scholarly journals Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries

2015 ◽  
Vol 61 (1) ◽  
pp. 231-238 ◽  
Author(s):  
Marta Futema ◽  
Sonia Shah ◽  
Jackie A Cooper ◽  
KaWah Li ◽  
Ros A Whittall ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Genetic Risk Score ◽  
Low Density Lipoprotein ◽  
Population Sample ◽  
Density Lipoprotein ◽  
Roc Curves ◽  
Optimum Number ◽  
Score Distribution ◽  
Autosomal Dominant Disorder

Abstract BACKGROUND Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12–single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M–), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M– and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M– cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10−16). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS A 6-SNP LDL-C score consistently distinguishes FH/M– patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

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 Familial Hypercholesterolemia: Do HDL Play a Role?

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 810
Author(s):  
Juan Pedro-Botet ◽  
Elisenda Climent ◽  
David Benaiges
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Density Lipoproteins ◽  
Cholesterol Transport ◽  
Human Metabolism ◽  
High Cardiovascular Risk ◽  
Monogenic Disorder ◽  
Cholesterol Levels

Cardiovascular disease (CVD) in heterozygous familial hypercholesterolemia (HeFH), the most frequent monogenic disorder of human metabolism, is largely driven by low-density lipoprotein (LDL) cholesterol concentrations. Since the CVD rate differs considerably in this population, beyond the lifetime LDL cholesterol vascular accumulation, other classical risk factors are involved in the high cardiovascular risk of HeFH. Among other lipoprotein disturbances, alterations in the phenotype and functionality of high-density lipoproteins (HDL) have been described in HeFH patients, contributing to the presence and severity of CVD. In fact, HDL are the first defensive barrier against the burden of high LDL cholesterol levels owing to their contribution to reverse cholesterol transport as well as their antioxidant and anti-inflammatory properties, among others. In this context, the present narrative review aimed to focus on quantitative and qualitative abnormalities in HDL particles in HeFH, encompassing metabolic, genetic and epigenetic aspects.

scholarly journals Microfluidic Amplification as a Tool for Massive Parallel Sequencing of the Familial Hypercholesterolemia Genes

2012 ◽  
Vol 58 (4) ◽  
pp. 717-724 ◽  
Author(s):  
Silke Hollants ◽  
Egbert J W Redeker ◽  
Gert Matthijs
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Massive Parallel Sequencing ◽  
Autosomal Dominant Disorder ◽  
Parallel Sequencing ◽  
Mutation Scanning ◽  
Variant Frequency ◽  
Positive Controls

Abstract BACKGROUND Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects cholesterol metabolism and is an important risk factor for heart disease. Three different genes were causally linked to this disorder: LDLR (low density lipoprotein receptor), APOB [apolipoprotein B (including Ag(x) antigen)], and PCSK9 (proprotein convertase subtilisin/kexin type 9). We evaluated a new amplicon preparation tool for resequencing these genes on next generation sequencing (NGS) platforms. METHODS For the 3 genes, 38 primer pairs were designed and loaded on the Fluidigm Access Array, a microfluidic array in which a PCR was performed. We amplified 144 DNA samples (73 positive controls and 71 patient samples) and performed 3 sequencing runs on a GS FLX Titanium system from Roche 454, using pyrosequencing. Data were analyzed with the SeqNext module of the Sequence Pilot software. RESULT From the 38 amplicons, 37 were amplified successfully, without any further optimization. Sequencing resulted in a mean coverage of the individual amplicons of 71-fold, 74-fold, and 117-fold for the 3 runs, respectively. In the positive controls, all known mutations were identified. In 29% of the patient samples, a pathogenic point mutation or small deletion/insertion was found. Large rearrangements were not detectable with NGS, but were picked up by multiplex ligation-dependent probe amplification. CONCLUSIONS Combining a microfluidic amplification system with massive parallel sequencing is an effective method for mutation scanning in FH patients, which can be implemented in diagnostics. For data analysis, we propose a minimum variant frequency threshold of 20% and a minimum coverage of 25-fold.

scholarly journals ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia

2021 ◽  
Author(s):  
Laurens F. Reeskamp ◽  
John S. Millar ◽  
Liya Wu ◽  
Hans Jansen ◽  
Dewi van Harskamp ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Human Monoclonal Antibody ◽  
Density Lipoprotein ◽  
Fractional Catabolic Rate ◽  
Homozygous Familial Hypercholesterolemia ◽  
Unique Identifier ◽  
Catabolic Rate ◽  
Before And After

Objective: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5- 2 H 3 )-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. Conclusions: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04722068.

