摘要
Dyslipidemia, highly elevated, low-density lipoprotein (LDL) cholesterol, is a major cardiovascular risk factor. Statins have been proven to effectively reduce the risk of atherosclerotic cardiovascular disease (ASCVD) and are recommended as a first-line therapy for the primary and secondary prevention of ASCVD. However, statins may not be sufficient in decreasing LDL cholesterol levels and pose a significant on-treatment residual risk of major cardiovascular events (i.e., residual cholesterol risk) according to meta-analyses of statin trials. Current guidelines for cholesterol management to achieve additional LDL cholesterol reduction and reduce ASCVD risk recommend two hyperlipidemic agents besides statins. Use of ezetimibe, a cholesterol absorption inhibitor, leads to additional LCL cholesterol reduction and decreased ASCVD risk, when added to statin therapy, without raising significant safety concerns. Furthermore, in combination with a mild-to-moderate statin intensity, ezetimibe is used in situations of statin-associated adverse effects such as myalgia and the combination therapy is relatively safer. Monoclonal antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab, and evolocumab, have been approved to lower LDL cholesterol level. While there are drawbacks to the use of PCSK9 inhibitors, including high cost and adverse events such as injection site reaction, they significantly decreased serum LDL cholesterol levels and thereby ASCVD risks when added to maximally tolerated statin therapy.
Subject(s)
Absorption , Cardiovascular Diseases , Cholesterol , Cholesterol, LDL , Dyslipidemias , Ezetimibe , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lipoproteins , Myalgia , Proprotein Convertases , Risk Factors , Secondary Prevention摘要
We previously demonstrated that atherogenic Ldlr(−/−)Apobec1(−/−) (LDb) double knockout mice lacking both low-density lipoprotein receptor (LDLR) and apolipoprotein B mRNA-editing catalytic polypeptide-1 (Apobec1) had increased serum IL-17 levels, with T cell programming shifted towards Th17 cells. In this study, we assessed the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in T cell programming and atherogenesis. We deleted the Pcsk9 gene from LDb mice to generate Ldlr(−/−)Apobec1(−/−)Pcsk9(−/−) (LTp) triple knockout mice. Atherosclerosis in the aortic sinus and aorta were quantitated. Lymphoid cells were analyzed by flow cytometry, ELISA and real-time PCR. Despite of dyslipidemia, LTp mice developed barely detectable atherosclerotic lesions. The IL-17, was very low in plasma and barely detectable in the aortic sinus in the LTp mice. In the spleen, the number of CD4⁺CD8⁻ cells and splenocytes were much lower in the LDb mice than LTp mice, whereas, the IL-17-producing cells of γδTCR⁺ T cells and effector memory CD4⁺ T cells (CD44(hi)CD4⁺) in the spleen were significantly higher in the LDb mice than in the LTp mice. The Rorc mRNA expression levels were elevated in LDb mice compared to LTp mice. When re-stimulated with an anti-CD3 Ab, CD44(hi)CD4⁺ T cells from LDb mice secreted more IL-17 than those from LTp mice. T cells from LDb mice (with PCSK9) produce more IL-17 at basal and stimulated conditions when compared with LTp mice (without PCSK9). Despite the dyslipidemic profile and the lack of LDLR, atherogenesis is markedly reduced in LTp mice. These results suggest that PCSK9 is associated with changes in T cell programming that contributes to the development of atherosclerosis.
