Yes, alpha-1 antitrypsin deficiency (AATD) is entirely genetic. It’s caused by mutations in the SERPINA1 gene on chromosome 14, which provides instructions for making a protein called alpha-1 antitrypsin. This protein protects your lungs from damage by blocking an enzyme that would otherwise break down lung tissue. When the gene is mutated, your body either makes too little of the protein or makes a misfolded version that gets stuck in liver cells instead of reaching your lungs.
The Gene Behind the Condition
The SERPINA1 gene comes in several variants, labeled with letters. The normal version is called M, and about 90% of people of Northern European descent carry two copies of it (MM genotype), giving them normal protein levels. The two most common problem variants are S and Z. The S variant produces moderately low levels of alpha-1 antitrypsin, while the Z variant produces very little.
You inherit one copy of the SERPINA1 gene from each parent, so your genotype is a two-letter combination. The most severe form of the condition occurs in people with two Z copies (ZZ genotype). People with one normal copy and one abnormal copy, like MZ or MS, are carriers. Their protein levels are lower than normal but generally still high enough to offer protection.
How It’s Inherited
AATD follows what geneticists call a codominant inheritance pattern. This means both copies of the gene are active at the same time. If you carry one M allele and one Z allele, your body makes some normal protein and some defective protein, landing you somewhere in between fully healthy and fully affected. This is different from conditions where one bad copy is completely masked by a good one.
If both parents are carriers (each with one Z allele), every pregnancy carries a 25% chance of producing a child with the ZZ genotype, a 50% chance of producing another carrier, and a 25% chance of producing a child with two normal copies. Because of this math, siblings of someone diagnosed with AATD face the highest risk among family members, with at least a 25% chance of also having the condition. Genetic testing is typically recommended for siblings first, while parents, children, and more distant relatives are often referred for genetic counseling to weigh the benefits and risks of testing.
What Different Genotypes Mean for Your Health
The combination of alleles you carry determines how much functional protein circulates in your blood, which in turn shapes your risk for lung and liver disease.
- MM: Normal. Full protein production, no increased risk.
- MS or MZ (carriers): Lower but generally sufficient protein levels. Most carriers never develop symptoms related to the deficiency.
- SS: Moderately reduced protein levels, but typically enough to prevent serious lung disease.
- SZ: Noticeably reduced levels. Some individuals develop lung or liver problems, particularly with additional risk factors like smoking.
- ZZ: Severely reduced levels. High risk of emphysema and liver disease.
People with the ZZ genotype face the greatest health consequences. About 10% of infants with the condition develop liver disease, often showing up as jaundice. In adults, roughly 15% develop cirrhosis from scar tissue building up in the liver. The lung damage typically appears as early-onset emphysema, often showing up in the 30s or 40s rather than the 60s or 70s as it does in smoking-related emphysema.
Carriers Are Not Risk-Free
For years, the MZ genotype was considered clinically insignificant. Newer evidence paints a more nuanced picture. A large Danish study followed over 9,000 adults for 21 years and found that MZ individuals had 50% more COPD diagnoses, hospitalizations, and deaths from COPD compared to people with the normal MM genotype, after adjusting for age, sex, and smoking history.
A separate meta-analysis estimated that MZ carriers face roughly 1.5 to 3 times the odds of developing COPD compared to MM individuals, depending on the study design. The risk is most pronounced in MZ carriers who smoke. A multicentre study across Europe and North America found that MZ individuals had more emphysema visible on CT scans and measurably lower lung function than their MM counterparts. The bottom line: carrying a single Z allele doesn’t guarantee problems, but it removes some of the buffer your lungs rely on, especially if you smoke or are exposed to dust, fumes, or other lung irritants.
How Common Is It
AATD is one of the most common genetic conditions in people of European descent, though it remains widely underdiagnosed. An estimated 235,000 people worldwide carry the ZZ genotype. About half of them live in Europe, 37% in the Americas, 9% in Asia, and 3% in Australasia. Many go undiagnosed for years because the symptoms, particularly shortness of breath and reduced exercise tolerance, overlap with ordinary asthma or smoking-related lung disease. The average person with AATD sees multiple doctors and waits years before receiving the correct diagnosis.
Treatments Targeting the Genetic Cause
Standard treatment today involves regular infusions of alpha-1 antitrypsin protein derived from donated blood plasma. This replaces what the body can’t make on its own and slows lung damage, but it doesn’t fix the underlying genetic problem and requires ongoing treatment.
Several experimental therapies are now targeting the condition at its genetic root. One approach uses RNA interference to silence the defective gene in liver cells, preventing them from producing the misfolded Z protein that causes liver damage. A drug called fazirsiran has shown significant reductions in abnormal protein buildup in the liver, along with improvements in liver inflammation and scarring, in phase II trials.
Even more ambitious are gene-editing therapies designed to correct the mutation itself. An early-phase trial of one such treatment, BEAM-302, has shown that a single intravenous dose can produce durable, dose-dependent increases in functional protein while reducing the harmful misfolded version. Other approaches using RNA editing to directly fix the genetic code are also in early clinical trials. These therapies are still years from widespread availability, but they represent a shift from managing symptoms to potentially correcting the condition at its source.
Testing and Family Planning
Diagnosis starts with a simple blood test measuring your alpha-1 antitrypsin level. If the level is low, genetic testing identifies which alleles you carry. This matters not just for your own treatment plan but for your family. Because the condition is inherited, one diagnosis often leads to the discovery of additional affected or carrier family members.
If you’re a known carrier considering having children, the risk to your future child depends entirely on your partner’s genotype. If your partner is also a carrier, each pregnancy carries a meaningful chance of producing a child with two abnormal copies. Genetic counseling can map out these probabilities and help you understand what they mean in practical terms.