TY - JOUR
T1 - PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses
AU - Benn, Marianne
AU - Nordestgaard, Børge G
AU - Grande, Peer
AU - Schnohr, Peter
AU - Tybjaerg-Hansen, Anne
AU - Benn, Marianne
N1 - Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PY - 2010/6/22
Y1 - 2010/6/22
N2 - Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life.
AB - Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life.
U2 - http://dx.doi.org/10.1016/j.jacc.2010.02.044
DO - http://dx.doi.org/10.1016/j.jacc.2010.02.044
M3 - Journal article
SN - 0735-1097
VL - 55
SP - 2833
EP - 2842
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 25
ER -