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Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study
Stella Trompet1, J Wouter Jukema, Martijn B Katan
1Department of Gerontology and Geriatrics, C-2-R Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands. s.trompet@lumc.nl
American Journal of Epidemiology
|November 6, 2009
Summary
Low plasma cholesterol is not causally linked to increased cancer risk. A Mendelian randomization study using apolipoprotein E (ApoE) genotype found no increased cancer risk in individuals with lower cholesterol levels.
Area of Science:
- Cardiovascular epidemiology
- Genetics
- Oncology
Background:
- Observational studies suggest a link between low cholesterol and cancer risk.
- Randomized trials of cholesterol-lowering drugs have not confirmed this association.
- Confounding and reverse causality complicate the interpretation of observational data.
Purpose of the Study:
- To investigate the causal relationship between plasma cholesterol levels and cancer risk.
- To overcome confounding and reverse causality using a Mendelian randomization approach.
- To utilize apolipoprotein E (ApoE) genotype as a genetic instrument for plasma cholesterol.
Main Methods:
- A Mendelian randomization study was conducted using data from 2,913 participants.
- Apolipoprotein E (ApoE) genotype, plasma cholesterol, and cancer incidence/mortality were assessed.
- Follow-up occurred over a 3-year period within the Prospective Study of Pravastatin in the Elderly at Risk.
Main Results:
- Individuals in the lowest third of plasma cholesterol showed increased cancer incidence (HR=1.90) and mortality (HR=2.03).
- ApoE2 genotype carriers, with lower cholesterol, did not exhibit increased cancer incidence (HR=0.86) or mortality (HR=0.70) compared to ApoE4 carriers.
- These results challenge the hypothesis that low cholesterol directly increases cancer risk.
Conclusions:
- Low plasma cholesterol levels are unlikely to be causally associated with an increased risk of cancer.
- Mendelian randomization provides stronger evidence than observational studies for this relationship.
- The findings support the use of genetic epidemiology to clarify complex etiological questions.
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