AATD: Genotypes, phenotypes, AAT levels, and clinical risk

Author: Sanofi

Editorial Team

Alpha-1 antitrypsin deficiency (AATD) is often introduced as a genetic condition, but genetics alone do not tell the whole story

Genotype identifies inherited risk¹
Phenotype reflects the protein variant(s) that are present¹
AAT levels quantify impact¹
Risk is multifactorial and can be influenced by lifestyle and environmental factors^2-4
Clinical outcomes emerge from the interaction of all the factors^1-4

Genotype, phenotype, and AAT levels serve different purposes

AATD is inherited in a codominant pattern through variants in the SERPINA1 gene.^1,5 The most common SERPINA1 alleles include M, S, and Z (often referred to as PiM, PiS, and PiZ).^1,5 The combination of alleles received from each parent creates a patient’s genotype.¹ The measurable expression of these alleles based on the characteristics of the AAT protein is known as the patient’s phenotype.¹

Pathogenic variants in the SERPINA1 gene may lead to low or undetectable levels of the serum AAT protein.^6,7 Genotype and AAT levels primarily contribute to the risk of lung decline in AATD.¹ Risk of accelerated lung decline is exacerbated by factors such as a patient's environment (eg, pollutants and respiratory infections) and lifestyle (eg, smoking).^2-4 Genotype can be determined through SERPINA1 genetic testing, which is used to confirm a diagnosis of AATD and predict AAT protein levels.^1,5,8 It is recommended to conduct genetic testing in parallel with AAT protein level testing, which can assess severity.⁹

Protein phenotypes across different genotypes in AATD

M allele: Baseline, normal function^1,5

Results in normal AAT
Not associated with increased lung or liver risk
Most common allele in the general population

S allele: Mild to moderate deficiency^1,5

Results in less AAT than M, but significantly more than Z
Polymerizes slowly, so the risk of liver involvement is low
Lung risk increases when paired with Z (eg, SZ genotype)

Z allele: Highest clinical impact^1,5

Severely reduced circulating AAT levels
Misfolded AAT accumulates in hepatocytes, contributing to liver injury
ZZ individuals have the highest risk for both lung disease and liver complications
Most frequent genetic risk for airflow obstruction

Q0/Null allele: No AAT production^1,5

No detectable AAT in circulation
High lung risk due to complete absence of AAT
Not associated with liver disease because no misfolded protein accumulates

Risk spectrum of AATD genotypes with expected AAT levels

Risk Spectrum

	MM	MZ	SZ	ZZ
	Normal⁵	Mild-to-moderate AAT deficiency⁵	Moderate AAT deficiency^5,10	Severe AAT deficiency⁵
Plasma AAT Levels	20-53 µM¹⁰ or 100-220 mg/dL	15-42 µM¹⁰ or 66-120 mg/dL	10-23 µM¹⁰ or 45-80 mg/dL	3.4-7 µM¹⁰ or 10-40 mg/dL
Mechanism	Balanced AAT and neutrophil elastase activity⁶	Variable AAT levels and partial or relative imbalance between AAT and neutrophil elastase^1,5 MZ individuals who smoke have a significantly increased risk for impaired lung function vs MZ nonsmokers¹²	Greater degree of imbalance between AAT and neutrophil elastase^1,5,12	Severe imbalance between AAT and neutrophil elastase^1,5
Implication	No AATD lung/liver disease⁵	Uncontrolled protease activity could lead to increase in destruction of elastin^1,5 Potentially faster lung function/density decline vs MM¹ Increased vasculitis and other inflammatory activity^1,14	Increased risk of emphysema¹⁰ Increased vasculitis and other inflammatory activity^1,14 Uncontrolled protease activity could lead to destruction of elastin^1,5	High risk of emphysema^1,10 Neutrophilic airway inflammation¹³ Hepatic involvement¹³ Uncontrolled protease activity could lead to increase in destruction of elastin^1,5 Increased vasculitis and other inflammatory activity^1,14
Key Takeaway	Normal, no AATD⁵	Some increased risk^1,5	Increased risk^10,11	Maximum risk^5,10

The lower AAT levels are, the higher the risk of emphysema¹⁰

Below-normal levels of AAT may lead to uninhibited neutrophil elastase in the lungs.^15-18 Normally, AAT protein inhibits neutrophil elastase, thus preventing elastin degradation.¹⁵ But without sufficient levels of the AAT protein, elastase activity is unchecked and excess proteolysis of alveolar elastin can occur.^15,16,18 This can cause damage to the alveoli, compromising their structure and function.^15,16,18 The resulting loss of lung elasticity and airflow limitation may contribute to the development of emphysema.^15,16,18

Historically, the putative threshold has been defined as 11 μM, while the normal range is 20 to 53 μM.^10,19 However, pulmonary risk exists along a continuum rather than at a strict threshold, with the likelihood of lung disease generally increasing as AAT levels decrease.¹⁰ Additionally, risk is multi-factorial and can be influenced by lifestyle and environmental factors.^2,3 Understand other pulmonary manifestations of AATD.

