Author + information
- Received June 27, 2012
- Revision received September 5, 2012
- Accepted September 11, 2012
- Published online December 25, 2012.
- Brian A. Ference, MD, MPhil, MSc⁎,†,‡,⁎ (, )
- Wonsuk Yoo, PhD§,
- Issa Alesh, MD‡,
- Nitin Mahajan, MD, MPH‡,
- Karolina K. Mirowska, MD∥,
- Abhishek Mewada, MD∥,
- Joel Kahn, MD¶,
- Luis Afonso, MD‡,
- Kim Allan Williams Sr, MD‡ and
- John M. Flack, MD, MPH⁎∥
- ↵⁎Reprint requests and correspondence:
Dr. Brian A. Ference, Division of Translational Research and Clinical Epidemiology (TRaCE), Wayne State University School of Medicine, UHC, 4H-34, Detroit, Michigan 48202
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 (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% 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.
- cardiovascular disease
- genetic polymorphism
- low-density lipoprotein cholesterol
- myocardial infarction
Funded by Wayne State University School of Medicine. Dr. Flack is a consultant to Novartis, Medtronic, Back Beat Hypertension, Boehringer Ingleheim, and Daiichi Sankyo; and has received research grants from Novartis, Medtronic, and the NIH. Dr. Williams is a consultant and speaker for Astellas Healthcare, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 27, 2012.
- Revision received September 5, 2012.
- Accepted September 11, 2012.
- American College of Cardiology Foundation