Can We Predict Who Will Develop Aspergillosis? Genetics, Epigenetics and the Search for Individual Risk

Everyone inhales Aspergillus spores, usually every day, but only a small minority of people develop aspergillosis. Asthma, bronchiectasis, previous tuberculosis, lung cavities, transplantation and immune-suppressing treatment explain much of this difference—but not all of it.

Why does one person develop allergic bronchopulmonary aspergillosis (ABPA), another develop chronic pulmonary aspergillosis (CPA), and most people remain unaffected?

Researchers increasingly think that part of the answer lies in inherited differences affecting the airway lining, fungal recognition, immune-cell behaviour and inflammation. Epigenetics—the processes that alter how genes behave without changing the DNA sequence—may add another layer by connecting genetics with environment, exposure, inflammation and treatment.

Manchester has played an important part in this research. By combining patient DNA with studies of macrophages, airway cells, fungal load and gene editing, researchers have begun to show not merely which genetic variants are associated with aspergillosis, but how some of them might alter what happens when a fungal spore reaches the lung.

The central puzzle: exposure is common, disease is rare

Aspergillus spores are found in soil, compost, dust, decaying vegetation and indoor and outdoor air. Healthy lungs normally trap and remove inhaled spores before they can grow.

Several protective systems work together:

• mucus and moving airway cilia remove inhaled particles;
• airway epithelial cells form a protective barrier and detect fungal material;
• macrophages engulf spores that reach the air sacs;
• neutrophils attack spores that begin to germinate;
• antibodies, complement proteins and immune signals coordinate the response.

Aspergillosis becomes more likely when one or more of these defences is impaired—or when the immune response becomes excessive and allergic rather than protective.

Even so, people with apparently similar risk factors can have very different outcomes. Many people with severe asthma never develop ABPA. Many people with old tuberculosis cavities never develop CPA. Some transplant recipients develop invasive aspergillosis while others undergoing similar treatment do not.

This unexplained variation is what susceptibility genetics is trying to understand.

Genetic susceptibility is not genetic destiny

There is no single “aspergillosis gene”. Researchers instead distinguish between two broad forms of inherited risk.

Rare, high-impact variants

Rare harmful variants can cause recognised immune disorders such as chronic granulomatous disease and some hyper-IgE or combined immune-deficiency syndromes. These can substantially impair antifungal defence and occasionally lead to severe or invasive aspergillosis.

These disorders are important, but they do not explain most cases of ABPA or CPA. They are covered in more detail in our article Aspergillosis, immunity, and risk.

Common susceptibility variants

Common variants normally have much smaller effects. A variant might make the airway barrier slightly less effective, alter the removal of spores or make allergic inflammation more likely. On its own, the difference may cause no illness.

Risk may emerge only when several factors coincide:

• a susceptible airway or immune response;
• asthma or existing structural lung disease;
• corticosteroids or another immune-modifying treatment;
• repeated or heavy fungal exposure;
• ageing, infection, smoking or other acquired influences.

A susceptibility variant changes probability, not destiny. Having one does not mean that someone has aspergillosis or will develop it.

The Manchester genetics story

In 2014, University of Manchester researchers announced an ambitious project to investigate genetic susceptibility to CPA using next-generation exome sequencing.

An exome represents the protein-coding part of a person’s DNA. Although it accounts for only a small proportion of the complete genome, it contains many of the variants most likely to alter the structure or function of proteins.

The original project planned to examine approximately 160 patients from across the UK. Earlier research had concentrated on a limited number of immune genes. Exome sequencing allowed researchers to search much more widely and investigate pathways that might not previously have been connected with fungal disease.

Manchester’s wider patient and research collections have subsequently supported studies involving CPA, ABPA, fungal asthma and suitable control groups. The most informative discoveries have come from combining genetic findings with laboratory experiments.

This is important because a statistical association alone does not prove that a variant causes disease. Researchers need to show that the variant changes the behaviour of a relevant cell or biological pathway.

ZNF77: how the airway lining can encourage fungal growth

One of the clearest discoveries from Manchester’s exome work involved a variant called rs35699176 in ZNF77.

ZNF77 is a transcription factor, meaning that it helps regulate the activity of other genes. Researchers suspected that the variant might affect the bronchial epithelium—the layer of cells lining the airways.

