Causal associations between plasma ADAMTS-5 protein level and cancer risk: a bi-directional mendelian randomization analysis

Abstract

Abstract Background According to relevant research, ADAMTS-5 was associated with some cancers. However, the causal relationship between ADAMTS-5 and different types of cancers is still unclear. Methods The genome-wide summary statistics of plasma ADAMTS-5 protein level and 17 differential types of cancers were acquired for the deCODE database, the IEU Open GWAS project and FinnGen database. The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used for two or more genetic instruments. Sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni corrected significance was set at P < 0.0015 (0.05/34) to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggestively relationship. To strengthen our findings in MR analysis, we conducted the Bayesian co-localization analysis for validation analyses apart from using an independent cohort. Results After Bonferroni correction, we only detected significant evidence for genetic prediction of the causal relationship between ADAMTS-5 and oropharyngeal cancer (OR: 0.62, 95%CI: 0.47–0.81, P = 0.0007). ADAMTS-5 had suggestive associations with esophagus cancer (OR: 0.73, 95%CI: 0.55–0.98, P = 0.034). There had no statistical effect on other cancers. There was also no evidence of the reverse causal relationships. Our findings also were found in independent cohort. Furthermore, we detected the presence of a shared variant for the association between ADAMTS-5 and oropharyngeal cancer by Bayesian co-localization analysis (PP4 > 0.8), strengthening our results. Conclusions MR analysis reveal that plasma ADAMTS-5 level had significantly causal association with oropharyngeal cancer. It also existed suggestive associations with esophagus cancer. ADAMTS-5 was a potential drug target for oropharyngeal cancer, thus providing guidance for further clinical research.