PI*SS Genotype Linked to Decreased Risk of AATD-Related Lung Disease

Findings from a recent study are providing clinicians with an overview of differences in the risk of alpha-1 antitrypsin deficiency (AATD)-related lung disease in patients with different genotypes, namely PI*SS, PI*ZZ, and PI*SZ.¹

Leveraging data from the European Alpha-1 Antitrypsin Deficiency Research Collaboration (EARCO) international registry, the study found a lower risk of lung disease among patients with the PI*SS genotype compared to those with the PI*ZZ genotype, although no significant differences were observed compared to the PI*SZ genotype.¹

An inherited genetic disorder, AATD is characterized by genetic changes attributed to mutations within the SERPINA1 gene causing low levels of AAT or no AAT in the lungs and/or a buildup of AAT in the liver. According to the American Lung Association, an estimated 80,000 to 100,000 people are living with AATD in the United States, putting them at greater risk for developing chronic obstructive pulmonary disease (COPD). However, the risk of developing lung disease among different variants is not well understood.^2,3

“The risk for developing AATD-related emphysema is well established for the PI*ZZ genotype, and an increased risk has been demonstrated for PI*SZ, particularly in smokers,” Marc Miravitlles, MD, a pulmonologist and senior researcher at the Vall d’Hebron University Hospital and the Vall d’Hebron Research Institute in Spain, and colleagues wrote.¹ “However, it remains unclear for other genotypes, such as PI*SS.”

To investigate the risk of lung disease associated with the PI*SS genotype compared with the PI*SZ or PI*ZZ genotypes, investigators leveraged data from the EARCO registry, an international, observational, multicenter study including individuals with AATD. In the present study, investigators examined baseline data from patients included in EARCO from February 1, 2020, to March 1, 2023. Patients with genotypes other than PI*SS, PI*SZ, or PI*ZZ were excluded from the analysis, as were those currently under augmentation therapy and those with missing information related to genotype or augmentation therapy status.¹

In total, the study population included 1007 individuals with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). Investigators assessed patients’ demographic data; proteinase inhibitor genotype; comorbidities; lung function; respiratory symptoms; presence of respiratory disease (including emphysema, COPD, chronic bronchitis, asthma, and bronchiectasis); and their exacerbations. Initially, they compared unmatched patients with the PI*SS genotype to those with the PI*ZZ and PI*SZ genotypes. Then, they used propensity score matching with a 1:3 nearest-neighbor approach to compare the characteristics of PI*SS with the controls, accounting for confounding variables.¹

PI*SS and PI*ZZ

In the PI*SS group, 58.9% of patients were male with a mean age of 59.2 years and as many as 71.4% had lung disease, with COPD being the most frequent (41.1%) and with a mean forced expiratory volume in one second (FEV1) below 80% of 83.4% (±29.9%). Investigators pointed out patients in the PI*SS group were significantly older than those with PI*ZZ (59.2±13.9 vs 54.0±14.4 years; P = .012), were less frequently never smokers (23.2% vs 51.4%; P <.001), and had greater smoking consumption (34.8±30.7 vs 14.6±12.9 pack years; P <.001). However, individuals with the PI*SS genotype less frequently had emphysema (23.2% vs 42.8%; P = .005), were older at symptom onset (49.6±19.4 vs 43±15.7 years; P = .010), and were older at diagnosis of the deficiency (54.4±16.6 vs 42.5±18 years; P <.001).¹

Further matched analysis showed similar results, revealing a lower disease burden in individuals with PI*SS and highlighting significant differences in lung disease (71.4% vs. 82.2%; P = .037), COPD (41.4% vs 60%; P = .002) and emphysema (23.2% vs 51.9%; P <.001). Additionally, patients with the PI*SS genotype were older at diagnosis (54.4±16.6 vs 44.6±16.7 years of age; P = .006). Lung function parameters were significantly better preserved in PI*SS subjects and they had less frequent exacerbations, a lower level of dyspnoea, a better body mass index, obstruction, dyspnoea and exacerbations (BODEx) index, and better quality of life compared to individuals with PI*ZZ.¹

PI*SS and PI*SZ

In the unmatched analysis, patients in the PI*SS group were older than those with PI*SZ (59.2±13.9 vs 52.2±16.2 years; P = 0.002) and were less frequently never smokers (23.2% vs 46.8%; P = .002). Patients with PI*SS more frequently had lung disease (71.4% vs 53.9%; P = .014), particularly COPD (41.1% vs 22.6%; P = .003) and chronic bronchitis (7.1% vs 1.6%; P = .030). Regarding lung function, only FEV1/FVC significantly differed, with lower values for PI*SS (0.67±0.17 vs 0.73±0.16; P = .008).¹

Of note, the matched analysis of PI*SS and PI*SZ individuals did not reveal significant differences in lung disease, including COPD, emphysema, bronchiectasis, and asthma, nor were there significant differences in the age at diagnosis, the Charlson comorbidity index, lung function, exacerbations, dyspnoea, quality of life indices, or physical activity. However, investigators pointed out AAT levels were significantly increased in PI*SS compared to PI*SZ subjects (81±23.9 mg/dL vs 54.3±17 mg/dL; P <.001).¹

Investigators mentioned several potential limitations to these findings, including additional confounders; selection bias; the inability to compare PI*SS with a matched cohort of PI*MM individuals; the small number of individuals with PI*SS included in the study; and the lack of prospective follow-up data detailing the risk of exacerbations and lung function decline associated with the PI*SS genotype.¹

“The results of our study suggest that subjects with the PI*SS genotype have a significantly lower risk of lung disease compared with the PI*ZZ genotype, but after careful matching accounting for the most important known confounders we did not find evidence for any significant difference in the risk of lung disease between the PI*SS and PI*SZ genotypes,” investigators concluded.¹

References

1. ^{Martín, T., Guimarães, C., Esquinas, C. et al. Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project. Respir Res 25, 260 (2024). https://doi.org/10.1186/s12931-024-02879-y}
2. ^{Cleveland Clinic. Alpha-1 Antitrypsin Deficiency. Diseases & Conditions. October 18, 2022. Accessed July 8, 2024. https://my.clevelandclinic.org/health/diseases/21175-alpha-1-antitrypsin-deficienc}
3. ^{American Lung Association. Learn About Alpha-1 Antitrypsin Deficiency. Lung Health & Diseases. October 2, 2023. Accessed July 8, 2024. https://www.lung.org/lung-health-diseases/lung-disease-lookup/alpha-1-antitrypsin-deficiency/learn-about-alpha-1-antitrypsin-defiency}