Subject(s)
Animals , Mice , Aorta , Apolipoproteins , Atherosclerosis , Dyslipidemias , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Hyperlipidemias , Interleukin-17 , Lymphocytes , Memory , Mice, Knockout , Negotiating , Plasma , Proprotein Convertases , Real-Time Polymerase Chain Reaction , Receptors, Lipoprotein , RNA, Messenger , Sinus of Valsalva , Spleen , T-Lymphocytes , Th17 Cells摘要
PURPOSE: To investigate associations for polymorphisms in β-carotene 9′,10′-oxygenase (BCO2, rs10431036 and rs11214109), proprotein convertase subtilisin kexin type 9 (PCSK9, rs11583680), and tribbles pseudokinase 1 (TRIB1, rs17321515 and rs2954029), as well as lifestyle factors, with ischemic stroke (IS). MATERIALS AND METHODS: This nested case-control study included 161 patients with IS and 483 matched control individuals. We collected medical reports, lifestyle details, and blood samples from individuals and used the PCR-ligase detection reaction method to genotype single nucleotide polymorphisms (SNPs). RESULTS: The GA+AA genotype of rs10431036 (p<0.001) and rs17321515 (p=0.003), the CT+TT genotype of rs11214109 (p=0.005), and the TA+AA genotype of rs2954029 (p=0.006) in dominant models increased the risk of IS. In additive models, the GG genotype of rs17321515 (p=0.005) and the TT genotype of rs2954029 (p=0.008) increased the risk of IS. Adequate intake of fruits/vegetables reduced the risk of IS (p=0.005). Although there was no interaction between genes and fruits/vegetables, people with inadequate intake of fruits/vegetables who carried a risk genotype had a higher risk of IS than those only having inadequate fruits/vegetables intake or those only carrying a risk genotype. Also, the haplotypes AC, AT, and GT (comprising rs10431036 and rs11214109) and GT (comprising rs2954029 and rs17321515) were found to be associated with an increased risk of IS (p<0.05). CONCLUSION: Polymorphisms in BCO2 and TRIB1 and fruits/vegetables intake were associated with IS. These results provide the theoretical basis for gene screening to prevent chronic cerebrovascular diseases.
Subject(s)
Humans , Case-Control Studies , Cerebrovascular Disorders , Genotype , Haplotypes , Life Style , Mass Screening , Methods , Polymorphism, Single Nucleotide , Proprotein Convertases , Stroke , Subtilisin摘要
We aimed to evaluate the prevalence of familial hypercholesterolaemia (FH) in a subject with hypercholesterolaemia from two population-based cohorts in South Korea. A total of 283 subjects with total cholesterol levels of 290 mg/dL (7.5 mmol/L) or higher were selected from the Namwon and Dong-gu Studies. We used next generation sequencing (NGS) to detect mutations in low-density lipoprotein receptors (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. We have confirmed 17 different mutations of the LDLR, APOB and PCSK9 in 23 subjects (8.1%). Eleven LDLR variants and one APOB variant have been previously reported. One LDLR and two PCSK9 rare variants were identified in the variants database, but not in the FH mutation database. Two novel LDLR variants were found, p.Leu680Val, and p.Thr734Phe. No LDLR, APOB or PCSK9 deletions nor insertions were found. When the subjects were restricted to 110 subjects with a total cholesterol ≥310 mg/dL, only 10 variants were found in the 10 subjects (9.1%). These results suggest that given the low prevalence of FH mutations in subjects with high total cholesterol levels, NGS-based testing for a population-based approach to FH detection may not be cost-effective.
Subject(s)
Apolipoproteins , Apolipoproteins B , Cholesterol , Cohort Studies , High-Throughput Nucleotide Sequencing , Hyperlipoproteinemia Type II , Korea , Prevalence , Proprotein Convertases , Receptors, Lipoprotein摘要
PURPOSE: Our previous study demonstrated that persimmon (Diospyros kaki Thumb.) at different stages of ripening provided different protective effects against high-fat/cholesterol diet (HFD)-induced dyslipidemia in rats. In this study, we compared the metabolites profile and gene expressions related to triglyceride (TG)/cholesterol metabolism in vitro and in vivo after treating with persimmon water extracts (PWE) or tannin-enriched persimmon concentrate (TEP). METHODS: Primary and secondary metabolites in test materials were determined by GC-TOF/MS, UHPLC-LTQ-ESI-IT-MS/MS, and UPLC-Q-TOF-MS. The expression of genes related to TG and cholesterol metabolism were determined by RT-PCR both in HepG2 cells stimulated by oleic acid/palmitic acid and in liver tissues obtained from Wistar rats fed with HFD and PWE at 0, 150, 300, and 600 mg/d (experiment I) or TEP at 0, 7, 14, and 28 mg/d (experiment II) by oral gavage for 9 weeks. RESULTS: PLS-DA analysis and heatmap analysis demonstrated significantly differential profiling of metabolites of PWE and TEP according to processing of persimmon powder. In vitro, TEP showed similar hypolipidemic effects as PWE, but significantly enhanced hypocholesterolemic effects compared to PWE in sterol regulatory element-binding protein 2 (SREBP2), HMG-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesterol 7α-hydroxylase (CYP7A1), and low density lipoprotein receptor (LDLR) gene expression. Consistently, TEP and PWE showed similar hypolipidemic capacity in vivo, but significantly enhanced hypocholesterolemic capacity in terms of SREBP2, HMGCR, and bile salt export pump (BSEP) gene expression. CONCLUSION: These results suggest that column extraction after hot water extraction may be a good strategy to enhance tannins and long-chain fatty acid amides, which might cause stimulation of hypocholesterolemic actions through downregulation of cholesterol biosynthesis gene expression and upregulation of LDL receptor gene expression.
