TY - JOUR
T1 - Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease
T2 - A mendelian randomization analysis
AU - Ference, Brian A.
AU - Yoo, Wonsuk
AU - Alesh, Issa
AU - Mahajan, Nitin
AU - Mirowska, Karolina K.
AU - Mewada, Abhishek
AU - Kahn, Joel
AU - Afonso, Luis
AU - Williams, Kim Allan
AU - Flack, John M.
N1 - Funding Information:
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.
PY - 2012/12/25
Y1 - 2012/12/25
N2 - 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.
AB - 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.
KW - cardiovascular disease
KW - genetic polymorphism
KW - low-density lipoprotein cholesterol
KW - myocardial infarction
KW - prevention
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U2 - 10.1016/j.jacc.2012.09.017
DO - 10.1016/j.jacc.2012.09.017
M3 - Article
C2 - 23083789
AN - SCOPUS:84871260146
SN - 0735-1097
VL - 60
SP - 2631
EP - 2639
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 25
ER -