Irish Alpha-1 research published last month in “Thorax”, one of the world’s leading respiratory medicine journals, highlights the crucial importance of patient registries for rare conditions.
Patient registries are confidential collections of data that store demographic (e.g. age, sex, height, weight) and medical information on individuals with various health conditions.
The key objectives of the Irish National AATD Registry are to:
- Increase our understanding of Alpha-1 Antitrypsin Deficiency (AATD or “Alpha-1”)
- Inform and improve the clinical care of people with AATD
- Provide early access to new treatments via clinical trials for people with AATD
The Alpha-1 Gene
Firstly, some information about the genetics of Alpha-1 to explain how the condition can be passed on or inherited from parent to child. Every human being carries 2 copies of their alpha-1 antitrypsin (AAT) gene, 1 inherited from their mother and 1 from their father. The types of AAT gene we can inherit include M (normal), S and Z. For those who are MM they have inherited an M from each parent and so have 2 normal copies of the AAT gene. This means the amount of alpha-1 antitrypsin protein in their blood is usually enough to protect their lungs. For those who are ZZ, both copies of the AAT gene are defective and this leads to low levels in the blood with a high risk of lung disease, especially if the person is a smoker. People who are SZ have inherited 1 S copy and 1 Z copy. This type of Alpha-1 has not been well studied to date and so there were gaps in our knowledge about the precise risk of lung disease in people who are SZ type Alpha-1. This is important to know as there are an estimated 12,000 people on the island of Ireland with SZ type Alpha-1 (Figure 1, adapted from Carroll et al., 2011).
Figure 1. Estimated numbers of people with the 3 major forms of AATD in Ireland, ZZ (severe), SZ and MZ (both moderate).
The SZ Registry Study
The SZ registry study, published in “Thorax” in September 2020, analysed the data of 486 people with different types of AATD who are currently participating in the Irish national AATD registry. The data analysed included age, gender, height, weight, smoking history, reason for diagnosis, breathing test results and CT scan findings. The MZ, SZ, and ZZ groups were then compared.
Figure 2. SZ never-smokers: relationship between age (year) and lung function (FEV1pp). No significant decrease in lung function (FEV1pp) with advancing age is observed in the MZ (red line) or SZ (green line) cohorts. No significant difference in the effect of age on FEV1pp between SZ and MZ cohorts is seen, while a significant difference between SZ and ZZ cohorts (red line, p=0.002) is demonstrated.
- Never-smoking MZ and SZ groups demonstrated a normal lung function, and no participants from either MZ or SZ group had emphysema on CT scan (see Figure 2).
- Even when MZ and SZ groups with a history of smoking were compared, no difference in lung function was observed.
- The results of this national registry analysis suggest that SZ-AATD poses a risk for the lung disease chronic obstructive pulmonary disease (COPD) which is similar to MZ, and not the ZZ genotype.
The SZ Family study
The registry study followed on from a family-based study of 44 Irish families containing at least 1 person who was SZ (see Figure 3 for study design). This study was led by Dr. Alex Franciosi and was published in the prestigious American Journal of Respiratory and Critical Care Medicine in July 2020.
This is the first study to compare a large number of SZ individuals with a “normal-risk” group of MM and MS relatives recruited from the same families. The family approach is a powerful method of answering research questions because subjects within the same families have experienced many of the same environmental conditions in childhood and adulthood (for example parental cigarette smoke), particularly so when comparing siblings from the same family.
Sophisticated statistical tools were used to analyse the data with the help of study collaborators Edwin Silverman, Craig Hersh, and Brian Hobbs of Brigham and Women’s Hospital in Boston, USA. There were 166 participants in total who all received breathing and blood tests along with a questionnaire. (https://www.atsjournals.org/doi/10.1164/rccm.202002-0262OC) in July 2020 with the accompanying editorial comment highlighting its importance (https://www.atsjournals.org/doi/10.1164/rccm.2020040922ED).
Figure 3. Study population recruitment for the SZ family study. SZ index cases (1) were invited to take part. Parents (2) and siblings (3) of the index SZ cases were next invited to take part and following testing for Alpha-1 are predicted to include SZ (red) and MS/MM (blue, control or “normal risk”) participants for the comparison cohorts.
