Erythema nodosum, malignant melanoma and non-melanoma skin cancer in relation to inflammatory bowel disease: a Mendelian randomization study

Inflammatory bowel disease (IBD) is a multisystem condition that could affect the cutaneous systems, namely cutaneous extraintestinal manifestations (EIMs). It has been suggested that IBD is associated with erythema nodosum (EN), malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, the potential causal relationship between IBD and the mentioned above cutaneous EIMs is still unclear. This study aims to determine the effect of IBD on EN, MM and NMSC within a Mendelian randomization (MR) design. Summary-level data for IBD, EN, MM, NMSC were obtained from large-scale genome-wide association studies. We utilized five different methods, including the inverse variance weighted model (IVW), MR Egger, Weighted median, Simple mode, Weighted mode in the MR analysis, then the Cochran's Q test, the MR-Egger pleiotropy test, the MR-PRESSO global pleiotropy test and leave-one-out sensitivity test were used to evaluate the heterogeneity and pleiotropy of identified IVs. To further ensure the validity of our findings, we evaluated the strength of the instrumental variables using the F-statistic and estimated the statistical power of our study. Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. MR analysis suggested that genetically determined IBD had a detrimental causal effect on NMSC (IVW: odds ratio [OR] = 1.002037, 95% confidence interval [CI] = 1.0001150-1.003962, P = 0.03776677), but not on EN (IVW: [OR] = 1.0937191, 95% [CI] = 0.9685831-1.235022, P = 0.1484349) and MM (IVW: [OR] = 0.9998064, 95% [CI] = 0.9994885-1.000124, P = 0.2326482). Besides, a positive causal effect of IBD on NMSC was verified in an independent validation dataset (IVW: [OR] = 1.002651, 95% [CI] = 1.0006524-1.004654, P = 0.009307506). The present study corroborated the causal relationship between IBD and NMSC. In contrast, our results showed no evidence of a causal association of IBD on EN and MM. These findings provide new insights into increasing attention to patients with IBD to prevent concurrent NMSC.