Subject(s)
Animals , Rats , Amides , Bile , Cholesterol , Diet , Diospyros , Down-Regulation , Dyslipidemias , Gene Expression , Hep G2 Cells , In Vitro Techniques , Liver , Metabolism , Oxidoreductases , Proprotein Convertases , Rats, Wistar , Receptors, LDL , Tannins , Triglycerides , Up-Regulation , Water摘要
Lowering serum low-density lipoprotein cholesterol (LDL-C) is the mainstay for reduction of risk of cardiovascular disease (CVD), the second most common cause of death in Korea. The 2015 Korean guidelines for management of dyslipidemia strongly recommend the use of statins in patients at risk of CVD. Statin therapy, which is the gold standard for CVD, reduces LDL-C level by 40% to 60% and is generally well tolerated. However, many patients are intolerant to statins and discontinue therapy or become nonadherent to therapy because of actual/perceived side effects. The most common of these side effects is the statin-associated muscle symptom (SAMS). Discontinuation and repetitive re-challenge with statins can help identify SAMS. If serum creatinine kinase level is more than 10 times the upper limit of normal, statin therapy must be stopped immediately, and the physician should identify possible causes including rhabdomyolysis and treat appropriately. In other patients, it might help to switch to a less potent statin or to use statins at intermittent non-daily dosing. To achieve target LDL-C level, non-statin lipid-lowering therapies such as dietary modifications, ezetimibe, and bile acid sequestrants may be added. Several new drugs have recently been approved for lowering LDL-C level. Alirocumab and evolocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, and both drugs cause large reductions in LDL-C, similar to statins. Lomitapide and mipomersen are orphan drugs used as adjuncts to other lipid-lowering therapies in patients with homozygous familial hypercholesterolemia.
Subject(s)
Humans , Antibodies, Monoclonal , Bile , Cardiovascular Diseases , Cause of Death , Cholesterol , Creatinine , Dyslipidemias , Ezetimibe , Feeding Behavior , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipoproteinemia Type II , Korea , Lipoproteins , Orphan Drug Production , Phosphotransferases , Proprotein Convertases , Rhabdomyolysis摘要
Based on evidence from numerous research studies, increased low-density lipoprotein cholesterol (LDL-C) is a clinically important factor for accelerated atherosclerosis and increased cardiovascular risk. The introduction of statin therapy has resulted in marked reductions in LDL-C and has proven to be clinically beneficial in cardiovascular events in patients with high cardiovascular risk. Nonetheless, many patients with elevated LDL-C do not achieve their LDL-C goals with current treatments. In addition, cardiovascular disease remains an important cause of mortality and morbidity worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors further reduce LDL-C, and potentially reducing cardiovascular events. Several PCSK9 inhibitors are currently under clinical development and some of them have been studied in completed cardiovascular outcome trials, including evolocumab, alirocumab, and bococizumab. The results of the FOURIER trial, which was the first cardiovascular outcome trial to examine the impact of PCSK9 inhibition with evolocumab therapy on cardiovascular events, were reported in March of 2017. The results of the ODYSSEY Outcomes trial with alirocumab therapy were released in March of 2018 at the American College of Cardiology Annual Scientific Session. The SPIRE-1 and -2 trials which examined a PCSK9 inhibitor, bococizumab, were prematurely terminated because of discontinued development of bococizumab in November 2016. This review will discuss 3 recent cardiovascular outcome trials with PCSK9 inhibitors, with an emphasis on clinical implications and future therapeutic perspectives.
