High Prevalence of Alpha-1 Antitrypsin Deficiency in Ireland

A new study which was presented at the Irish Thoracic Society annual scientific meeting for 2008 held in Belfast in November highlighted the high prevalence of Alpha-1 in Ireland.

The Prevalence of Alpha-1 Antitrypsin Deficiency in Ireland

Authors: T. CARROLL, O. FLOYD, C. O’CONNOR, J. McPARTLIN*, C. TAGGART, R. COSTELLO, S. J. O’NEILL and N. G. McELVANEY

Institution: Department of Respiratory Research, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. *Trinity Biobank, Institute of Molecular Medicine, Trinity Centre, St James's Hospital, Dublin.

Rationale: AAT deficiency is a hereditary autosomal codominant disorder, resulting from mutations in the AAT gene, and classically presents with emphysema and liver disease.  The most common phenotype presenting with clinical evidence of AAT deficiency is the Z phenotype, resulting in decreased levels of circulating AAT due to retention of the aberrantly folded protein in the liver.  It is unclear whether the carrier status confers increased risk for disease.  Demographic studies indicate that AAT deficiency is under-diagnosed and prolonged delays in diagnosis are common.  World Health Organisation guidelines advocate targeted detection programmes of patients with COPD and asthma. 

Methods: A combination of serum AAT measurement by radial immunodiffusion (RID) or nephelometry, phenotyping by isoelectric focussing (IEF), and genotyping of DNA isolated from dried blood spot samples was used to identify AAT variants.   

Results: 2,000 individuals with COPD or asthma attending respiratory outpatient clinics were screened in a national targeted detection programme.  A further 1,000 healthy individuals in the general population were also screened for S and Z alleles in a pilot study.  The targeted programme identified 43 ZZ, 28 SZ, 7 SS, 195 MZ, 158 MS, and 6 MI individuals, as well as several other rarer phenotypes.  The pilot screen of 1,000 healthy individuals identified 98 MS, 46 MZ, 2 SZ, and a single SS case. 

Conclusions: The percentage of deficiency alleles detected in the targeted population was higher than anticipated from studies in other populations.  The S variant, thought common to the Iberian Peninsula, was detected with unusually high frequency in both targeted and the general population.  Several other rarer phenotypes were also detected.  Further analysis will reveal whether these phenotypes predispose individuals to lung disease.   

Acknowledgements: Alpha One Foundation Ireland, Alpha-1 Foundation U.S., Irish Department of Health and Children, Royal College or Surgeons in Ireland and Talecris Biotherapeutics.

 

American Thoracic Society Annual Conference 2008

Researchers from the Department of Medicine at RCSI Beaumont Hospital attended the American Thoracic Society Annual Conference 2008 recently to present some of their findings in the area of Alpha-1.

Title: Evidence for the Activation of the Unfolded Protein Response (UPR) in Monocytes from Alpha-1 Antitrypsin Deficient Individuals

Author: T. CARROLL, C. GREENE, C. TAGGART, S. J. O’NEILL and N. G. McELVANEY

Institution: Department of Respiratory Research, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.

Rationale: Alpha-1 antitrypsin (AAT) is a serine protease inhibitor synthesised mainly in the liver and functions as the most important antiprotease in the lung. AAT deficiency (AATD) is a hereditary disorder resulting from mutations in the AAT gene and presents with emphysema in young adults and liver disease in childhood. The most common phenotype presenting with clinical evidence of AATD is the Z phenotype, with decreased levels of circulating AAT due to retention of the aberrantly folded protein in the endoplasmic reticulum (ER) of hepatocytes. AAT is also synthesised in monocytes, and locally produced within the lung by alveolar macrophages and epithelial cells. Having shown previously that ER stress pathways are activated in the liver we sought to elucidate whether misfolded Z AAT can induce ER stress pathways, specifically the UPR, in monocytes from AATD patients.

Methods: Monocytes were isolated from healthy individuals and from AATD ZZ patients. Immunoblotting and quantitative RT-PCR were used to investigate UPR activation.

Results: We show that elements of the UPR, such as the chaperones glucose-regulated protein 78 and 94 (grp78 and grp94), the activated transcription factors 3 and 4 (ATF3 and ATF4) and C/EBP-homologous protein (CHOP), can be activated in monocytes by treatment with Thapsigargin, a known ER stress inducer. To further evaluate UPR activation in vivo we show the transcription factor X-box binding protein-1 (XBP-1) is spliced and activated in ZZ monocytes, and not in monocytes from normal (MM) individuals. In addition, we demonstrate the phosphorylation of eukaryotic initiation factor 2α (eIF2α) in ZZ monocytes, responsible for shutting down global protein synthesis, the first step in the UPR. Finally, we show that the chaperones grp78 and grp94, and components of the ER-associated degradation pathway (ERAD) are induced in ZZ monocytes, and not in MM monocytes.

Conclusions: Monocytes produce AAT, representing another source of misfolded protein. We have shown for the first time that the unfolded protein response is activated in monocytes from AATD patients, probably by misfolded Z AAT. This UPR activation may impair monocyte function and contribute to the pro-inflammatory milieu of the AATD lung.

Acknowledgements: Alpha One Foundation Ireland, Royal College of Surgeons of Ireland, and the Department of Health and Children.

 

Award to Study Immune Cell Function in Alpha-1 Antitrypsin Deficiency

Researchers in the Department of Medicine at RCSI Beaumont Hospital have been awarded a prestigious European award to study cells of the immune system from people with alpha-1 antitrypsin deficiency (Alpha-1).

European Alpha-1-Antitrypsin Laurell’s Training Award (eALTA) is given to young investigators around Europe who are trying to understand more about Alpha-1 and its causes.

Project Description:
Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder characterised by lung and liver manifestations. The most common form of AAT deficiency occurs due to the Z mutation, which encodes a glutamine to lysine substitution at position 342 of the AAT protein. This mutation causes the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER) of hepatocytes. The liver disease is believed to be associated with intracellular accumulation of AAT in the ER leading to ER stress responses whilst the lung disease is due to decreased levels of the AAT antiprotease in the airways, thereby facilitating proteolytic damage. In addition to hepatocytes, AAT is also expressed by other cell types including monocytes and neutrophils. We aim to demonstrate that ER accumulation of Z AAT in monocytes and neutrophils impacts on specific phenotypes and functions of these immune cells, contributing to the overall inflammatory disease process.

The project will run for 12 months from September 2007.

What is Alpha-1 Antitrypsin?
Alpha-1 antitrypsin is a vital protein produced by the liver to protect the lungs. It provides protection from the harmful effects of infections and inhaled irritants, particularly tobacco smoke. It can be easily measured by a simple blood test. 
What is Alpha-1 Antitrypsin Deficiency?
Alpha-1 antitrypsin deficiency (Alpha-1) is a genetic condition which, after cystic fibrosis, is the commonest genetic disorder in Ireland. It severely affects more than 15,000 people, with another 250,000 carriers also at risk of lung and liver disease on the island of Ireland. It is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD).
How Do I Get Tested?
The Alpha One Foundation provides free testing for Alpha-1 as part of a national screening programme which is funded by the HSE. For more details ring 01-8093871 or email alpha1@rcsi.ie.