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.
OBJECTIVE
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.
Division of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan 48202, USA. bference@med.wayne.edu
Brian A
BA
Ference
Wonsuk
W
Yoo
Issa
I
Alesh
Nitin
N
Mahajan
Karolina K
KK
Mirowska
Abhishek
A
Mewada
Joel
J
Kahn
Luis
L
Afonso
Kim Allan
KA
Williams
John M
JM
Flack
D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003324:Coronary Artery Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics; D005500:Follow-Up Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014943:Global Health; D006801:Humans; D015994:Incidence; D057182:Mendelian Randomization Analysis; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D008078:Cholesterol, LDL; D005819:Genetic Markers