Mendelian randomization analysis provides insights into the relationship between inflammatory bowel disease and skin...

Limited and conflicting data have been available regarding the association between inflammatory bowel disease and skin cancer. It was hypothesized that inflammatory bowel diseases [Crohn's disease (CD) and ulcerative colitis (UC)] harbor a genetically increased risk of skin cancer [skin cutaneous melanoma (SKCM), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and performed two-sample mendelian randomization (MR) analysis using genome-wide association (GWAS) studies of European ancestry retrieved from FinnGen R8. The inverse variance weighted method was used to approximate MR effects. Sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier were performed to estimate pleiotropy and heterogeneity a priori. MR results suggest a significant causal association between UC and SKCM, (beta=0.097, P=0.0138) and UC and SCC (beta=0.171, P=0.0014). These findings were then validated using summary-level GWAS from the UK Biobank and an independent meta-analysis which demonstrated a suggestive or causal genetic association between UC and SCC (beta=0.065, P=0.036), UC and BCC (beta=0.056, P=0.002), but not UC and SKCM (beta=0.02, P=0.432). Due to limited sample size for CD instruments, only 5 significant single nucleotide polymorphisms were found with no significant causal effects on skin cancer. These results provide evidence for a causal genetic association between UC and skin cancer through shared polymorphisms involving the IL-23/Th17 axis, which may inform preventative counseling and precision medicine in the future.