[EN] Colorectal cancer (CRC) has been associated with both genetic and environmental risk factors such as diet1,2, alcohol3, smoking4, physical activity5 and metabolic syndrome6,7. Metabolic syndrome is a cluster of important cardiovascular risk factors: high fasting glucose, abdominal obesity, high triglycerides (TG), reduced high density lipoprotein cholesterol (HDL) and high blood pressure. As one of the components, dyslipidemia has been thought to have an important role in inflammatory pathways, oxidative stress and insulin resistance, which could contribute to the pathogenesis of cancer. However, findings from prospective studies that have examined the association between serum dyslipidemia (TG, HDL, low density lipoprotein cholesterol (LDL) or total cholesterol (TC)) and colorectal neoplasia have been inconsistent6,8,9,10,11. It is unknown whether lipids and lipoproteins cause cancer or are intermediate or correlated factors within carcinogenic pathways. The Mendelian randomization approach can be used to establish a causal relationship between dyslipidemia and CRC. Mendelian randomization studies use the distribution of alleles in the population to simulate randomized assignment to lower or higher lipids. A previous Mendelian randomization analysis assessing the causality of dyslipidemia and CRC has been published before11. It reported an association between a genetic score for TC and the risk of CRC (OR per unit SD increase = 1.46; 95% CI: 1.20–1.79) but no significant association was found for LDL, HDL or TG. While the association of TC was strong, the interpretation of the results is not straightforward, since TC is the sum of LDL and HDL cholesterol, fractions that have been reported to have opposite effects regarding CRC and may explain the controversial findings of studies that have analyzed the association between high levels of serum TC and CRC risk8,9,12. A causal effect of lipids regarding CRC risk should have a clear mechanistic interpretation. Being TC essentially the sum of HLD and LDL, genetic instruments for TC are correlated either with LDL, HDL or both, which violates the pleiotropy assumption of Mendelian randomization studies.S
