Mendelian randomisation studies of lipid traits and risk of colorectal cancer: a systematic review

Abstract

Background Colorectal cancer (CRC) is a leading cause of global cancer morbidity and mortality. Lipid metabolism dysregulation has been implicated in CRC development, yet evidence for the causal role of specific lipid traits remains largely inconsistent. Mendelian randomisation (MR) studies provide a means to strengthen causal inference by using genetic variants as proxies for lipid levels and limiting reverse causation. This study aimed to systematically review MR studies assessing the causal association between lipid traits and CRC risk and outcomes. Methods We conducted a systematic review following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) and the Centre for Reviews and Dissemination (CRD) guidelines with due registration on PROSPERO (CRD42024586248). PubMed and Embase databases were searched for relevant MR studies published up to December 2025. Eligible studies were critically assessed using a modified Strengthening the Reporting of Observational Studies in Epidemiology using MR (STROBE-MR) checklist. Consequently, meta-analysis was not performed due to heterogeneity in exposures, populations and methods across studies. Results 20 MR studies published between 2017 and 2025 were included out of 979 identified records. Most studies employed two-sample MR with genetic instruments primarily derived from European populations. Findings indicated that elevated low-density lipoprotein cholesterol, total cholesterol and arachidonic acid were positively associated with CRC risk, whereas linoleic acid, oleic acid and phosphatidylcholine showed protective effects. High-density lipoprotein cholesterol and triglycerides demonstrated inconsistent or null associations. A study suggested stronger associations in younger populations with marked reductions with increased age. Conclusion This review highlights a complex and trait-specific relationship between lipid traits and CRC risk. These findings also support the role of lipid traits as potential biomarkers for CRC risk stratification and underscore the need for further MR studies across diverse populations especially in the under-represented African continent, age groups and lipid subtypes.