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American Journal of Epidemiology Advance Access published online on November 4, 2009
American Journal of Epidemiology, doi:10.1093/aje/kwp294
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American Journal of Epidemiology © The Author 2009. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

Original Contribution

Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study

Stella Trompet*, J. Wouter Jukema, Martijn B. Katan, Gerard J. Blauw, Naveed Sattar, Brendan Buckley, Muriel Caslake, Ian Ford, Jim Shepherd, Rudi G. J. Westendorp and Anton J. M. de Craen

* Correspondence to Stella Trompet, Department of Gerontology and Geriatrics, C-2-R Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands (e-mail: s.trompet{at}lumc.nl).

Received for publication May 8, 2009. Accepted for publication August 17, 2009.

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

apolipoproteins E; cholesterol; genetics; neoplasms; random allocation

Abbreviations: ApoE, apolipoprotein E; CI, confidence interval; HR, hazard ratio; LDL, low density lipoprotein; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; SE, standard error


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