I study a genetic disease called alpha-1 antitrypsin deficiency. People with antitrypsin deficiency typically suffer from lung diseases, like emphysema, and liver diseases, like cirrhosis. Technically, it is considered a rare disease – around 1 in 4000 people in the US have severe antitrypsin deficiency – but the mutations that cause this disease are actually very common.
How common? About 10% of people in Australia, New Zealand, and North America have at least one copy of a disease-associated mutation in the antitrypsin gene. Only those with two copies of a mutation – one inherited from Mum and one from Dad – will suffer from a severe deficiency of antitrypsin that puts them at very high risk for chronic lung disease. The question is, do all the hundreds of millions of people with only one antitrypsin mutation also experience higher risk for disease?
This question was controversial for some time because most people with only one mutation (called ‘carriers’) do not show obvious signs of respiratory or liver disease. However, over the years it has become clear that even though most carriers will stay healthy, they still bear some increased health risks.
This was most dramatically demonstrated last year, with the publication of a study of rescue workers present at the collapse of the World Trade Center buildings. David Prezant, a Chief Medical Officer at the FDNY, and one those serving on September 11, 2001, led studies of the medical follow-ups, and showed that many rescue workers suffered acute lung damage from the smoke and fine dust produced by the collapse.
For most rescue workers, the bad news was that they never recovered the function that they lost immediately after the attacks. The good news was that they didn’t suffer any further unusual loss in lung function in subsequent years (a small amount of lung function decline is normal with age). But unfortunately, there were also some people that suffered accelerated declines in lung functions long after exposure to the WTC dust. Prezant and his team tested for antitrypsin mutations to see if part of this variability in response could be explained by differences in genetic risk.
The results firmly supported the idea that antitrypsin mutations can affect risk of lung disease even in the absence of full-blown antitrypsin deficiency. Of the 90 participants in the study, 11 had an antitrypsin mutation, but none had antitrypsin deficiency. Of the 11 carriers, those with mutations that have a relatively mild effect on antitrypsin function had double the normal rate of lung function loss over four years. Those with more severe mutations had triple the rate of lung function loss.
The continuing decline of lung function in rescue workers with antitrypsin mutations exposed a previously ‘hidden’ genetic risk. It taught us that even a very low genetic risk for disease can become significant under extreme environmental conditions.
Accelerated Spirometric Decline in New York City Firefighters With α1-Antitrypsin Deficiency
Banauch et al. 2010. CHEST vol. 138 no. 5 1116-1124