Secrets of Our Immune System: How Genes Influence Inflammation

 

Image credit: https://openai.com/index/dall-e/

Our bodies have a complex system to fight off infections and heal injuries, known as the immune system. This system relies on tiny proteins called cytokines, which act like messengers to orchestrate our immune response. When things go wrong, these cytokines can cause inflammation, which is linked to many diseases like allergies, autoimmune conditions, heart problems, and even cancer. Scientists are keen to find ways to control these cytokines to treat such illnesses.
 
Peering into our genes: Recent scientific advancements now allow us to look at our genes to understand what causes different levels of these cytokines in our blood. This is done through large studies called genome-wide association studies (GWAS). These studies analyze the DNA of many people to find genetic variants that are linked to differences in cytokine levels. Using this information helps identify potential drug targets. In this study, researchers pooled data from three separate studies involving nearly 75,000 individuals. This allowed them to identify 359 significant links between our genes and the levels of 40 different cytokines circulating in our blood. These links are called "associations" or "loci".
 
How genes affect cytokine levels: The study found that some genetic variants have a ‘local’ effect (cis-acting) on the cytokine levels, while others have more ‘distant’ effects (trans-acting). The local variants are usually located near the gene that makes the specific cytokine and tend to have a stronger effect on levels of that cytokine. The study also used a technique called fine-mapping to pinpoint the most likely causal variants responsible for these genetic associations.
 
Key players in the immune system: One particular gene called ACKR1 was found to influence the levels of multiple chemokines (a type of cytokine). ACKR1 acts like a "scavenger" for these chemokines and is important in regulating inflammatory responses. A genetic variant in ACKR1 can reduce its ability to bind to chemokines, leading to higher levels in the bloodstream. Another gene, TRAFD1, was found to act like a master regulator, influencing the levels of several cytokines. It plays a role in how our cells respond to a protein called tumors necrosis factor (TNF) which is a key player in inflammation.
 
Cytokines working together: The study also found that many cytokines are interconnected. Some cytokines act as “master regulators”, influencing a wide range of other cytokines. For example, TNF-b, VEGF, and IL-1ra were identified as having widespread effects on other cytokines. These are like key switches in the network of communication between these proteins.
 
Finding new drug targets: Using the genetic data, the scientists employed a method called Mendelian randomization (MR) to investigate which cytokines could be targets for treating diseases. This method uses genetic variants to infer cause-and-effect relationships between cytokine levels and the risk of various diseases. It can help to identify whether changing levels of a particular cytokine will help to treat a disease. They found that genetically higher levels of a cytokine called G-CSF/CSF-3 were linked to a higher risk of asthma, while higher levels of CXCL9/MIG were linked to a higher risk of Crohn’s disease. Interestingly, genetically lower levels of TNF-b were linked to a lower risk of multiple sclerosis. Further analysis supported these findings, showing that gene expression and clinical data supported the idea that these cytokines play a role in these diseases.
 
Potential new treatments: These results suggest that targeting these cytokines with specific drugs may help treat these conditions. For instance, treatments that reduce the levels of G-CSF/CSF-3 might help to manage asthma, while those that lower CXCL9/MIG could help those with Crohn’s disease. The finding that TNF-b may be protective in MS is particularly interesting, as some existing treatments for other autoimmune diseases block TNF-b and could be detrimental for MS patients. The study also identified other genes that could be targeted, such as PPP1R37 in asthma and TRAFD1 in Crohn’s disease.
 
Important caveats: It's essential to acknowledge that these findings are based on data primarily from individuals of European, Finnish, and Icelandic descent. This means the results might not be directly applicable to other groups of people. Also, the study looked at a selected panel of 40 cytokines, so other cytokines could also be important. Moreover, different methods used to measure cytokine levels might affect the results.
 
Looking ahead
This research offers a comprehensive overview of the genetic architecture of circulating cytokines and offers possibilities for the development of new targeted immunotherapies. It highlights the complex network of interactions between genes and cytokines and their influence on human diseases. This research provides a strong foundation for future studies which could explore more cytokines and also analyze the effects of these cytokines in different populations. Ultimately, this could lead to the development of new and better ways to treat a range of inflammatory diseases.
 
Additional information: The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases. Communications Biology (2025). https://www.nature.com/articles/s42003-025-07453-w

Journal information: https://www.nature.com/commsbio/