Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER

Authors: POLISECKI, ELIANA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MUALLEM, HIND - University Of North Carolina; MAEDA, NOBUYO - University Of North Carolina; PETER, INGA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; 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; WESTENDORP, RUDI - Leiden University Medical Center; DE CREAN, ANTON - Leiden University Medical Center; BUCKLEY, BRENDAN - 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; JUKEMA, J WOUTER - Leiden University Medical Center

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2007
Publication Date: 9/20/2008
Citation: Polisecki, E., Muallem, H., Maeda, N., Peter, I., Robertson, M., Mcmahon, A.D., Ford, I., Packard, C., Shepherd, J., Westendorp, R.G., De Crean, A.J., Buckley, B.M., Ordovas, J.M., Schaefer, E.J., Jukema, J. 2008. Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Atherosclerosis. 200:109-114.

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 in people 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 the LDL receptor and HMG CoA reductase would affecr baseline LDL cholesterol levels, LDL lowering response to pravastatin, and heart disease risk. We did not find significant nrelationships with genetic variation at the HMG CoA reductase gene locus and any of these previously mentioned parameters. We did see significant relationships with genetic variation at the LDL receptor locus, baseline LDL cholesterol levels, percentage LDL cholesterol lowering with pravastatin, and heart disease risk while on study. Therefore our data suggests that genetic variation at the LDL receptor locus can have a significant impact on baseline LDL cholesterol levels, the degree of LDL cholesterol lowering achieved by a statin, and heart disease risk reduction associated with statin therapy. 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 LDL receptor locus can be used to predict those most likely to benefit from statin treatment, and exhibit the greatest reductions in LDL cholesterol levels with statin treatment.

Technical Abstract: Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLRC44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCRi18 T >G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease (CVD) on trial. Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.