Subject(s)
Humans , Atherosclerosis , Cardiology , Cardiovascular Diseases , Cholesterol , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Lipoproteins , Mortality , Proprotein Convertases摘要
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown. METHODS: From December 2009 to July 2012, 121 individuals who underwent coronary angiography (CAG) because of clinically suspected acute coronary syndrome were enrolled in this study. Serum levels of PCSK9 and metabolic parameters were measured. SYNTAX (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) and GRACE (Global Registry of Acute Coronary Events) scores were calculated. RESULTS: Individuals with CAG lesions (n=100) had significantly higher levels of PCSK9 than those without lesions (n=21). The study population was stratified into three groups according to serum levels of PCSK9. The odds radio for occurrence of one or more CAG lesions was significantly higher in the group with the highest level of PCSK9 (odds ratio, 7.468; P=0.011) than in the group with the lowest level of PCSK9. Serum PCSK9 was positively associated with the number of involved coronary arteries. Multivariable linear regression indicated that levels of PCSK9 were positively correlated with GRACE risk scores and SYNTAX scores. CONCLUSION: Serum PCSK9 concentrations are higher in patients with coronary artery lesions, and are associated with SYNTAX and GRACE scores, suggesting that PCSK9 is a potential biomarker of the severity of coronary artery disease.
Subject(s)
Humans , Acute Coronary Syndrome , Cardiovascular Diseases , Coronary Angiography , Coronary Artery Disease , Coronary Disease , Coronary Vessels , Linear Models , Percutaneous Coronary Intervention , Proprotein Convertases , Receptors, LDL , Stents , Taxus摘要
In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. Although cascade genetic screening is a good option for efficient identification of affected patients, diagnosis using only clinical criteria is more common in real clinical practice. Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. Although guidelines emphasize aggressive LDL-C reduction, the majority of patients cannot reach the LDL-C goal by conventional pharmacotherapy. Novel therapeutics such as proprotein convertase subtilisin/kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in FH patients.
Subject(s)
Humans , Cholesterol, LDL , Coronary Disease , Diagnosis , Drug Therapy , Genetic Testing , Genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipoproteinemia Type II , Prevalence , Proprotein Convertases , Risk Factors摘要
Although statins have demonstrated consistent and strong effects on cardiovascular prevention, non-statin drugs have failed to show additional clinical benefit. Consequently, statins are currently recommended as first-line therapy in dyslipidemia. On the contrary, non-statin drugs are indicated in limited cases in which statins are not sufficiently effective or intolerable. A recent trial on ezetimibe provides evidence supporting further prescription of this agent. Proprotein convertase subtilisin-kexin type 9 inhibitors have strong low-density lipoprotein-cholesterol-lowering effects and were just approved in Western countries. However, results of clinical outcomes are not yet available. Other non-statin lipid-modifying agents have their own roles and limitations. Thus, it is important to have correct knowledge on these agents for optimal treatment of dyslipidemic patients.
Subject(s)
Humans , Cholesterol Ester Transfer Proteins , Dyslipidemias , Fatty Acids, Omega-3 , Fibric Acids , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Niacin , Prescriptions , Proprotein Convertases , Ezetimibe摘要
PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low density lipoprotein receptor (LDLR) and promotes degradation of the LDLR. Inhibition of PCSK9 either by reducing its expression or by blocking its activity results in the upregulation of the LDLR and subsequently lowers the plasma concentration of LDL-cholesterol. As a modality to inhibit PCSK9 action, we searched the chemical library for small molecules that block the binding of PCSK9 to the LDLR. MATERIALS AND METHODS: We selected 100 chemicals that bind to PCSK9 where the EGF-AB fragment of the LDLR binds via in silico screening of the ChemBridge chemical library, using the computational GOLD algorithm analysis. Effects of chemicals were evaluated using the PCSK9-LDLR binding assay, immunoblot analysis, and the LDL-cholesterol uptake assay in vitro, as well as the fast performance liquid chromatography assay for plasma lipoproteins in vivo. RESULTS: A set of chemicals were found that decreased the binding of PCSK9 to the EGF-AB fragment of the LDLR in a dose-dependent manner. They also increased the amount of the LDLR significantly and subsequently increased the uptake of fluorescence-labeled LDL in HepG2 cells. Additionally, one particular molecule lowered the plasma concentration of total cholesterol and LDL-cholesterol significantly in wild-type mice, while such an effect was not observed in Pcsk9 knockout mice. CONCLUSION: Our findings strongly suggest that in silico screening of small molecules that inhibit the protein-protein interaction between PCSK9 and the LDLR is a potential modality for developing hypercholesterolemia therapeutics.
