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

Study Questions:

What is the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD)?


A series of meta-analyses were conducted to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by nine polymorphisms in six different genes. The Mendelian randomization studies were combined in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compare it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin.


The exposure allele for each single nucleotide polymorphism (SNP) was associated with a lower LDL-C level that varied significantly between 2.6 and 16.7 mg/dl. Among the included SNPs, the reduction in risks of CHD ranged between 6% and 28%. All nine polymorphisms were associated with a highly consistent reduction in the risk of CHD per 38.7 mg/dl lower LDL-C, with no evidence of heterogeneity of effect (I2 = 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, 48.8-59.5%) reduction in the risk of CHD for each 38.7 mg/dl lower LDL-C. This represents a three-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).


The authors concluded that 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.


The suggestion that earlier intervention with lipid-lowering agents (statins) should be considered has been proposed for years. But the absence of controlled trials demonstrating very long-term safety and the very significant cost of statins had a negative influence on this aggressive approach. These data strongly support a very early approach to lifestyle change that can impact lipids, and potentially the use of statins, for those young individuals at high risk. The strongest effect was found in the loss of function of the PCHK-9 gene that was associated with a modest 15% reduction in LDL-C, but a >50% decrease in CHD. It is not at all clear whether the difference between protective genes throughout life and statins is simply the LDL-C.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Life Style, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Disease, Cholesterol, Polymorphism, Single Nucleotide, Troponin I, Cardiology, Mendelian Randomization Analysis, Hypolipidemic Agents, Confidence Intervals, Pregnancy, Naphazoline

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