B102-10 The ZZ Family Study: Quantification of Disease Risk in Severe Alpha-1 Antitrypsin Deficiency

Abstract Introduction Alpha-1 antitrypsin deficiency (AATD) is a genetic condition caused by a myriad of SERPINA1 gene variants, resulting in low plasma levels of alpha-1 antitrypsin (AAT). This most commonly results in varying risks of emphysema and liver disease. Homozygosity for the Z allele represents the most common severe AATD genotype. Individuals diagnosed due to the presence of respiratory symptoms commonly exhibit established, irreversible lung disease. Consequently, previous studies which primarily focus on such lung-index cases, are prone to ascertainment bias and inadequate controls. Methods This novel family-based study aims to quantify the risk of lung and liver disease in ZZ individuals, by comparing ZZ lung-index cases with their ‘normal risk’ MM siblings as well-matched controls. We also perform ZZ specific analysis, comparing lung-index versus non-index ZZ individuals. Results We present spirometric, oscillometry, CT thorax and Fibroscan data from more than 110 families and quantify the risk and disease trajectory in ZZ AATD, considering sex, smoking and mode of presentation. As anticipated, ZZ lung-index cases demonstrate significantly higher rates of obstruction, and more advanced GOLD staging than their MM (control) and ZZ non-lung index counterparts. Non-lung index cases, which represent an asymptomatic population, also show higher than anticipated rates of obstruction, indicating a critical need for earlier diagnosis. Considering modifiable risk factors, smoking is the predominant risk, yet occupational exposure is a consistently observed feature within the never-smoking population with obstructive lung disease. Conclusions With trials underway in exciting novel genetic therapies, an accurate understanding of the natural history of disease in the most common severe AATD phenotype is vital. The classic detection method of targeted symptom-based testing misses vital opportunities for disease prevention in individuals with ZZ AATD. This study supports the role for formal family screening pathways, however, high rates of obstruction in our ‘asymptomatic’ family screened population highlights the need for even earlier screening. Early identification prior to the uptake of risk behaviours, chiefly smoking and career selection, is key. Newborn screening in AATD would provide ample opportunity for risk-reducing lifestyle changes and the potential prevention of the development of lung disease in susceptible individuals. It would also identify those within the population who would be eligible for treatment. This abstract is funded by: US Alpha-1 Foundation