Mendelian randomization analysis rules out disylipidaemia as colorectal cancer cause

Abstract

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A case-control study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72–1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95–1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81–1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84–1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70–1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66–0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels.

Long-Term Statin Use, Total Cholesterol Level, and Risk of Colorectal Cancer: A Prospective Cohort Study

“…One plausible explanation includes the potential link between statin use and development of incident diabetes, although the risk elevations are generally slight in previous trials (44,45). It is still controversial whether dyslipidemia is directly involved in colorectal neoplastic transformation given inconsistent results from previous Mendelian randomization analyses (46–48) and other studies (25,49–51). However, our current result does not support an association between total cholesterol level and CRC risk.…”

Prognostic nomograms integrating preoperative serum lipid derivative and systemic inflammatory marker of patients with non-metastatic colorectal cancer undergoing curative resection

“…found that increased adipose triglyceride lipase is negatively correlated with the OS of CRC patients, and in vivo experiments showed that it could promote the progression of CRC by enhancing lipid mobilization or lipolysis ( 40 ), which also reflects that high serum TG level are related to the improvement of prognosis. Other studies showed that increased TG or decreased HDL-C are associated with poor prognosis in CRC ( 11 , 41 ), or not ( 13 , 42 ). However, although some studies seem to support THR as an independent protective factor for CRC patients, further exploration is needed.…”

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

“…It is also likely that statins (which is a drug prescribed to reduce LDL-cholesterol levels) could confound the dyslipidemia-CRC associations. Findings from prospective and MR studies of either dyslipidemia or statins with CRC risk are inconsistent in this respect (34)(35)(36)(37). Collectively, it remains to be clarified whether dyslipidemia plays a causal role in CRC development or is only a bystander.…”