- SZ never-smokers demonstrated no increased risk of COPD when compared to their never smoking MM and MS relatives.
- Smoking combines with the SZ genotype to significantly increase the severity of COPD when compared to ever smoking MM and MS relatives. This means that smoking cigarettes (or long periods of exposure to workplace chemicals, dusts and fumes) is required before significant lung disease will develop.
- A history of smoking alone is not associated with greater lung function decline in SZ Alpha-1, suggesting that stopping smoking prevents lung disease from getting worse.
- People with MS genotype of Alpha-1 were no different to people with 2 normal copies of their Alpha-1 gene (MM). This is reassuring for many people who are MS (1 in 10 in Ireland are MS) as this means there is no evidence for any increased risk of lung disease due to this type. This observation has been confirmed in other large studies outside of Ireland.
The SZ registry study and the SZ family study tell us a number of important things (already outlined above) about Alpha-1. However, the most significant finding is that SZ can no longer be considered a severe form of Alpha-1. This is a belief which has persisted for decades. This is a positive message for all those with SZ as the risk of lung disease can be practically eliminated if people never start smoking. For those SZs who are already smoking, if they stop as soon as possible they can prevent any further lung damage. In fact, for all types of Alpha-1 (ZZ, SZ, and MZ) stopping smoking is the most important way to protect your lungs. Stopping vaping is also advised although the recent studies did not contain enough people using vaping or e-cigarette devices to conclusively prove a risk of lung disease.
We are grateful to each and every person who took part in either the SZ family study or the national Alpha-1 registry. Without your help none of this research would have been possible. We are also grateful to Alpha-1 Foundation USA for their constant support and encouragement, as well as funding for the SZ family study (Research Grant 2017 “Clarifying the Risk of Lung Disease in SZ AATD”). A special thank you to the HSE who continue to fund the national AATD targeted detection programme (https://www.alpha1.ie/who-weare/national-screening-programme). Without this funding, the vast majority of people with Alpha-1 in Ireland would not have received a diagnosis. Finally, we would like to sincerely thank Kitty O’Connor, Laura Fee, Margaret Molloy, Siobhán Lee, and Geraldine O’Brien, former staff of Alpha-1 Foundation Ireland for invaluable help with registry recruitment and data collection over the past 14 years.
Contact Details: For more information on Alpha-1 please contact Alpha-1 Foundation Ireland on: 01-8093871, 01-8093876, or email: firstname.lastname@example.org
Special Acknowledgment: We are grateful to Michelle Hughes (person diagnosed with AATD) for her help in writing and reviewing this article to make it less technical and more readable. Our goal is to ensure the research can be understood by as wide an audience as possible.
- The prevalence of alpha-1 antitrypsin deficiency in Ireland. Carroll TP, O’Connor CA, Floyd O, McPartlin J, Kelleher DP, O’Brien G, Dimitrov BD, Morris VB, Taggart CC, McElvaney NG. Respir Res. 2011 Jul 13;12(1):91. https://respiratory-research.biomedcentral.com/articles/10.1186/1465-9921-12-91.
- SZ alpha-1 antitrypsin deficiency and pulmonary disease: more like MZ, not like ZZ. Franciosi AN, Carroll TP, McElvaney NG. Thorax. 2020 Sep 11:thoraxjnl-2020-215250. https://thorax.bmj.com/content/early/2020/09/11/thoraxjnl-2020-215250.
- Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency. Franciosi AN, Hobbs BD, McElvaney OJ, Molloy K, Hersh C, Clarke L, Gunaratnam C, Silverman EK, Carroll TP, McElvaney NG. Am J Respir Crit Care Med. 2020 Jul 1;202(1):73-82. https://www.atsjournals.org/doi/10.1164/rccm.202002-0262OC.
- Alpha-1 Antitrypsin Deficiency: The Learning Goes On. Stockley RA. Am J Respir Crit Care Med 2020 Jul 1;202(1):6-7. https://www.atsjournals.org/doi/10.1164/rccm.202004-0922ED.