Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Area of Science:

• Genetics
• Epidemiology
• Oncology

Background:

• Observational studies suggest a link between high blood cholesterol and colorectal cancer (CRC) risk, but causality remains unclear.
• Mendelian randomization (MR) offers a robust method to investigate causal relationships using genetic variants as instrumental variables.
• Understanding the causal role of lipid profiles in CRC development is crucial for effective prevention strategies.

Purpose of the Study:

• To investigate the potential causal effect of key lipid traits—total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)—on colorectal cancer (CRC) risk.
• To evaluate the impact of genetically predicted statin therapy on CRC risk.

Main Methods:

• Employed Mendelian randomization (MR) analysis using single nucleotide polymorphisms (SNPs) associated with lipid levels as instrumental variables.
• Utilized SNP-CRC associations from a large dataset comprising 9,254 CRC cases and 18,386 controls.
• Constructed a genetic risk score for HMGCR to simulate the effect of statin therapy.

Main Results:

• Genetically predicted higher total cholesterol (TC) was significantly associated with an elevated risk of colorectal cancer (CRC) (OR=1.46, p=1.68 × 10^-4).
• No significant causal associations were found for triglycerides (TG), LDL, or HDL with CRC risk (pooled ORs between 0.94-1.05).
• A genetic risk score mimicking statin therapy showed a reduced CRC risk (OR=0.69, p=0.046).

Conclusions:

• This MR study provides evidence for a causal relationship between elevated total cholesterol (TC) and increased colorectal cancer (CRC) risk.
• The findings support public health initiatives aimed at reducing hyperlipidemia prevalence to mitigate CRC risk.
• Genetically predicted statin effects suggest a potential therapeutic avenue for CRC prevention.