Abstract
BACKGROUND: This study aimed to investigate the associations between serum lipoprotein subclasses and the long-term risk of gastrointestinal (GI) cancers to enhance our understanding of the etiology of GI cancers. METHODS: This prospective cohort study included 249,450 participants from the UK Biobank. Cox proportional hazard models were used to assess the association between 17 serum lipoprotein subclasses with the risk of GI cancers. Restricted cubic spline (RCS) analysis was employed to assess the corresponding dose-response relationships. Additionally, Mendelian randomization (MR) analysis was used to evaluate the causal relationships between the lipoproteins and the risk of GI cancers. RESULTS: A total of 4,787 cases of GI cancers were recorded over a median follow-up period of 12.92 years. Our results revealed that the majority of the high-density lipoprotein (HDL) subclasses, such as very large-, large-, and medium-HDL-particles, were positively associated, while several low-density lipoprotein (LDL) subclasses were negatively associated with the risk of overall GI cancer. Additionally, RCS analysis revealed a linear dose-response relationship between elevated levels of most lipoprotein particles and the risk of overall GI cancer development. Additionally, subgroup analysis indicated a significant sex-dependent interaction between lipoprotein particles and the risk of GI cancers. However, MR analysis revealed a different causal relationships between lipoprotein and GI cancers at the genetic level. CONCLUSION: In this large-scale metabolomics study, we identified several associations between lipoprotein subclasses and the long-term risk of GI cancers. However, further research is needed to fully elucidate their roles in the mechanisms of cancer development.