Genetically Assessed Risk Factors of Colorectal Cancer: a Literature Review of Mendelian Randomization Study

Abstract

Introduction: Colorectal cancer (CRC) ranks as the third most common cancer and the second leading cause of cancer-related mortality globally. Despite substantial progress, the causal mechanisms linking various risk factors to CRC remain unclear due to confounding and reverse causality in observational studies. Mendelian Randomization (MR), which utilizes genetic variants as instrumental variables, offers a robust alternative for inferring causal relationships.

Method: This narrative literature review evaluates MR studies published in the last decade that investigated genetically predicted risk factors associated with CRC. Articles were selected through systematic searches using PubMed and Cochrane databases. Inclusion criteria comprised relevance to CRC, MR methodology, full-text availability, and publication in peer-reviewed journals.

Discussion: A total of seven MR studies were analyzed. The findings indicated that higher levels of total bilirubin, epigenetic clock GrimAge acceleration, insulin-like growth factor-1 (IGF-1), alcohol consumption, air pollutants (PM2.5), and specific gut microbiota (e.g., Porphyromonadaceae, Anaerotruncus, Intestinibacter) were causally associated with increased CRC risk. Conversely, Gammaproteobacteria and Enterobacteriaceaeappeared protective. While MR reduces confounding and reverse causality, limitations such as horizontal pleiotropy and ancestry-specific biases (primarily European and East Asian populations) may affect generalizability, particularly to Southeast Asian populations.

Conclusion: Genetically predicted exposures including biochemical markers, microbiota, and environmental factors demonstrate significant causal associations with CRC. However, future MR studies involving Southeast Asian populations, especially Indonesians, are needed to validate these findings within different genetic and environmental contexts.