Elevated remnant cholesterol and increased risk of colorectal cancer and atherosclerotic cardiovascular diseases: a prospective cohort study

Abstract Background Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Remnant cholesterol (RC), a novel lipid biomarker with intrinsic pro-atherogenic capacity, is increasingly considered a potential contributor to carcinogenesis. However, its relationship with CRC risk remains unclear. Purpose This study aimed to evaluate serum RC as a predictor of CRC incidence within a large prospective cohort, and further investigate the relationship between high RC levels and the risk of CRC as well as atherosclerotic cardiovascular diseases (ASCVD) in individuals with low-density lipoprotein cholesterol (LDL-C) levels below 2.6 mmol/L. Methods Between 2006 and 2021, 80,197 participants were enrolled from a multi-center cohort in Northern China. Participants were grouped into RC quartiles (0.58 mmol/L, 0.58-1.07 mmol/L, 1.07-1.69 mmol/L, and ≥1.69 mmol/L). The primary endpoint was CRC incidence. The secondary endpoint was ASCVD incidence, defined as the occurrence of myocardial infarction and stroke. Cox proportional hazards models were utilized to assess the association between RC levels and study outcomes, adjusting for age, gender, high-sensitivity C-reactive protein, body mass index, hypertension, physical activity, smoking, alcohol consumption, and educational status. Chi-square tests were used to calculate the differences in CRC and ASCVD incidence rates in LDL-C 2.6 mmol/L subgroup. Results During a median follow-up of 15.01 years, 635 CRC events occurred. Each 1 mmol/L increase in RC levels was associated with a 15% higher CRC risk (95% confidence interval CI: 1.06-1.25), which remained significant after adjusting for potential confounders (adjusted hazard ratio HR=1.12, 95%CI: 1.03-1.22). Participants in the highest RC quartile (≥1.69 mmol/L) had a significantly increased risk of CRC compared to those in the lowest quartile (0.58 mmol/L) (crude HR Q4 vs. Q1=1.52, 95%CI: 1.22-1.90; adjusted HR Q4vs.Q1=1.40, 95%CI: 1.12-1.75). Among patients with LDL-C 2.6 mmol/L, participants with RC ≥1.96 mmol/L had a higher incidence rate of both CRC (1.03% vs. 0.72%, P0.0001) and ASCVD (9.69% vs. 7.42%, P0.0001), compared to those with RC 1.69 mmol/L. Conclusions Serum RC level was a robust predictor of CRC incidence. Notably, an RC level of ≥1.69 mmol/L was associated with an elevated risk of CRC. Furthermore, among patients with LDL-C 2.6 mmol/L, RC level ≥1.69 mmol/L were linked to a heightened incidence of both CRC and ASCVD, posing a dual threat to cardiovascular and colorectal health. This underscores the importance of monitoring RC levels as a potential biomarker for both CRC and ASCVD risk.Association between RC and CRC risk Incidence rate of CRC and ASCVD