Genetic Insights into Inflammatory Proteins: Uncovering Targets for Immune-Mediated Diseases
In September 2023, a study published in Nature Immunology presented groundbreaking findings on how genetic factors influence circulating inflammatory proteins and their roles in immune-mediated diseases. By mapping protein quantitative trait loci (pQTLs) for inflammation-related proteins across nearly 15,000 participants, researchers uncovered genetic variations that regulate the levels of 91 plasma proteins linked to inflammation, providing new insights into the molecular mechanisms underlying conditions like multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease (IBD). Here’s a deep dive into their methodology, findings, and implications.
1. Methodology and Scope
To capture the genetic landscape influencing inflammation-related proteins, the team utilized the Olink Target Inflammation platform, profiling 91 proteins in plasma samples from 14,824 participants of European ancestry. They identified 180 significant genetic loci (pQTLs) associated with protein levels: 59 cis-pQTLs (close to the gene encoding the protein) and 121 trans-pQTLs (distant from the gene). Importantly, this study integrated data from genome-wide association studies (GWAS), which map gene-disease associations, to enhance understanding of immune-mediated disease mechanisms and identify potential therapeutic targets.
2. Protein Variants and Disease Associations
Through Mendelian randomization (MR), the researchers examined causal links between protein levels and disease risk. This analysis revealed both shared and distinct protein impacts across diseases. Notably, lymphotoxin-α (LTA) was implicated in multiple sclerosis (MS), while CXCL5 and CD40 exhibited divergent effects on diseases like rheumatoid arthritis, MS, and IBD. For instance, higher CD40 levels were associated with increased rheumatoid arthritis risk but reduced risk of MS and IBD, highlighting the complex interplay of inflammatory proteins in different immune conditions.
3. Highlighting Key Pathways
Among the significant findings, the study linked CD40 to rheumatoid arthritis and LTA to MS through distinct pathways. CD40, involved in activating immune cells, was shown to drive rheumatoid arthritis risk but reduce susceptibility to other immune conditions. Similarly, the LTBR–LTA axis was implicated in MS, where reduced expression of LTBR was associated with increased LTA levels in circulation, potentially disrupting immune regulation. These insights not only underscore the role of specific proteins in disease susceptibility but also indicate pathways that could be targeted in future therapies.
4. Tissue-Specific Expression and Protein Interactions
Understanding the tissue-specific origins of plasma proteins is essential. The researchers compared their pQTLs with expression quantitative trait loci (eQTLs), which regulate gene expression in various tissues. Interestingly, only 6 of the 59 cis-pQTLs had corresponding cis-eQTLs in blood, while over half matched with eQTLs from different tissues, such as the liver. This tissue specificity suggests that many inflammatory proteins in plasma originate outside of blood cells, such as in the liver or gut, and have distinct regulatory mechanisms depending on the cell types involved.
5. Insights into Ulcerative Colitis (UC) and CXCL5
One of the study's most notable findings was the role of CXCL5, a chemokine involved in neutrophil recruitment, in UC. Elevated gut expression of CXCL5 was associated with UC, yet genetic variants linked to higher CXCL5 levels in plasma were protective against UC. This paradox suggests that while CXCL5 overexpression in the gut may drive UC pathology, genetically predisposed lower CXCL5 expression could impair immune homeostasis, predisposing individuals to UC. The study posits that CXCL5’s protective or pathogenic role may depend on tissue context and disease stage.
6. Validation and Replication
To validate their pQTL findings, the researchers tested their associations in an independent cohort, demonstrating consistent effects in 71% of cases. This high replication rate strengthens the study’s conclusions and suggests robust genetic influences on the plasma proteome. Additionally, they confirmed many of their associations in the Icelandic deCODE study, underscoring the broader applicability of these findings across different European populations.
7. Therapeutic Implications
The study’s findings offer a wealth of potential therapeutic targets. Proteins such as IL-12B, already targeted by drugs like ustekinumab for IBD, were linked to disease risk through MR, supporting their causal role in disease. Moreover, the contrasting effects of CD40 on rheumatoid arthritis and other immune conditions suggest a need for caution in developing therapies. Blocking CD40 could alleviate rheumatoid arthritis but might increase susceptibility to MS and IBD, much like anti-TNF therapies, which alleviate rheumatoid arthritis but exacerbate MS symptoms.
Conclusion
This large-scale study demonstrates the power of integrating genetic and proteomic data to elucidate the molecular basis of immune-mediated diseases. By identifying genetic drivers of protein levels in plasma, the research provides actionable insights for future drug development, with a focus on inflammation-related proteins like CD40, LTA, and CXCL5. These findings underscore the complexity of inflammatory diseases and highlight the necessity for targeted therapeutic approaches that consider disease-specific pathways and tissue contexts.
References:
Zhao, J.H., Stacey, D., Eriksson, N. et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 24, 1540–1551 (2023).
