Cross-Ancestry Whole-Blood Transcriptomic Profiling Reveals Bidirectional Immune and Pharmacogenomic Relevant Differences in Severe Asthma: A Sex-Adjusted Analysis

Asthma is not a single disease that affects everyone in the same way. It is a condition where the airways become inflamed and narrow, making it hard to breathe, but the reasons why it happens and how severe it becomes can differ greatly from person to person. Scientists have long known that asthma does not affect all racial and ethnic groups equally. In many places, people of African descent experience higher rates of severe asthma, more emergency room visits, and more hospitalizations than their white counterparts. This disparity is driven by a complex mix of social factors, such as access to healthcare and exposure to pollution, but researchers also wonder if biology plays a role. To investigate this, scientists look at the body's immune system through the lens of genetics and molecular activity. They examine the "transcriptome," which is essentially a snapshot of all the active genes in a cell at a given moment. By reading these genetic messages in blood samples, researchers hope to see if the underlying biology of asthma differs between populations in ways that could explain why some people struggle more with the disease than others.

A new study set out to explore these biological differences by looking at the blood of people with severe asthma. The researchers focused on a specific group of twenty-four participants from a larger international project called U-BIOPRED. This group was carefully chosen to include twelve individuals recorded as being of African ancestry and twelve recorded as being of European ancestry. To ensure a fair comparison, the team balanced the groups by sex, with eight women and four men in each category. The scientists analyzed the genetic activity in the whole blood of these participants, which acts as a window into the body's systemic immune response. Because blood is a mixture of many different types of cells, such as neutrophils and lymphocytes, the researchers had to be very careful to account for sex differences, which are known to influence gene activity, before looking for signals related to ancestry.

The analysis revealed that the most significant source of variation in the genetic data was indeed the ancestry group. When the researchers mapped out the differences, they found that the genetic profiles of the two groups were distinct, but not in the simple way one might expect. A common assumption is that one group might be uniformly more inflamed than the other, but the data showed a much more complex picture. Instead of a single direction of change, the differences were bidirectional. This means that while some genes associated with inflammation and airway damage were more active in the European-ancestry group, other genes related to immune regulation and metabolism were more active in the African-ancestry group. It was not a case of one group being "worse" or "more inflamed" overall; rather, the two groups showed opposing patterns of biological activity.

Among the specific genes that stood out, the researchers identified a set of thirteen key genes that are known to be involved in asthma. These genes were split almost evenly between the two groups. In the European-ancestry group, genes linked to airway remodeling—the process where the structure of the airways changes and thickens—and certain chemical signals that attract immune cells were more active. In the African-ancestry group, genes involved in controlling the immune response and managing oxidative stress, which is a type of cellular damage, showed higher activity. This finding challenges the idea that severe asthma in different populations is driven by a single, uniform biological mechanism. Instead, it suggests that the disease manifests through different biological pathways in different groups.

However, the study also highlighted a crucial complication in interpreting these results. The researchers noticed a very strong signal in a gene called ACKR1, which is known to be influenced by a genetic variant common in people of African descent. This variant is associated with lower counts of a specific type of white blood cell called neutrophils. Because the blood samples were a mixture of many cell types, the lower activity of certain immune genes in the African-ancestry group could simply be because there were fewer neutrophils in the blood, rather than because the genes themselves were turned down. This is similar to how a choir might sound quieter not because the singers are singing less loudly, but because there are fewer singers in the room. The researchers could not separate the effect of cell numbers from the effect of gene activity within the cells because they did not have detailed counts of the different blood cells for these specific participants.

The study also looked at whether the differences were driven by sex, but the results confirmed that the ancestry-related patterns were distinct from sex-related ones. The genes that varied between men and women were the ones scientists already expected to see, such as those on the X and Y chromosomes, and none of the key asthma genes showed a significant difference based on sex alone. This gave the researchers confidence that the ancestry-related differences they found were not just an artifact of having more women or men in one group.

Despite these interesting findings, the researchers are cautious about what these results mean for treatment. The study was small, involving only twenty-four people, and it did not have information on important factors like the patients' ages, smoking history, or the specific medications they were taking. These missing details mean that other factors could be influencing the results. The authors emphasize that their work does not prove that ancestry itself causes these differences, nor does it identify a specific "African type" or "European type" of asthma that requires a different drug. Instead, the study provides a list of specific genes and biological pathways that deserve further investigation.

The ultimate goal of this research is to move toward a future where asthma treatment is tailored to the individual's biology. By identifying that the disease can look different at the molecular level across populations, scientists hope to eventually develop better tests and treatments that work for everyone. But before that can happen, these findings need to be confirmed in larger groups of people with more detailed health records. For now, the study serves as a reminder that the biology of asthma is diverse and complex, and that understanding it requires looking beyond simple categories to see the intricate, bidirectional patterns that shape how the disease affects different people.