Alpha-1 antitrypsin deficiency: Which is important phenotype, level, activity or all three?

Alpha-1 antitrypsin (AAT) deficiency (AATD) is generally regarded as a rare condition but more recently, evidence points towards it being a condition that is relatively common but rarely diagnosed. The most severe form of this genetic disorder, where people carry two bad AAT genes (Z) is known as ZZ-AATD and this affects around 2000 people in Ireland. People with ZZ-AATD are at high risk of developing emphysema, a destructive irreversible lung disease, where the ability to get oxygen from the air into the bloodstream is reduced. If unchecked this eventually leads to respiratory failure and death. In addition there are over 250,000 people in Ireland who have one bad AAT Z gene and one normal M gene, and they are called MZ heterozygotes. MZs have lower than normal levels of AAT in their blood and if they smoke, have a greater risk of developing lung disease compared to smokers who have two good AAT genes (MM). Yet another heterozygote group are SZ individuals who get an abnormal Z gene from one parent and an abnormal S gene from the other parent. They are also predisposed to lung disease, particularly if they smoke. There are other heterozygotes in Ireland such as IZ or FZs, but their risk remains uncertain due to their low numbers diagnosed to date. In all heterozygotes who carry the Z gene have AAT blood levels that are lower than normal levels and this results in low AAT levels in the lung. In addition to the levels being low, the Z, S, I and F forms of AAT are less able to protect the lung against inflammation than the M form. Therefore, in these groups there is a double hit whereby there are low levels of AAT in the lung and the type of AAT that is there is ineffective. To compound this, cigarette smoke further impairs the ability of AAT to protect the lung showing why AATD smokers do so badly but also suggesting that even MM smokers are at risk of developing emphysema. Added to all this is the fact that AAT levels vary greatly within the different types of AATD and during times of infection. In this study we will evaluate how the levels and activity of AAT in blood determines the predisposition to lung disease and other inflammatory processes. We will also determine how AATD heterozygotes and MM smokers react to infection and whether the AAT they produced during infection is as effective as that produced by non- smoking MMs.

Award Date
20 June 2014
Award Value
Principal Investigator
Ms Kitty O'Connor
Host Institution
Alpha One Foundation
MRCG-HRB Joint Funding Scheme