PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

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.

[1]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[2]  R. Collins,et al.  Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. , 1999, American journal of epidemiology.

[3]  W. Boden,et al.  Management of Stable Angina Pectoris , 1999 .

[4]  L. Tavazzi,et al.  Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. , 1997, European heart journal.

[5]  V. Salomaa,et al.  Hemostatic factors as predictors of stroke and cardiovascular diseases: the FINRISK ’92 Hemostasis Study , 2005, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[6]  Alexander Pertsemlidis,et al.  Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 , 2005, Nature Genetics.

[7]  J. Ordovás,et al.  Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. , 2008, Atherosclerosis.

[8]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[9]  Jonathan C. Cohen,et al.  Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. , 2006, The New England journal of medicine.

[10]  S. Kathiresan.  A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. , 2008, The New England journal of medicine.

[11]  R. Płoski,et al.  Effect of protein convertase subtilisin/kexin type 9 (PCSK9) 46L gene polymorphism on LDL cholesterol concentration in a Polish adult population. , 2008, Molecular genetics and metabolism.

[12]  E. Boerwinkle,et al.  Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study). , 2007, The American journal of cardiology.

[13]  J. Goldstein,et al.  Lowering LDL--Not Only How Low, But How Long? , 2006, Science.

[14]  Douglas G Altman,et al.  Interaction revisited: the difference between two estimates , 2003, BMJ : British Medical Journal.

[15]  J. Weissenbach,et al.  Mutations in PCSK9 cause autosomal dominant hypercholesterolemia , 2003, Nature Genetics.

[16]  A. Tall.  Protease variants, LDL, and coronary heart disease. , 2006, The New England journal of medicine.

[17]  S. Fortmann,et al.  A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[18]  Jonathan C. Cohen,et al.  A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. , 2006, American journal of human genetics.

[19]  Jonathan C. Cohen,et al.  Molecular biology of PCSK9: its role in LDL metabolism. , 2007, Trends in biochemical sciences.

[20]  S. Humphries,et al.  The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. , 2007, Clinical science.

[21]  S. Kathiresan,et al.  Polymorphisms Associated With Cholesterol and Risk of Cardiovascular Events , 2008 .

[22]  Jonathan C. Cohen,et al.  Genetic and metabolic determinants of plasma PCSK9 levels. , 2009, The Journal of clinical endocrinology and metabolism.

[23]  B. Nordestgaard,et al.  Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. , 2007, JAMA.

[24]  Jonathan C. Cohen,et al.  PCSK9: a convertase that coordinates LDL catabolism Published, JLR Papers in Press, November 19, 2008. , 2009, Journal of Lipid Research.