Examining complex cancer etiologies within the Korean population: A high-throughput multivariable Mendelian randomization study

Abstract Background Despite an extensive body of observational research related to risk factors for cancer incidence, it is unclear whether the estimated associations are causal or a result of unmeasured confoundingfactors. To consider this possibility, this study explored a range of candidate epidemiological factors associated with the onset of cancer within a Mendelian randomization framework. Methods Multivariate Mendelian randomization (MVMR) analyses were conducted using data from the Korean Cancer Prevention Study-II Biobank and the Korean Genome Epidemiologic Study. Analyses were performed to investigate 13 cancer-related risk factors and 13 types of cancer. Initially, univariate Mendelian randomization analyses were performed for each factor, estimating its association with cancer. Subsequently, a set of factors was explored using MVMR. Results By analyzing factors related to the onset of cancer, it was determined that smoking is associated with lung cancer, while hepatitis B surface antigen (HBsAg) positivity is significantly linked to gastric cancer, liver cancer, and cervical cancer. PSA levels are estimated to be causally related to prostate cancer, while bilirubin has emerged as a novel factor showing a positive association with lung cancer. To confirm the causal effect between HBsAg and cancer, a MVMR was conducted, controlling for bilirubin and gamma-glutamyl transferase. The results indicated a positive association between HBsAg and cervical cancer, liver cancer, and lung cancer. Conversely, breast cancer and pancreatic cancer showed a negative association. In the case of breast cancer, individuals with HBsAg at the age of over 50 years exhibited a significantly lower risk, with an odds ratio of 0.87 (P = 3.07 × 10-16). Conclusions Smoking status, HBsAg, and PSA levels replicated findings from previous studies suggesting causal relationships. However, bilirubin and HBsAg demonstrated positive causal associations with some cancers, while HBsAg exhibited negative associations with other cancers. Further research is warranted to explore the cancer-specific causality of HBsAg.