Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Abstract

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, P=1.68x10-4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, P=0.49), 0.94 (95% CI: 0.84-1.05, P= 0.27), and 0.98 (95% CI: 0.85-1.12, P=0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR=0.69, 95% CI: 0.49-0.99, P=0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

“…Metabolic factors related to the metabolic syndrome other than body fatness, such as blood pressure and blood lipids, are associated with CRC risk, independently of BMI . While the evidence for causality for these factors is limited compared to for body fatness, there is genetic evidence supporting a causal, BMI‐independent, role for total cholesterol . To our knowledge, no previous study has investigated whether metabolic factors related to the metabolic syndrome demonstrate subtype‐specific relationships with CRC risk …”

“…This was, to our knowledge, the first molecular pathological epidemiology study of CRC and several metabolic factors other than BMI. By studying several metabolic factors, we were able to assess several aspects of metabolic health, which do not always co‐exist with obesity, and are independently associated with CRC risk . The prospective cohort design with long follow‐up (up to 31 years) reduces the risk of recall bias and reverse causation.…”

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

“…Finally, a case–control CRC study from Croatia consisting of 764 cases and 460 population-based controls was also included in the analysis. Details of study genotyping, quality control procedures and imputations are presented in Additional file 1 and elsewhere [ 30 , 31 ]. A total of 9940 cases and 22,848 controls with genotyping data were included after extensive quality control procedures (Additional file 1 ).…”

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

“…A limited number of Mendelian randomization studies have investigated the relationship between HMGCR inhibition and cancer [37][38][39][40][41] , with protective associations observed for prostate cancer 37 , colorectal cancer 38 , breast cancer 39,40 , and ovarian cancer 41 . However, no comprehensive Mendelian randomization investigation has evaluated the predicted impact of HMGCR inhibition or the causal role of specific lipid fractions on the risk of many of the most common site-specific cancers.…”