Subject(s)
Animals , Humans , Mice , Cholesterol/blood , Cholesterol, LDL/blood , Hep G2 Cells , Mice, Knockout , Proprotein Convertases/metabolism , Receptors, LDL/metabolism , Serine Endopeptidases/metabolism , Small Molecule Libraries摘要
Statins are the preferred treatment for hypercholesterolemia and several studies have demonstrated their long-term safety and efficacy in reducing cardiovascular morbidity and mortality. However, in some cases of severe hypercholesterolemia such as homozygous and heterozygous familial hypercholesterolemia or statin intolerant patients, statins can be less efficient. In recent years, new lipid-lowering agents with novel mechanisms of action have been developed to reduce LDL-cholesterol in patients with severe hypercholesterolemia, associated or not to conventional lipid-lowering therapy. These therapies include microsomal transfer protein inhibitor (Lomitapide), antisense oligonucleotide to Apo B100 (Mipomersen) and monoclonal antibodies against Proprotein convertase subtilisin/kexin type 9 (PCSK9). Different studies have shown the great effectiveness of these new therapies. Short-term studies confirmed their adequate security profile, especially in patients with homozygous familiar hypercholesterolemia or severe hypercholesterolemia. Some of these agents have been also tested in statin-intolerant patients. However, long-term studies are needed to evaluate their safety, effectiveness and impact on cardiovascular risk reduction.
Subject(s)
Humans , Anticholesteremic Agents/therapeutic use , Hypercholesterolemia/drug therapy , Antibodies, Monoclonal/therapeutic use , Benzimidazoles/therapeutic use , Clinical Trials as Topic , Oligonucleotides/therapeutic use , Proprotein Convertases/therapeutic use , Serine Endopeptidases/therapeutic useSubject(s)
Humans , Atherosclerosis/therapy , LDL-Receptor Related Proteins/metabolism , Proprotein Convertases/metabolism , Proprotein Convertases/therapeutic use , Serine Endopeptidases/metabolism , Serine Endopeptidases/therapeutic use , Cholesterol, LDL/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Polymorphism, Genetic , Proprotein Convertases/pharmacology , Risk Factors , Serine Endopeptidases/pharmacology摘要
<p><b>OBJECTIVE</b>To study the effects of hepatitis B virus (HBV) infection on the expression of Furin, an important proprotein convertase, in liver cells to provide insights towards its potential as a therapeutic target for improved antiviral efficacy.</p><p><b>METHODS</b>Furin expression was measured in human liver specimens (infected tissues from patients with chronic HBV hepatitis vs. normal tissues from healthy donors) and in hepatoma cell lines (HBV-infected HepG2.2.15 cells vs. uninfected parental cell lines HepG2) using quantitative real-time RT-PCR (for mRNA), western blotting and immunohistochemistry (for protein).</p><p><b>RESULTS</b>Compared to the uninfected tissues and cells, the HBV-infected tissue and cells showed down-regulated expression of furin at both the mRNA and protein levels. In particular, the HepG2.2.15 cells showed -50% less furin mRNA expression than the HepG2 cells and the difference was statistically significant (P less than 0.05).</p><p><b>CONCLUSION</b>HBV may suppress the host cell's expression of furin, possibly to benefit its survival and replication in the host cell.</p>
Subject(s)
Humans , Cell Line , Furin , Metabolism , Gene Expression Regulation , Hep G2 Cells , Hepatitis B virus , Physiology , Hepatitis B, Chronic , Metabolism , Host-Pathogen Interactions , Liver , Metabolism , Virology , Proprotein Convertases , Metabolism , Virus ReplicationSubject(s)
Humans , Proprotein Convertases , Cholesterol , Hypercholesterolemia , Lipids , Mutation , Antibodies, Monoclonal摘要
This is a remarkable progress; since the finding of statins, there was no new way of reducing, significantly, cholesterol and LDL fraction. It is also clear that this decrease, by statins, is related to future cardiovascular lesions, being useful in its primary and secondary prophylaxis. The authors presented studies on research to promote the falling of blood cholesterol by means of antibodies, which inhibit the pro-protein PCSK9, as well as agents that act performing the RNA interference. We had two advantages immediately: for patients with myopathy associated with statins, and the fact of being injected every 15 days, that may contribute to better treatment adherence.
