Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity.

Chemistry and Biochemistry Department, George Mason University, Manassas, VA 20110, USA.
Indian journal of biochemistry & biophysics (Impact Factor: 1.03). 12/2010; 47(6):331-9.
Source: PubMed

ABSTRACT While statins, hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitors, are clinically proven to reduce plasma cholesterol levels, a wide variation in inter-individual response to statin therapy has been observed. Pharmacogenetic studies have identified multiple loci that potentially contribute towards the statin response, including the HMGCR gene. To examine, if a statin-resistant, catalytically-active isoform of the human HMGCR could be generated, we have rationally altered the protein to include additional residues in the flap domain, which has a role in statin binding. Comparative enzyme assays with purified wild-type and mutant isoforms reveal the alteration imposes a slight (38%) decrease in the K(app)(M) for the substrate, a near 2-fold increase in turnover number, and a 480% increase in the Ki for lovastatin. Thus, alterations in HMGCR could contribute towards the synergistic effects of multiple loci in the statin response.

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    ABSTRACT: Hydroxymethylglutaryl-Coenzyme A Reductase (HMGCR) catalyzes the rate-limiting step of cholesterol biosynthesis. This enzyme is the target of the widely available cholesterol lowering statins. In this population-based case-control study, the frequencies of -911 C>A polymorphism (rs3761740) of the HMGCR gene in patients with coronary heart disease (CHD) and healthy subjects were investigated and the correlations between the different genotypes and hypercholesterolemia with cardiovascular risk factors were analyzed. The HMGCR genotypes were determined in 365 patients with CHD and 365 controls by PCR-RFLP assay. Anthropometric measurements were measured in all participants. There was no significant difference in the genotype frequencies of the HMGCR polymorphism between the male subjects of both patient and control groups, however, the HMGCR-CC genotype was found to be more frequent in female patients with CHD than female controls (p=0.002). The HMGCR-CC genotype showed higher total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels than the CA+AA genotypes in male CHD patients (p=0.018). Due to this significant sex interaction, a multivariate analysis was conducted on the patient group. In the multivariate logistic regression analysis, the HMGCR-CC genotype was significantly associated with age<55 (OR=2.837, p=0.001) and TC≥5.18mmol/L (OR=1.970, p=0.027) in male subjects. However, this association was not observed in female patients (p>0.05). This analysis confirmed that the HMGCR-CC genotype was associated with elevated TC levels in male CHD patients with age<55years. These results suggest that age and sex modify the contribution of the HMGCR-911 polymorphism to fasting serum TC, LDL-C levels and risk of CHD.
    Gene 08/2013; · 2.20 Impact Factor
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    ABSTRACT: Hypercholesterolemia and dyslipidemia are independent risk factors for cardiovascular disease and death. Statins are the drugs of choice to decrease plasma cholesterol and have other beneficial actions beyond lipid-lowering leading to substantial improvements in cardiovascular morbidity and mortality. However, evaluation of the effects of statins to reduce overall morbidity and mortality must integrate metabolic consequences of statin therapy with its lipid-lowering effect. Indeed, reduction in LDL-cholesterol to target level achieved by statins does not completely eliminate risk of cardiovascular disease and may elevate metabolic risk factors that contribute to dysregulation of metabolic homeostasis. This may lead to increased incidence of diabetes and its cardiovascular complications that are explained, in part, by reciprocal relationships between insulin resistance and endothelial dysfunction. Genetic factors may determine 40-60% of total cholesterol levels and 70% of the efficacy of statin treatments. Metabolic and cardiovascular phenotypes that are either genetically determined or environmentally acquired are also important determinants of responses to specific statins. Moreover, differences between biological outcomes of specific statins or increasing dosages of statins result in differential metabolic actions due to off-target or unknown mechanism that have important implications for the use of statins to reduce overall morbidity and mortality. In this review, we discuss differential cardiovascular and metabolic pleiotropic actions of specific statins that interact in a context-dependent manner with patient phenotypes and genotypes. These important considerations may influence progression of atherosclerosis, risk of diabetes, and modulation of insulin resistance that help determine overall morbidity and mortality in patients undergoing statin therapy.
    International journal of cardiology 11/2012; · 6.18 Impact Factor

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Safdar Jawaid