Range of plasma AAT levels based on allele combination¹⁰

^aAAT levels may also be measured as mg/dL. MM: 90-200 mg/dL; MZ: 66-120 mg/dL; SZ: 45-80 mg/dL; ZZ: 10-40 mg/dL.^10,20
^bThis is not a comprehensive list of genotypes. Patients may also be affected by additional genotypes, including F, I, and Q0/null.

Other factors that can affect clinical outcomes in AATD

Risk is multifactorial and influenced by both genetic and environmental factors.² In addition to genotype and AAT levels, behavioral, environmental, and lifestyle factors may contribute to disease risk and progression.² Smoking, air pollution, and occupational inhalants are associated with^2,19,21: 

Accelerated emphysema progression
Increased frequency and duration of COPD exacerbations
More rapid decline in lung function

Respiratory infections may further exacerbate lung injury and contribute to progressive loss of lung function over time.⁴ Recognizing AATD may enable implementation of risk-reduction strategies.^19,22,23

FAQs

Can two AATD patients with the same genotype have different AAT levels?

Can AAT levels change over time?

Do normal AAT levels rule out AATD?

References: 1. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. 2. Torres-Durán M, Lopez-Campos JL, Barrecheguren M, et al. Alpha-1 antitrypsin deficiency: outstanding questions and future directions. Orphanet J Rare Dis. 2018;13(1):114. doi:10.1186/s13023-018-0856-9 3. Wang T, Shuai P, Wang Q, et al. α‑1 Antitrypsin is a potential target of inflammation and immunomodulation (Review). Mol Med Rep. 2025;31(4):107. doi:10.3892/mmr.2025.13472 4. Kokturk N, Khodayari N, Lascano J, et al. Lung inflammation in alpha‑1‑antitrypsin deficient individuals with normal lung function. Respir Res. 2023;24(1):40. 5. Feitosa PHR, de Oliveira Castellano MVC, da Costa CH, et al. Recommendations for the diagnosis and treatment of alpha-1 antitrypsin deficiency. J Bras Pneumol. 2024;50(5):e20240235. doi:10.36416/1806-3756/e20240235 6. Cazzola M, Stolz D, Rogliani P, Matera MG. α1-Antitrypsin deficiency and chronic respiratory disorders. Eur Respir Rev. 2020;29(155):190073. doi:10.1183/16000617.0073-2019 7. Karatas E, Bouchecareilh M. Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathways. Int J Mol Sci. 2020;21(4):1493. doi:10.3390/ijms21041493 8. Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016;3(3):668-682. 9. Abboud RT, Nelson TN, Jung B, et al. Alpha1-antitrypsin deficiency: a clinical-genetic overview. Appl Clin Genet. 2011;4:55-65. 10. Mulkareddy V, Roman J. Pulmonary manifestations of alpha 1 antitrypsin deficiency. Am J Med Sci. 2024;368(1):1-8. 11. Molloy K, Hersh CP, Morris VB, et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am J Respir Crit Care Med. 2014;189(4):419-427. 12. McElvaney GN, Sandhaus RA, Miravitlles M, et al. Clinical considerations in individuals with α1-antitrypsin PI*SZ genotype. Eur Respir J. 2020;55(6):1902410. doi:10.1183/13993003.02410-2019 13. Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. 1996;154(6)(pt 1):1718-1725. 14. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259. 15. University of Utah Health. Alpha-1 antitrypsin deficiency. Accessed February 6, 2026. https://learn.genetics.utah.edu/content/genetics/alpha1/ 16. Viglio S, Iadarola P, D’Amato M, Stolk J. Methods of purification and application procedures of alpha1 antitrypsin: a long-lasting history. Molecules. 2020;25(17):4014. 17. Abdulkarim A, Craig TJ. Alpha-1 antitrypsin mutation (archived). In: StatPearls [Internet]. StatPearls Publishing; September 26, 2022. Accessed February 20, 2026. https://www.ncbi.nlm.nih.gov/books/NBK482180 18. Kalfopoulos M, Wetmore K, ElMallah MK. Pathophysiology of alpha-1 antitrypsin lung disease. In: Borel F, Mueller C, eds. Alpha-1 Antitrypsin Deficiency: Methods in Molecular Biology. Humana Press; 2017:9-20. 19. Barjaktarevic I, Campos M. Management of lung disease in alpha-1 antitrypsin deficiency: what we do and what we do not know. Ther Adv Chronic Dis. 2021;12:49-63. 20. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443-1455. 21. Bernhard N, Lepper PM, Vogelmeier C, et al. Intensive smoking diminishes the differences in quality of life and exacerbation frequency between the alpha-1-antitrypsin deficiency genotypes PiZZ and PiSZ. Respir Med. 2017;130:1-8. 22. Craig TJ, Corbett ML, Meadows JA. Improving detection of alpha-1 antitrypsin deficiency: role of the allergist. J Allergy Clin Immunol Pract. 2023;11(8):2348-2354. 23. Beiko T, Strange C. Anxiety and depression in patients with alpha-1 antitrypsin deficiency: current insights and impact on quality of life. Ther Clin Risk Manag. 2019;15:959-964.

MAT-US-2609353-v1.0-09/2026. Last Updated: September 2026