scholarly journals The LDLR c.501C>A is a disease-causing variant in familial hypercholesterolemia

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Haochang Hu ◽  
Ruoyu Chen ◽  
Yingchu Hu ◽  
Jian Wang ◽  
Shaoyi Lin ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Lipid Level ◽  
Density Lipoprotein ◽  
Hek293 Cells ◽  
Lipid Lowering ◽  
Therapeutic Effects ◽  
Autosomal Dominant Disorder ◽  
Pcsk9 Inhibitor ◽  
Inhibitor Treatment

Abstract Background As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. Methods The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. Results All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. Conclusions LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

Role of PCSK9 Inhibitors in High Risk Patients with Dyslipidemia: Focus on Familial Hypercholesterolemia

2019 ◽  
Vol 24 (31) ◽  
pp. 3647-3653 ◽  
Author(s):  
Vasilios Papademetriou ◽  
Konstantinos Stavropoulos ◽  
Christodoulos Papadopoulos ◽  
Konstantinos Koutsampasopoulos ◽  
Kiriakos Dimitriadis ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Population Characteristics ◽  
Lipid Lowering ◽  
Pcsk9 Inhibitors ◽  
Autosomal Dominant Disorder ◽  
Pcsk9 Inhibitor ◽  
Cv Disease ◽  
The Impact

Background: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is characterized by substantially increased Low-Density Lipoprotein Cholesterol (LDL-C) levels. Patients with FH have a significantly higher risk for Cardiovascular (CV) events, and the timely reduction of LDL-C is of paramount importance to ameliorate the risk for CV disease. Among the available lipid-lowering therapies, the novel Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have emerged as a very promising class of drugs for the management of such patients. Objective: The purpose of this review is to present available data on the efficacy and safety of the two available PCSK9 inhibitors in patients with FH, and importantly to discuss potential differences between the two drugs. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the impact of evolocumab or alirocumab on lipid and CV parameters in patients with FH. Results: Several studies have assessed the lipid-lowering profile of PCSK9 inhibitors in patients with FH. Both evolocumab and alirocumab were found to significantly reduce LDL-C by more than 50-60% in FH patients. Furthermore, data also support a lower rate of lipid apheresis in FH patients receiving a PCSK9 inhibitor. In terms of CV outcomes, both drugs were found to possess CV-ameliorating effects of the same extent in patients with CV disease. However, alirocumab reduced all-cause mortality, as well, a finding not observed with evolocumab. Several differences in the study population characteristics might explain this and other mild differences observed in the CV trials of these drugs. Conclusion: Available evidence suggests similar potency of alirocumab and evolocumab in reducing lipids and CV events.

scholarly journals Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Haochang Hu ◽  
Tian Shu ◽  
Jun Ma ◽  
Ruoyu Chen ◽  
Jian Wang ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
High Throughput Sequencing ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Bioinformatic Analysis ◽  
Genetic Mutations ◽  
Missense Mutations ◽  
Autosomal Dominant Disorder ◽  
Lipid Clinic

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

scholarly journals Analysis of Arterial Stiffness and Sexual Function after Adding on PCSK9 Inhibitor Treatment in Male Patients with Familial Hypercholesterolemia: A Single Lipid Center Real-World Experience

2020 ◽  
Vol 9 (11) ◽  
pp. 3597
Author(s):  
Roberto Scicali ◽  
Giorgio Ivan Russo ◽  
Marina Di Mauro ◽  
Flavia Manuele ◽  
Grazia Di Marco ◽  
...  
Keyword(s):  
Sexual Function ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Pcsk9 Inhibitor ◽  
Male Patients ◽  
Atherosclerotic Cardiovascular Diseases ◽  
Male Subjects ◽  
Inhibitor Treatment

