Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis

Objectives: The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD).

Background: LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified.

Methods: We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin.

Results: All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)).

Conclusions: Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.