Severe asthma is the most common cause of hospitalization among children. Nevertheless, the reasons why some children are affected and others are not remain incompletely understood. New research now suggests that blood group (such as A, B, AB and O) and the related antigens secreted in the respiratory airways may be crucial in determining whether a child develops severe asthma. The new knowledge is a major research breakthrough and may be an important step towards being able to vaccinate children at higher risk of developing severe asthma.
One in ten school-age children in Denmark have asthma. This percentage has doubled in high-income countries in recent decades – without doctors and researchers knowing why. One reason for the lack of clarity is that asthma is not a singular disease but a diverse disorder that results in irritated and inflamed respiratory airways. A research group therefore decided to focus on asthma with severe exacerbation among children 2–6 years old, leading to a research breakthrough.
“These children with severe asthma had specific mutations in the FUT2 gene more often than people without asthma. FUT2 determines whether the ABO blood group antigens are secreted on mucosal surfaces and in the mucus produced in the respiratory airways. We also found that FUT2 was only a risk factor for children secreting A or B blood group antigens and not O,” explains Klaus Bønnelykke, Clinical Professor, at University of Copenhagen and Senior Hospital Physician, Copenhagen Prospective Studies on Asthma in Children (COPSAC), Herlev & Gentofte Hospital.
Secretor status is crucial
Researchers have long sought the genes that might be associated with the risk of asthma but have only found a minority of the responsible genes even though asthma has a strong hereditary component.
“We used genetic data from two studies, Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). They included more than 68,000 children in Denmark, 2,866 of whom had been hospitalized at least once with severe asthma exacerbation at 2–6 years of age. Focusing on this very specific group enabled us to find a signal in the FUT2 gene,” says Klaus Bønnelykke.
This is no ordinary gene: FUT2 encodes the enzyme fucosyltransferase 2, which determines the ability to secrete the ABO antigens on mucosal surfaces. A mutation in the FUT2 gene stops this secretion.
“One in five children are non-secretors, and they were especially protected against severe asthma. This gave us the idea that people’s ABO blood group and the associated antigens, determined by another gene, also play a role, and we found that only the children with the gene that produced A and B antigens were at higher risk. Children with blood group O had a lower risk,” says Klaus Bønnelykke.
Comparing the data with clinical reality
To understand whether FUT2 actually interacted with the genes determining the children’s ABO blood group, the researchers confirmed that being a secretor was only a risk factor for children who had A or B antigens and not O. Conversely, having A or B antigens was only a risk factor for secretors. They had found a possible explanation and a way to check children’s risk of severe asthma.
“The results suggest that secreting A and B antigens in the respiratory airways increases the risk of severe childhood asthma. Identifying the 3–4% of children with both FUT2 genes having secretor status and having either A or B blood type considerably narrows down the group at higher risk of developing severe childhood asthma,” explains Klaus Bønnelykke.
The association between asthma and blood group suggests that this mechanism could be related to infections, since blood group has been shown to influence susceptibility to infections. For example, the AB blood group is also a risk factor for severe COVID-19, and being a secretor increases the risk of viral gastrointestinal infections. The researchers investigated this in the COPSAC birth cohorts, in which about 1,000 children were followed from birth and examined for viral and bacterial infections when they had troublesome lung symptoms.
“This showed that the underlying mechanism for the increased risk of asthma appears to be related to infections with Streptococcus pneumoniae, a frequent cause of pneumonia that can exacerbate asthma symptoms,” says Klaus Bønnelykke.
Improving understanding and treatment
The Comparative Outcomes and Service Utilization Trends (COAST) birth cohort study in the United States subsequently confirmed the results. Similar to childhood asthma, children with FUT2 secretor status and A, AB or B blood group had the greatest risk of infections.
“Older people with asthma and other lung diseases benefit greatly from being vaccinated against Streptococcus pneumoniae. We have identified a group of children at especially high risk of pneumococcal infection and this should maybe give priority to getting them vaccinated. We hope that linking even more high-risk genes together can enable us to predict more precisely which children are at high risk of respiratory infections and severe asthma and thus to enable them to have a better start in life,” explains Klaus Bønnelykke.
The researchers from COPSAC are therefore collaborating with a group from the Technical University of Denmark led by Anders Gorm Pedersen that is actively working to better understand the interaction between genetic variants, called epistasis. This occurs when the effect of a genetic mutation depends on the presence or absence of mutations in one or more other genes, although human studies have only demonstrated a few examples of epistasis. However, as the new study shows, this association may be the key to understanding and treating people severely affected by asthma.
“We are well on the way and have already found other examples of genes influencing each other. Further, we just started a nationwide study of children with severe asthma aiming to correlate the genetic data with the clinical reality and the problems these children have with acute viral and bacterial infections. This will enable us to better understand their illness and treat them accordingly,” concludes Klaus Bønnelykke.