Familial hypercholesterolemia (FH) subjects have high low-density lipoprotein cholesterol (LDL-C) and may be at high risk of erectile dysfunction and atherosclerotic cardiovascular diseases. We evaluated the effect of PCSK9-i on sexual function evaluated by the Male Sexual Health Questionnaire (MSHQ) and the International Index of Erectile Function (IIEF-5) questionnaire and on pulse wave velocity (PWV) in FH male subjects. In this prospective observational study, we evaluated 30 FH male patients on high-intensity statins plus ezetimibe and with an LDL-C off-target. All patients added PCSK9-i treatment and obtained clinical assessment at baseline and after six months of PCSK9-i. As expected, LDL-C significantly decreased after adding-on PCSK9-i (−48.73%, p < 0.001). MSHQ and PWV significantly improved after adding-on PCSK9-i (for MSHQ 93.63 ± 6.28 vs. 105.41 ± 5.86, p < 0.05; for PWV 9.86 ± 1.51 vs. 7.7 ± 1.42, p < 0.05); no significant change of IIEF-5 was found. Finally, a simple regression showed that ∆ MSHQ was significantly associated with ∆ LDL-C and ∆ PWV (p value for both <0.05). In conclusion, PCSK9-i therapy significantly improves lipid profile, PWV, and sexual function in FH male patients; our results support the favorable function of PCSK9-i on these parameters.

Study of Antihyperglycemic, Antihyperlipidemic and Antioxidant Activities of Tannins Extracted from Warionia saharae Benth. & Coss

2019 ◽  
Vol 19 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Mohammed Ajebli ◽  
Fadwa El Ouady ◽  
Mohamed Eddouks
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
Histopathological Examination ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Glucose Levels ◽  
Soxhlet Apparatus

Background and Objective: Warionia saharae Benth & Coss, a plant belonging to Asteraceae family, is used for its anti-diabetic properties in Morocco. The objective of this study was to evaluate the effect of tannins extracted from Warionia saharae (W. saharae) on blood glucose levels and lipid profile in normal and streptozotocin(STZ)-induced diabetic rats. Methods: Tannins (TE) were extracted from W. saharae using Soxhlet apparatus and different organic solvents. Single and once daily repeated oral administration of TE (10 mg/kg) for 15 days were used to evaluate the glucose and lipid-lowering activity in normal and diabetic rats. Furthermore, glucose test tolerance, liver histopathological examination and in vitro antioxidant activity of TE were carried out in this study. Results: The results showed that TE was able to exert antihyperglycemic and lowering total cholesterol effects as well as improvement of the high-density lipoprotein (HDL)-cholesterol serum level after 15 days of treatment. Furthermore, TE improved glucose tolerance, histopathological status of liver in diabetic rats and demonstrated interesting antioxidant activity. Conclusion: In conclusion, the present investigation revealed that TE possesses potent antidiabetic and antihyperlipidemic activities as claimed in different ethnopharmacological practices.

scholarly journals FAMILIAL HYPERCHOLESTEROLEMIA: DIAGNOSTIC ISSUES AND THERAPEUTIC POSSIBILITIES

2019 ◽  
Vol 26 (1) ◽  
pp. 175-186
Author(s):  
Vitalii K. Zafiraki ◽  
Alim M. Namitokov ◽  
Elena D. Kosmacheva
Keyword(s):  
Familial Hypercholesterolemia ◽  
Conflict Of Interest ◽  
Screening Program ◽  
Genetic Defect ◽  
Clinical Manifestations ◽  
Density Lipoprotein ◽  
Premature Death ◽  
Lipid Lowering ◽  
Monogenic Disease ◽  
Lipid Lowering Therapy

Familial hypercholesterolemia (FHC) is a common monogenic disease that occurs with a frequency of ~1:250 and is characterised by a high content of low-density lipoprotein (LDL) in the blood. This disease leads to the early development of atherosclerotic cardiovascular diseases (ACVD). Although the screening and diagnostics issues concerned with FHC are well developed and the modern lipid-lowering therapy can significantly improve the prognosis, the detectability of this disease remains extremely low. In recent years, the concept of FHC has undergone significant changes under the influence of large epidemiological studies, including verification of the FHC diagnosis using genetic tests. The article is aimed at discussing the clinical manifestations of FHC, as well as modern medical and extracorporal approaches to its treatment.Conclusion.Until the advent of modern lipid-lowering drugs, FHC had remained to be a disease with a poor prognosis due to early ACVD and the associated premature death. Today, the diseases is amenable to successful treatment, which, though not eliminating the genetic defect, allows almost the same life duration as in the general population to be achieved. However, all the possibilities of modern approaches to the treatment of this serious disease can be realized provided that a state-level screening program for such patients has been implemented.Conflict of interest: the authors declare no conflict of interest.

scholarly journals Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

2021 ◽  
Vol 23 (12) ◽  
Author(s):  
Angela Pirillo ◽  
Alberico L. Catapano ◽  
Giuseppe D. Norata
Keyword(s):  
Monoclonal Antibodies ◽  
High Risk ◽  
Familial Hypercholesterolemia ◽  
Plasma Levels ◽  
Low Density Lipoprotein ◽  
Genetic Defect ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Low Density ◽  
Premature Cardiovascular Disease

Abstract Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.