Using CRISPR gene editing, the Manchester team recreated the variant in human bronchial epithelial cells. The altered cells:

• failed to form a normal, tightly joined epithelial layer;
• produced abnormal amounts of extracellular-matrix and adhesion proteins;
• allowed more Aspergillus fumigatus spores to attach;
• permitted earlier spore germination;
• supported greater subsequent fungal growth;
• produced altered inflammatory signals following fungal exposure.

Some extracellular-matrix proteins appeared to act rather like glue, making it easier for spores to adhere to the airway surface. Once attached, the spores germinated earlier and produced more extensive hyphal growth.

The researchers then looked for the same effect in patients. In the relatively small groups studied:

• people carrying the variant had approximately 15 times more A. fumigatus DNA in bronchoalveolar-lavage samples;
• among 45 people with ABPA, the variant was found in 9 of 32 with a positive sputum PCR but in none of the 13 with a negative PCR;
• carriers had approximately twice the fungal burden in sputum.

The major insight was that susceptibility does not have to involve conventional immune deficiency. An inherited difference in the physical and biochemical properties of the airway lining may make fungal colonisation easier.

However, the patient numbers were small and the association requires further validation. ZNF77 testing is not currently used routinely to predict fungal colonisation or ABPA.

EEA1: susceptibility can involve an overactive response

A separate Manchester study used exome sequencing in 96 people with ABPA and 167 asthmatic controls. Researchers identified variants in EEA1, a gene involved in the internal cellular compartments used to engulf and process material.

To test whether the association had a functional effect, the researchers studied macrophages obtained from people with ABPA.

Macrophages carrying the ABPA-associated EEA1 variants showed:

• increased uptake of A. fumigatus spores;
• increased acidification of the compartments containing them;
• an unusually active response to fungal material.

This finding was initially counterintuitive. The problem was not that the macrophages simply failed to respond. Instead, an exaggerated cellular response could contribute to the excessive inflammation characteristic of ABPA.

The study therefore provided another important lesson: genetic susceptibility can produce disease through too much inflammation as well as too little protection.

What has Manchester learned about CPA?

CPA usually develops in lungs already altered by previous tuberculosis, bronchiectasis, COPD, emphysema, sarcoidosis, non-tuberculous mycobacterial infection or other structural disease.

However, most people with these conditions do not develop CPA. Manchester researchers therefore compared immune responses and genetic variants in people with chronic cavitary pulmonary aspergillosis and control groups.

Their macrophage studies suggested a distinctive pattern:

• the initial response to fungal stimulation could be delayed;
• later production of inflammatory signals was greater;
• expression of several fungal-recognition receptors differed from healthy controls.

This supports a model in which early fungal clearance is not sufficiently effective, but is followed by a prolonged or excessive inflammatory response. That combination could allow Aspergillus to persist while also contributing to continuing lung damage.

Reported CPA associations have involved:

• IL1B, IL1RN and IL15, which participate in inflammatory signalling;
• TLR1 and CLEC7A/Dectin-1, which help recognise fungal material;
• VEGFA, involved in blood vessels and tissue repair;
• PLAT, involved in fibrinolysis and tissue remodelling;
• DENND1B, which participates in immune signalling.

These findings suggest relevant pathways, but they have not produced a clinically validated CPA screening panel.

Although the original Manchester project planned exome sequencing of approximately 160 people with CPA, a comprehensive final analysis of that entire cohort does not appear to have been published as a single definitive study. The available publications provide important mechanistic findings, but not a complete catalogue of validated CPA susceptibility variants.

What has been found more widely in ABPA?

Research from Manchester and elsewhere points towards several interacting processes in ABPA.

Type 2 allergic inflammation

IL-4 and IL-13 promote IgE production, eosinophilic inflammation, mucus secretion and other components of allergic immunity.

A Manchester-led association study investigated 195 variants across 22 genes. Associations involving IL13, IL4R and TLR3 remained significant after correction for multiple testing.

The findings support the idea that ABPA is not simply severe asthma combined with fungal exposure. Some people may inherit a tendency to mount an unusually strong or poorly regulated response to Aspergillus.

Airway clearance

CFTR is best known as the gene responsible for cystic fibrosis when a person inherits two disease-causing variants. Cystic fibrosis impairs mucus clearance and substantially increases the risk of ABPA.

Some people without cystic fibrosis carry one CFTR variant or have a milder CFTR-related disorder. Researchers are investigating whether reduced CFTR function contributes to mucus retention and fungal persistence in a subset of people with ABPA or bronchiectasis.

