APOE and cancer: Mendelian randomization was first proposed in 1986 to evaluate whether the association between cholesterol concentrations and cancer was really causative using apoE genotypes (ε2, ε3, ε4),107 and has been reviewed extensively.108 It is a method in which measured variation in genes of interest is used to evaluate the effects of a measure of exposure (e.g., concentrations of cholesterol or TG) on disease states (e.g., incidence of CHD).109 The design is highly resistant to reverse causation and confounding, which often impede or mislead epidemiological studies.