Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study.
Level 3 - non-randomized controlled study
Prospective cohort study and Mendelian randomization instrumental variable analysis
PubMed 21285406 · doi:10.1093/jnci/djr008
What was done
The authors evaluated whether low low-density lipoprotein (LDL) cholesterol causally increases cancer risk using observational and Mendelian randomization analyses. They studied 10,613 participants from the Copenhagen City Heart Study (CCHS) and 59,566 from the Copenhagen General Population Study, among whom 6,816 developed cancer by May 2009. Participants were genotyped for genetic variants associated with lifelong lower LDL cholesterol: PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE (rs429358 and rs7412). Risk of cancer was evaluated prospectively with Cox proportional hazards regression and causality was evaluated using instrumental variable analysis.
What was found
In CCHS, observational plasma LDL cholesterol below the 10th percentile (<87 mg/dL) compared with above the 66th percentile (>158 mg/dL) was associated with a 43% increase in cancer risk (95% CI = 15% to 79%). The genetic variants reduced LDL cholesterol by up to 38% (95% CI = 36% to 41%) but were not associated with increased cancer risk. The instrumental variable causal odds ratio for cancer per 50% genetically predicted reduction in LDL cholesterol was 0.96 (95% CI = 0.87 to 1.05), contrasting with an observational hazard ratio of 1.10 (95% CI = 1.01 to 1.21) per 50% lower LDL cholesterol in CCHS (P for difference = .03).
Why it matters
These findings suggest that the observed association between low circulating LDL cholesterol and higher cancer risk is non-causal and likely reflects reverse causation or confounding, supporting the safety of LDL-lowering therapies regarding cancer risk.
Limits
The study was conducted in a single Danish population, which may limit generalizability to other ethnic groups. Site-specific cancer outcomes and potential horizontal pleiotropy beyond the chosen genetic instruments were not detailed in the abstract.
Cited by
- supports Mendelian randomization studies show no causal association between low LDL cholesterol and increased cancer incidence.