Fungal recognition

Associations have also been reported involving HLA variants, surfactant proteins and fungal-recognition pathways.

A 2023 study linked a heterozygous variant in CARD9 with ABPA. CARD9 transmits signals after immune cells recognise fungi. The finding is interesting, but it is not yet a clinically validated predictor.

PTX3 and invasive aspergillosis

The strongest progress towards clinically useful susceptibility testing has occurred in invasive aspergillosis, particularly after transplantation or intensive chemotherapy.

Pentraxin 3, or PTX3, binds to Aspergillus spores and helps neutrophils and other immune cells recognise and remove them.

Studies involving stem-cell and solid-organ transplant recipients have associated certain PTX3 variants with impaired antifungal activity and a higher risk of invasive aspergillosis.

In stem-cell transplantation, the donor’s genotype can matter because the donated cells produce the recipient’s new blood and immune cells.

A genetically guided prevention trial

The PTX3-targeted Antifungal Prophylaxis trial is testing whether genetic screening can help determine which people receiving intensive treatment for acute myeloid leukaemia should receive broad-spectrum antifungal prophylaxis.

Participants are tested for two PTX3 variants and placed into higher- or lower-risk groups. They are then assigned different prophylactic strategies involving posaconazole or fluconazole.

This is a significant step because the genetic result is not collected merely for future research: it is being used to stratify prevention within the trial.

There is currently no comparable genetic-screening trial for ABPA or CPA.

Summary of the principal candidate pathways

Gene or pathway	Possible relevance	Current position
ZNF77	Airway-barrier integrity, fungal adhesion and colonisation	Strong functional Manchester study; requires larger clinical validation
EEA1	Macrophage uptake and processing of spores	ABPA association with supporting laboratory evidence
IL13 and IL4R	Type 2 allergic inflammation and IgE responses	Associated with ABPA, but not clinically predictive
HLA	Presentation and recognition of fungal proteins	Several reported ABPA associations; variable between populations
TLR and CLEC7A pathways	Recognition of fungal material	Candidate associations in ABPA, CPA and invasive disease
CFTR	Mucus clearance and airway defence	Important in cystic fibrosis; wider contribution remains under investigation
CARD9	Signalling after fungal recognition	Rare deficiency causes major susceptibility; ABPA association is emerging
PTX3	Labels spores for immune recognition and clearance	Strongest translational evidence in invasive aspergillosis

What can epigenetics add?

The DNA sequence inherited from our parents is not the complete set of instructions used by every cell. Cells also regulate which genes are active, when they are activated and how strongly they are expressed.

Epigenetics describes mechanisms that influence gene activity without changing the underlying DNA sequence. These include:

• DNA methylation;
• chemical modification of histone proteins around which DNA is packaged;
• changes in chromatin accessibility;
• microRNAs and other molecules that regulate gene expression;
• longer-lasting reprogramming of innate immune cells, sometimes called trained immunity.

Some epigenetic patterns can change during life. They may be influenced by ageing, infection, smoking, air pollution, medication, inflammation and environmental exposure.

This makes epigenetics a plausible bridge between genes and environment. Two people could inherit similar genetic risks but develop different immune responses because their cells have experienced different exposures or illnesses.

Does DNA methylation cause susceptibility?

There is substantial evidence that DNA methylation is involved in asthma, allergy and immune development. Experimental work also shows that exposure to Aspergillus can alter gene expression and regulatory pathways in epithelial and immune cells.

However, direct human evidence that a particular methylation pattern causes susceptibility to ABPA or CPA remains very limited.

A methylation difference detected in someone with established aspergillosis could:

• have existed before the illness and contributed to susceptibility;
• have developed in response to fungal exposure or disease;
• reflect asthma, bronchiectasis or chronic inflammation;
• have been influenced by smoking, corticosteroids or other treatment;
• reflect a change in the types of cells present in the sample.

Researchers therefore need studies that collect samples before disease develops, or compare carefully matched groups, to distinguish cause from consequence.

Methylation is currently a promising research direction—not an established explanation for why an individual developed aspergillosis.

Patient genetics and fungal genetics are different

Manchester also maintains major resources relating to the genome of Aspergillus fumigatus itself.

The COFUN project aims to create approximately 10,000 fungal strains, each with a different gene removed. By observing what happens when individual genes are deleted, researchers can identify genes involved in:

• fungal growth and survival;
• pathogenicity and tissue damage;
• stress responses;
• azole and other antifungal resistance;
• potential new drug targets.

