,424) genotype of the SERPINA1 gene. These associations were stronger amongst smokers. Moreover, a phenome-wide association study (PheWAS) was conducted and demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythemia, aneurysm, and pancreatitis.

Failing to diagnose the vast majority of individuals with PI*ZZ is a missed opportunity to target at-risk people with smoking cessation programs, an assessment of other family members who may have inherited the same mutation, as well as disease-specific interventions.

Dr. Nakanishi is quick to point out that not everyone with the genetic predisposition for AATD will go on to develop disease. However, knowing whether one has the mutation offers the opportunity to intervene with preventive measures. “For example, by not smoking a person could mitigate the effects for COPD, bronchiectasis and asthma,” she said. This could be great benefit to the individual’s quality of life, as well as reducing the burden of serious disease on the health care system.

Now, in the midst of the novel coronavirus pandemic, it is more important than ever to diagnose those with respiratory illness. “People with respiratory issues are at higher risk of severe infection if they were to get COVID-19,” affirms Dr. Nakanishi. “In this circumstance, the under-diagnosis of AATD could have significant consequences because so many people are unaware that they should be taking extra precautions against exposure.”

“Our research reinforces the value of using wide-spread genetic screening to identify individuals with high-risk genotypes and put in place appropriate diagnostic programs to reduce the burden of this disease,” concludes Dr. Brent Richards, a genetic epidemiologist at the LDI, the senior investigator leading the group that conducted this research.


“The Undiagnosed Disease Burden Associated with Alpha-1 Antitrypsin Deficiency Genotypes,” T. Nakanishi, et el, European Respiratory Journal


For media inquiries, please contact:

Tod Hoffman
Research Communications Officer
Lady Davis Institute at the Jewish General Hospital
Tel.: 514-340-8222 x 28661
Email: tod.hoffman@ladydavis.ca

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