Clinical Research
Lipids and Risk
PCSK9R46L, Low-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease: 3 Independent Studies and Meta-Analyses

https://doi.org/10.1016/j.jacc.2010.02.044Get rights and content
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Objectives

The aim of this study was to examine the effect of PCSK9R46L 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 PCSK946L 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.

Key Words

cholesterol
epidemiology
genetics of cardiovascular disease
LDL cholesterol
lipids
PCSK9

Abbreviations and Acronyms

CI
confidence interval
HDL-C
high-density lipoprotein cholesterol
HR
hazard ratio
IHD
ischemic heart disease
LDL-C
low-density lipoprotein cholesterol
LDLR
low-density lipoprotein receptor
MI
myocardial infarction
OR
odds ratio
PCSK9
proprotein convertase subtilisin/kexin type 9

Cited by (0)

This work was supported by the Danish Medical Research Council, the Danish Heart Foundation, the Research Fundat Rigshospitalet, Copenhagen University Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund, Ingeborg and Leo Dannin's Grant, and Henry Hansen and Wife's Grant, Copenhagen, Denmark.