Manchester research has identified both conventional resistance mechanisms involving cyp51A and non-target mechanisms involving transporters, transcription factors, mitochondrial function and cellular signalling.

This is fungal genomics rather than human susceptibility genomics. Both are important, but they answer different questions: one examines why a patient may be vulnerable, while the other examines why a fungal strain may be particularly resistant or capable of causing disease.

Why is there still no clinical susceptibility test?

Several obstacles have slowed translation into patient care:

• ABPA, CPA and invasive aspergillosis have different mechanisms;
• many studies have included relatively few patients;
• variant frequencies differ between populations;
• underlying diseases and treatments are powerful confounding factors;
• some associations disappear when examined in independent cohorts;
• the effect of any one common variant is usually small;
• a statistical association does not necessarily demonstrate causation.

The Manchester ZNF77 and EEA1 studies are valuable because they went beyond association and demonstrated biological effects in relevant human cells. Even so, they require larger prospective clinical validation before testing can guide care.

Could several markers be combined?

A useful prediction system is unlikely to depend on one gene. It may combine:

• multiple genetic variants in a polygenic risk score;
• immune-cell function and inflammatory biomarkers;
• gene-expression and epigenetic patterns;
• CT findings and the extent of lung damage;
• asthma, bronchiectasis, COPD or previous tuberculosis;
• corticosteroids and other immune-modifying treatments;
• fungal sensitisation, antibodies, culture and PCR;
• environmental exposure.

This combined approach is sometimes called multi-omics or precision medicine. Rather than searching for one faulty gene, researchers examine how inherited variation, gene regulation, immune cells, lung structure, fungal biology and exposure interact.

Is testing useful for patients now?

There is currently no clinically validated genetic, polygenic or methylation test that can reliably predict ABPA or CPA.

Specialist genetic or immunological investigation may nevertheless be appropriate when aspergillosis:

• occurs unusually early in life;
• is recurrent, invasive or affects unusual sites;
• occurs without the expected lung or treatment-related risk factors;
• is accompanied by recurrent bacterial, viral or other fungal infections;
• occurs alongside features suggesting an inherited immune disorder.

Commercial sequencing can also identify a variant of uncertain significance. This means that a DNA difference has been found but there is insufficient evidence to determine whether it affects health. Such a result is not a diagnosis and requires specialist interpretation.

Routine genetic testing of healthy relatives of people with ABPA or CPA is not currently recommended solely because of the family connection.

What this means for patients

The Manchester research has helped replace a simple idea—“some patients have weak immunity”—with a more sophisticated picture.

Susceptibility may involve:

• an airway surface that allows spores to adhere and germinate;
• immune recognition that starts too slowly;
• a later response that becomes excessive or damaging;
• mucus that is difficult to clear;
• several small inherited differences acting alongside lung damage and exposure.

Genetics probably contributes to the striking differences between people exposed to the same fungus. Epigenetic regulation may add another layer by allowing inflammation, treatment and environment to influence how genes behave.

But current evidence does not show that most people with aspergillosis carry a single faulty gene. Nor can a genetic or methylation test yet tell most patients precisely why they became ill or predict what will happen next.

The immediate value of this research is a better understanding of disease mechanisms. Its longer-term promise is more practical: identifying people who need closer monitoring, selecting preventive treatment for those at greatest risk and matching treatment to the biological pathway driving disease.

For now, symptoms, clinical history, lung structure, immune status, imaging and established fungal tests remain much more important than susceptibility genetics in diagnosing and managing aspergillosis.

Selected research and further reading

• University of Manchester: the original CPA exome-sequencing project.
• Gago S et al. Lung colonisation by Aspergillus fumigatus is controlled by ZNF77.
• Overton NLD et al. EEA1 variants, ABPA and macrophage phagocytosis.
• Overton NLD et al. Genetic susceptibility to ABPA in asthma.
• Smith NL et al. IL-1 and IL-15 pathways in chronic cavitary pulmonary aspergillosis.
• Smith NL et al. Macrophage receptor expression and genetic associations in chronic cavitary pulmonary aspergillosis.
• PTX3-targeted antifungal prophylaxis trial.
• Manchester Fungal Infection Group.
• Aspergillosis, immunity, and risk.

Last reviewed: August 2026

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