Assessing inflammatory protein factors in inflammatory bowel Disease using multivariable mendelian randomization

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Gastroenterology

Background:

• Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), significantly impacts patient quality of life and leads to disability.
• The precise underlying biological mechanisms driving IBD pathogenesis remain incompletely understood.
• Identifying specific molecular factors associated with IBD is crucial for advancing early diagnosis and therapeutic strategies.

Purpose of the Study:

• To employ Mendelian randomization (MR) analysis to identify specific inflammatory cytokines and proteins genetically associated with UC and CD.
• To explore the shared genetic architecture between inflammatory proteins and IBD subtypes.
• To provide insights into potential biomarkers for IBD screening, prevention, and treatment.

Main Methods:

• Utilized genome-wide association study (GWAS) data for inflammatory cytokine levels from a European cohort (n=14,824).
• Performed Mendelian randomization (MR) analysis using inverse-variance weighted (IVW), MR-Egger, and weighted median methods with summary-level GWAS data for UC and CD.
• Conducted sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out), Steiger and reverse MR tests, multivariable MR (MVMR), LDSC, and colocalization analysis.

Main Results:

• Identified significant genetic associations between specific inflammatory proteins and IBD subtypes post-FDR correction.
• CXCL5 and CXCL9 were significantly associated with UC; CXCL5 and IL-18R1 were significantly associated with CD.
• Colocalization analyses revealed shared genetic variants between inflammatory proteins (CXCL5 with UC, CXCL9 with CD) and IBD, indicating common genetic determinants.

Conclusions:

• This study provides robust evidence for genetic associations between several inflammatory protein factors and UC and CD.
• Findings highlight specific proteins like CXCL5, CXCL9, and IL-18R1 as potential contributors to IBD pathogenesis.
• The identified genetic links offer novel insights into IBD's biological mechanisms and suggest potential targets for future therapeutic interventions.