Abstract 406: Achievement of Treatment Target in Korean Patients With Familial Hypercholesterolemia

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chan Joo Lee ◽  
Jaewon Oh ◽  
Jung Sun Kim ◽  
Sang-Hak Lee
Keyword(s):  
Total Cholesterol ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Treatment Target ◽  
Evaluation Point ◽  
The Mean ◽  
Artery Disease ◽  
Primary Evaluation

Background: In many cases of familial hypercholesterolemia (FH), there remains difficulty in achievement of treatment target. However, despite growing attention to FH, data on the treatment and its results in these patients are very limited. Methods: From nine sites in Korea, 122 consecutive unrelated men and women who were diagnosed with heterozygous FH by Simon Broome criteria were initially enrolled. Atorvastatin 20 mg or similar-potency drugs were prescribed and the dose was escalated every 2 months (for the first 6 months) or 6 months (thereafter) if needed. Forty one subjects were dropped and 81 subjects who underwent regular laboratory check-up were finally analyzed. The primary evaluation points were achievement rates of low-density lipoprotein cholesterol (LDL-C) <70 mg/dL, LDL-C<100 mg/dL, and LDL-C down to 50% of baseline levels at 12 month. The secondary evaluation point was % change of LDL-C at 12 month. Results: Patients’ mean age was 53 years and 59.3% were males. 21.0% were definite type FH and 28.4% had coronary artery disease (CAD). The mean total cholesterol and LDL-C were 319 mg/dL and 232 mg/dL, respectively. At 12 month, 7.4% received atorvastatin 10mg or similar, 21.0% received atorvastatin 20mg or similar, 16.0% received atorvastatin 40mg or similar, 4.9% received atorvastatin 80mg or similar, and 49.4% received atorvastatin (mean 57 mg) or similar plus ezetimibe 10mg. The mean follow-up total cholesterol and LDL-C were 201 mg/dL and 124 mg/dL, respectively. The mean % change of LDL-C was -45.6%. The achievement rates of LDL-C<70 mg/dL, <100 mg/dL, and LDL-C down to 50% of baseline were 1%, 21%, and 44%, respectively. The achievement rates were not significantly different between the patients without or with CAD (1.8%, 26.3%, 47.4% vs. 0%, 8.7%, 34.8%, respectively, all p values > 0.05). Conclusions: The achievement rate of treatment target in FH was low in Korea even after maximum tolerable dose of lipid lowering drugs. Improvement of awareness on this issue and more aggressive treatment are needed for this population.

scholarly journals Potential Health Benefit of Garlic Based on Human Intervention Studies: A Brief Overview

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 619 ◽  
Author(s):  
Johura Ansary ◽  
Tamara Yuliett Forbes-Hernández ◽  
Emilio Gil ◽  
Danila Cianciosi ◽  
Jiaojiao Zhang ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Health Benefit ◽  
Garlic Extract ◽  
Lipid Lowering ◽  
Therapeutic Effects ◽  
Bioactive Constituents ◽  
Comprehensive Overview ◽  
Potential Health ◽  
Common Diseases

Garlic is a polyphenolic and organosulfur enriched nutraceutical spice consumed since ancient times. Garlic and its secondary metabolites have shown excellent health-promoting and disease-preventing effects on many human common diseases, such as cancer, cardiovascular and metabolic disorders, blood pressure, and diabetes, through its antioxidant, anti-inflammatory, and lipid-lowering properties, as demonstrated in several in vitro, in vivo, and clinical studies. The present review aims to provide a comprehensive overview on the consumption of garlic, garlic preparation, garlic extract, and garlic extract-derived bioactive constituents on oxidative stress, inflammation, cancer, cardiovascular and metabolic disorders, skin, bone, and other common diseases. Among the 83 human interventional trials considered, the consumption of garlic has been reported to modulate multiple biomarkers of different diseases; in addition, its combination with drugs or other food matrices has been shown to be safe and to prolong their therapeutic effects. The rapid metabolism and poor bioavailability that have limited the therapeutic use of garlic in the last years are also discussed.

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