Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

Thompson, John F.; Hyde, Craig; Wood, Linda; Paciga, Sara A.; Hinds, David A.; Cox, David; Hovingh, G. Kees; Kastelein, John J.P.

doi:10.1161/circgenetics.108.818062

Cited by 174 publications

(140 citation statements)

References 27 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…In the literature, it was shown that the MTHFR C677T polymorphism causes high levels of homocysteine, which can be decreased by statins (1,6). Recent studies suggested that multiple genetic factors, especially MTHFR, which plays a role in the methylation pathway, act for personal therapy (19,20). However, in the present study, we could not find any relationship between the studied polymorphism and impact of statin.…”

Section: Discussioncontrasting

confidence: 84%

Statin and MTHFR C677T Polymorphism in Patients with Cardiovascular Diseases

İzmirli¹,

Bacaksız²,

Alptekin³

et al. 2014

Bezmialem Science

View full text Add to dashboard Cite

Objective: Cardiovascular disease (CVD) is the leading cause of death worldwide. The methylenetetrahydrofolate reductase (MTHFR) gene, located on the short (p) arm of chromosome 1 at position 36.3 (1p36.3), might be a possible risk factor for the pharmacogenetics in CVD. A common polymorphism in MTHFR (C677T, Ala→Val) decreases this enzyme activity and increases the homocysteine concentrations, predisposing one to heart disease. Alternatively, statins, cholesterol-reducing agents, are also used to reduce the homocysteine blood concentrations; the aim of the present study was to evaluate how the genotype frequencies of the MTHFR C677T polymorphism, namely rs1801133, change in the cardiovascular system in patients treated with statin. Methods:In this study, the genotype distribution of the MTHFR C677T polymorphism in CVD patients treated with statin (hydrophilic and lipophilic) (n=290) and healthy controls (n=151) was assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results:In this study, a statistically significant difference in genotype frequencies for the MTHFR C677T polymorphism was found between CVD patients treated with statin and controls (p=0.037). Yöntemler: Bu çalışmada, lipofilik ve hidrofilik statinler ile tedavi edilen kardiyovasküler sistem hastalarında (n=290) ve sağlıklı kontrollerde (n=151) MTHFR C677T polimorfizmindeki genotip dağılımları incelenmiştir. Genotipleme, Polimeraz zincir reaksiyonu (PCR) ve restriksiyon parça uzunluk polimorfizm (RFLP) yöntemi ile yapılmıştır. Bulgular: Bu çalışmada, MTHFR C677T polimorfizminin genotip dağılımında statin tedavisi gören kardiyovasküler sistem hastaları ile kontrol grubu arasında istatistiksel olarak anlamlı bir fark gözlenmiştir (p=0,037). ConclusionSonuç: Türk popülasyonunda statin ile tedavi edilen kardiyovasküler sistem hastaları ile MTHFR C677T polimorfizmi arasında istatistiksel olarak anlamlı bir ilişki ilk kez gösterilmiştir.

show abstract

Section: Discussioncontrasting

confidence: 84%

Statin and MTHFR C677T Polymorphism in Patients with Cardiovascular Diseases

İzmirli¹,

Bacaksız²,

Alptekin³

et al. 2014

Bezmialem Science

View full text Add to dashboard Cite

show abstract

“…Several studies analysing the influence of genetic variants on the individual variability of statin efficacy have focused on candidate genes obviously involved in cholesterol metabolism and disease progression. These studies have focused on genes such as the cholesterol receptors LDLR and SCARB1, the cholesterol-metabolizing enzymes HMGCR and CYP7A1, or the cholesterol transporter ABCG8 and ABCA1 [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Schwabedissen

