Preclinical Protein Signatures of Crohn’s Disease and Ulcerative Colitis: A Nested Case-Control Study Within Large Population-Based Cohorts
Gastroenterology, 2024
Grännö O., Bergemalm D., Salomon B., Lindqvist C., Hedin C., Carlson M., Dannenberg K., Andersson E., Keita ?., Magnusson M., Eriksson C., Lanka V., Almer S., Blomberg A., Bresso F., Carstens A., Hjortswang H., Hreinsson J., Ling Lundström M., Marsal J., Strid H., Magnusson P., D’Amato M., Öhman L., Söderholm J., Hultdin J., Kruse R., Cao Y., Repsilber D., Grip O., Karling P., Halfvarson J.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Patient Stratification | Plasma | O Olink Target 96 |
Abstract
Background and aims
Biomarkers are needed to identify individuals at elevated risk of inflammatory bowel disease (IBD). This study aims to identify protein signatures predictive of IBD.
Methods
Using large population-based cohorts (n≥180,000), blood samples were obtained from individuals who later in life were diagnosed with IBD and compared to age and sex-matched controls, free from IBD during follow-up. 178 proteins were measured on Olink platforms. We used machine learning methods to identify protein signatures of preclinical disease in the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222) and assessed in an inception cohort (n=144) and a preclinical twin cohort (n=102).
Results
In the discovery cohort, a signature of 29 proteins differentiated preclinical Crohn’s disease (CD) cases from controls, with an area under the curve (AUC) of 0.85. Its performance was confirmed in the preclinical validation (AUC=0.87) and the inception cohort (AUC=1.0). In preclinical samples, downregulated (but not upregulated) proteins related to gut barrier integrity and macrophage functionality correlated with time to diagnosis of CD. The preclinical ulcerative colitis (UC) signature had a significant, albeit lower, predictive ability in the discovery (AUC=0.77), validation (AUC=0.67), and inception cohorts (AUC=0.95).
The preclinical signature for CD demonstrated an AUC of 0.89 when comparing twins with preclinical CD to matched external healthy twins, but its predictive ability was lower (AUC=0.58; P=.04) when comparing them with their healthy twin siblings, i.e., when accounting for genetic and shared environmental factors.
Conclusion
We identified protein signatures for predicting a future diagnosis of CD and UC, validated across independent cohorts. In the context of CD, the signature offers potential for early prediction.