Genetic variation at the PCSK9 locus, low density lipoproteins, response to pravastatin and coronary heart disease: results from PROSPER

Authors: POLISECKI, ELLENA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PETER, INGA - Tufts - New England Medical Center; ROBERTSON, MICHELE - University Of Glasgow; MCMAHON, ALEX - University Of Glasgow; FORD, IAN - University Of Glasgow; PACKARD, CHRISTOPHER - University Of Glasgow; SHEPHERD, JAMES - University Of Glasgow; JUKEMA, J WOUTER - Leiden University Medical Center; BIAUW, GERARD - Leiden University Medical Center; WESTENDROP, RUDI - Leiden University Medical Center; DE CREAN, ANTON - Leiden University Medical Center; TROMPET, STELLA - Leiden University Medical Center; BUCKLEY, BRENDAN - Cork Institute Of Technology; MURPHY, MICHAEL - Cork Institute Of Technology; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; SCHAEFER, ERNST - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2007
Publication Date: 9/20/2008
Citation: Polisecki, E., Peter, I., Robertson, M., Mcmahon, A.D., Ford, I., Packard, C., Shepherd, J., Jukema, J., Biauw, G.J., Westendrop, R.G., De Crean, A.J., Trompet, S., Buckley, B.M., Murphy, M.B., Ordovas, J.M., Schaefer, E.J. 2008. Genetic variation at the PCSK9 locus, low density lipoproteins, response to pravastatin and coronary heart disease: results from PROSPER. Atherosclerosis. 200:95-101.

Interpretive Summary: The major cholesterol carrying particles in the bloodstream are known as low density lipoproteins or LDL. High levels of LDL cholesterol (> 160 mg/dl) have been associated with an increased risk of heart disease, a leading cause of death and disability in our society. Another cholesterol carrying particle in the bloodstream is known as high density lipoprotein cholesterol. Low levels of high density lipoprotein (HDL) cholesterol (< 40 mg/dl in men and < 50 mg/dl in women) have also been associated with an increased risk of heart disease. LDL is known to deposit cholesterol in tissues, while HDL is known to remove it for return to the liver and excretion from the body. LDL cholesterol can be increased because of diets high in animal fat and cholesterol, or on an inherited basis, or both. Diets low in animal fat and cholesterol and enriched in plant food and vegetable oil have been shown to lower LDL cholesterol and reduce the risk of heart disease. In addition, medications have been developed that decrease cholesterol production in the body and also lower LDL cholesterol and reduce the risk of developing heart disease. These medicines are called statins. Statins work by inhibiting the enzyme HMG CoA reductase, the rate limiting enzyme in cholesterol production. When statin decrease cholesterol production in the liver, they also upregulate the levels of the LDL receptor that is responsible for removing LDL from the bloodstream, and this causes the LDL cholesterol to be lowered. One statin that is widely used is pravastatin. This stain at a dose of 40 mg/day was used in a study of 5,804 elderly men and women about half of whom had heart disease. In this study pravastatin lowered LDL cholesterol 32%, and decreased heart disease risk about 20%. In this population, we tested whether genetic variation at the gene locus for proprotein convertase subtilisin/kexin type 9 (PCSK9) would affect baseline LDL cholesterol levels, LDL lowering response to pravastatin, and heart disease risk. The production of this gene PCSK9 has been reported to affect LDL cholesterol levels, LDL receptor activity, and heart disease risk. We noted that genetic variation at PCSK9 did have a significant effect on baseline LDL cholesterol levels, no effect on percentage LDL cholesterol lowering with pravastatin, and a modest effect on heart disease risk while on study. Therefore our data indicate that genetic variation at the PCSK9 locus can have a significant impact on baseline LDL cholesterol levels and heart disease risk in an elderly population. It is known that lowering elevated blood cholesterol ( > 240 mg/dl) and elevated low density lipoprotein (LDL) cholesterol ( > 160 mg/dl) with diet and statin medications can reduce the risk of heart disease. This study shows that genetic variation at the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene locus that can affect LDL receptor activity can be used to predict baseline LDL cholesterol levels, and those most likely to benefit from statin treatment in terms of heart disease risk reduction.

Technical Abstract: Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5783 elderly participants in Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p < 0.001) lower levels of LDL C (mean, -10%), no difference in LDL C lowering response to pravastatin, and a non-significant 19% unadjusted and 9% adjusted decreased risk of vascular disease at baseline, with no on trial effect. Moreover, 6.0% were carriers of the G allele at E670G with no significant relationships with baseline LDL C, response to pravastatin, or vascular disease risk being observed. Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.