Albers²,

Baumeister³

et al. 2015

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Background The efficacy of statins, which are used commonly in primary and secondary prevention of cardiovascular diseases, shows a wide range of interindividual variability. Genetic variants of OATP1B1, a hepatic uptake transporter, can modify access of statins to its therapeutic target, thereby potentially altering drug efficacy. We studied the impact of genetic variants of OATP1B1 on the lipid-lowering efficacy of statins in a population-based setting. Materials and methodsThe basis of the analysis was the Study of Health in Pomerania, a cohort of 2732 men and women aged 20-81 years. Included in the statistical analysis to evaluate the impact of OATP1B1 on therapeutic efficacy of statins were 214 individuals diagnosed with dyslipidaemia during initial recruitment and receiving statins during the 5-year follow-up.Results Analysing the impact of the OATP1B1 genotype, we observed a trend for lower statin-induced total cholesterol reduction in carriers of the SLCO1B1 512C variant. Restricting the analysis to patients receiving simvastatin, pravastatin, lovastatin and fluvastatin indicated a statistically significant association of the OATP1B1 genotype on lipid parameters at the 5-year follow-up. No such effect was observed for atorvastatin. Calculation of achievement of treatment goals according to the NCEP-ATPIII guidelines showed a lower rate of successful treatment when harbouring the mutant allele for patients taking simvastatin (46.7 vs. 73.9%). A similar trend was observed for pravastatin (34.4 vs. 70.4%).Conclusion Genetic variants of OATP1B1 leading to impaired hepatic uptake of statins translated into reduced drug efficacy in a population-based cohort.

show abstract

“…The importance of HDL-C in disease makes it amenable to candidate-gene and whole-genome association studies (5)(6)(7)(8)(9). Because of the accuracy with which HDL-C can be determined and its high heritability, studies with HDL-C often yield positive results with cholesteryl ester transfer protein (CETP) generally found to be the most highly associated gene.…”

mentioning

confidence: 99%

Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1

Zhu

Gardner

Pullinger

et al. 2009

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations controlling the levels of risk factors associated with the development of the disease continues. Multiple genetic association studies suggest the involvement of procollagen C-proteinase enhancer-2 (PCPE2) in modulating HDL-C levels. Therefore biochemical and mechanistic studies were undertaken to determine whether there might be a basis for a role of PCPE2 in HDL biogenesis. Our studies indicate that PCPE2 accelerates the proteolytic processing of pro-apolipoprotein (apo) AI by enhancing the cleavage of the hexapeptide extension present at the N terminus of apoAI. Surface Plasmon Resonance and immunoprecipitation studies indicate that PCPE2 interacts with BMP-1 and pro-apoAI to form a ternary pro-apoAI/BMP-1/PCPE2 complex. The most favorable interaction among these proteins begins with the association of BMP-1 to pro-apoAI followed by the binding of PCPE2 which further stabilizes the complex. PCPE2 resides, along with apoAI, on the HDL fraction of lipoproteins in human plasma supporting a relationship between HDL and PCPE2. Taken together, the findings from our studies identify a new player in the regulation of apoAI post-translational processing and open a new avenue to the study of mechanisms involved in the regulation of apoAI synthesis, HDL levels, and potentially, cardiovascular disease.-Zhu, J., J. Gardner, C. R. Pullinger, J. P. Kane, J. F. Thompson, and O. L. Francone. Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1. J. Lipid Res. 2009Res. . 50: 1330Res. -1339 Supplementary key words apoAI synthesisDyslipidemia is a major risk factor for premature development of cardiovascular disease. A high ratio of atherogenic lipoproteins (VLDL, LDL, and IDL) to HDL leads to endothelial dysfunction, focal inflammation, and oxidative stress resulting in the initiation and progression of atherosclerosis. Plasma levels of HDL are inversely correlated with the onset of coronary artery disease as attested to by the outcome of several large prospective epidemiological studies (1, 2). The protective effect of HDL is due, at least in part, to the role of this class of lipoproteins in modulating inflammation and mediating cholesterol transport from peripheral cells to sites of reutilization and degradation (3). Apolipoprotein AI (apoAI); the main protein moiety of HDL; drives the formation and speciation of HDL resulting in a very heterogeneous class of particles, particularly with respect to particle size, density, protein content, and surface charge, which determines their functional role and metabolic fate (4). Understanding the processes involved in the synthesis and maturation of HDL species will ultimately provide the knowledge required to understand and appreciate the functional significance of each of the HDL subpopulations and their impact in the development of atherosclerosis.The importance of HDL-C in disease makes it amenable to candidate-gene an...

show abstract

Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

Cited by 174 publications

References 27 publications

Statin and MTHFR C677T Polymorphism in Patients with Cardiovascular Diseases

Statin and MTHFR C677T Polymorphism in Patients with Cardiovascular Diseases

Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1

Contact Info

Product

Resources

About