Este é um progresso sensível; desde a descoberta das estatinas, não havia novas maneiras de diminuir, de maneira significativa, o colesterol e a fração LDL. Também está claro que essa redução, pelas estatinas, tem relação com futuras lesões cardiovasculares, sendo útil na profilaxia primária e secundária destas. Os autores apresentaram estudos sobre pesquisas para promover a queda do colesterol sanguíneo por meio de anticorpos que inibem a pró-proteína PCSK9, bem como agentes que atuam realizando a interferência no RNA. Duas vantagens se afiguram imediatamente: para pacientes que têm a miopatia relacionada às estatinas e por ser droga injetável a cada 15 dias, o que pode colaborar para maior adesão ao tratamento.
Subject(s)
Humans , Dyslipidemias/therapy , Proprotein Convertases/immunology , Serine Endopeptidases/immunology , Antibodies, Monoclonal/administration & dosage , Clinical Trials as Topic , Cholesterol, LDL/blood , RNA Interference摘要
As estatinas são produtos farmacêuticos de grande sucesso em todo mundo. Entretanto, muitos pacientes, ou por não as tolerarem adequadamente, ou por necessitarem de taxas mais baixas de LDL-colesterol estabelecidas como metas, poderão ter benefícios clínicos com o emprego de novos medicamentos. Numerosas linhas de pesquisa encontram-se em evolução, avaliando produtos com atuação em diferentes vias moleculares: inibidores de síntese da apolipoproteína B, inibidores da DGAT2, da ACAT2, da MTP, da esqualeno sintase, tireoidemiméticos e inibidores da PCSK9. Espera-se, para futuro próximo, a introdução no mercado desses medicamentos, que poderão auxiliar ainda mais na prevenção primária e secundária da doença aterosclerótica coronária, flagelo deste novo século.
Statins are pharmaceutical products that obtained worldwide success. However, some patients with inadequate tolerability to these medications and the need of achieving lower LDL-cholesterol levels as recommended targets, may receive clinical benefits with the use of new drugs. Many research lines have been in evolution evaluating products that act in different molecular pathways: inhibitors of apoliprotein B synthesis, inhibitors of DGAT2, ACAT2, MTP, squalene synthase, thyromimetics, and inhibitors of PCSK9. It is a hope that the future introduction of many of these products on the market will help furthermore primary and secondary prevention of coronary heart disease, a scourge of this new century.
Subject(s)
Humans , Apolipoproteins B/analysis , Atherosclerosis/complications , Atherosclerosis/mortality , Cholesterol, LDL/analysis , Cardiovascular Diseases/complications , Cardiovascular Diseases/mortality , Thyroid Hormones/analysis , Oligonucleotides, Antisense , Proprotein Convertases摘要
Familial hypercholesterolemia [FH] is caused by mutations in the genes coding for the low-density lipoprotein receptor [LDLR], apolipoprotein B-100, or proprotein convertase subtilisin/kexin type 9 [PCSK9]. In this study, a molecular analysis of LDLR gene and APOB gene was performed in a group of 17 unrelated patients from Pakistan. All patients were clinically diagnosed with definite or possible hypercholesterolemia according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and fragments of exon 26 and exon 29 of APOB. In our study, SNPs within LDLR exon 12, rs688 and LDLR exon 13, rs5925 were identified. We identified associations between SNPs and increased levels of cholesterol in Pakistani population. We failed to detect polymorphisms in the APOB gene