Abstract
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.