Pediatric Familial Type II Hyperlipoproteinemia: Therapy With Diet and Colestipol Resin

PEDIATRICS ◽  
1976 ◽  
Vol 57 (1) ◽  
pp. 68-74
Author(s):  
C. J. Glueck ◽  
R. W. Fallat ◽  
M. Mellies ◽  
R. C. Tsang
Keyword(s):  
Total Cholesterol ◽  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Diet ◽  
Normal Limits ◽  
Habitual Diet ◽  
Familial Type ◽  
Low Cholesterol

Effects of a low-cholesterol, polyunsaturate rich diet and a synthetic organic bile sequestrant polymer (U26,597A, colestipol) were studied in 21 children, heterozygous for familial hypercholesterolemia. Total cholesterol, β-lipoprotein cholesterol, and triglyceride were measured twice on habitual diet, monthly for six months on a low-cholesterol diet, and monthly for six months on low-cholesterol diet plus 10 gm of colestipol per day. Total cholesterol (mean ± 1 SD) was 295 ± 37 on habitual diet, 278 ± 29 on low-cholesterol diet, and fell significantly to 242 ± 29 mg/100 ml on diet plus colestipol. Low-density lipoprotein (LDL) cholesterol was 234 ± 37 on habitual diet, 220 ± 28 on low-cholesterol diet, and fell significantly to 179 ± 26 mg/100 ml on diet plus drug. Plasma triglyceride levels on habitual diet were 79 ± 31, remained unchanged on low-cholesterol diet, 86 ± 22, and were unaffected by low-cholesterol diet plus drug, 85 ± 17 mg/100 ml. On diet alone, plasma LDL was not normalized (< 170 mg/100 ml) in any of the 21 children, and cholesterol fell to within normal limits (< 230 mg/100 ml) in only one child. The combination of diet plus colestipol resin normalized total and LDL cholesterol in 52% of the children. Cholesterol was lowered to a "moderately elevated" range of 230 to 250 mg/100 ml in an additional 14% of the children and LDL was lowered to a range of 170 to 190 mg/100 ml in an additional 29%. In 33% of the children, cholesterol remained > 250 mg/100 ml despite diet plus colestipol, while LDL was > 190 mg/100 ml in 19%. Colestipol is an effective and well-tolerated cholesterol lowering compound which, in conjunction with diet, may prove to be very useful in the treatment of children heterozygous for familial hypercholesterolemia.

scholarly journals Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Hayato Tada ◽  
Kan Yamagami ◽  
Nobuko Kojima ◽  
Junichi Shibayama ◽  
Tetsuo Nishikawa ◽  
...  
Keyword(s):  
General Population ◽  
Familial Hypercholesterolemia ◽  
Serum Lipids ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pathogenic Mutation ◽  
Lipid Levels ◽  
Coding Regions ◽  
Cholesterol Levels

Background: It has been suggested that a rare mutant apolipoprotein E7, APOE7 (p.Glu262Lys, p.Glu263Lys), has been identified to be associated with hyperlipoproteinemia in the general population. Moreover, its prevalence has been shown to be 0.005–0.06%. However, there are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH).Methods: We recruited 1,138 patients with clinically diagnosed FH [mean age = 48, men = 512, median low-density lipoprotein (LDL) cholesterol = 231 mg/dl]. The coding regions of three FH genes (LDLR, APOB, and PCSK9) and apolipoprotein E (APOE) gene were sequenced. We investigated the prevalence and impact of APOE7 mutant on serum lipid levels in patients with FH.Results: We identified 29 patients (2.5 %) with a mutant APOE7 (heterozygote), which is apparently much higher than that of the general population. Moreover, when we focus on those without FH mutation (n = 540), we identified 21 patients (3.9 %) with a mutant APOE7. Patients with a mutant APOE7 exhibited significantly higher median LDL cholesterol and triglyceride levels compared with those without this rare mutant (249 vs. 218 mg/dl, p < 0.05, 216 vs. 164 mg/dl, p < 0.05, respectively). Moreover, LDL cholesterol levels in the APOE7-oligogenic FH individuals, with a pathogenic mutation in FH genes and APOE7 mutant, were significantly higher than that in monogenic FH patients (265 vs. 245 mg/dl, p < 0.05).Conclusion: We identified more patients with a mutant APOE7 than expected among those diagnosed with FH clinically, especially among those without FH-causing mutation. This implies a mutant APOE7 may be one of the causes FH, especially among those without FH mutations.

Therapy of Familial Hypercholesterolemia in Childhood: Diet and Cholestyramine Resin for 24 to 36 Months

PEDIATRICS ◽  
1977 ◽  
Vol 59 (3) ◽  
pp. 433-441
Author(s):  
C. J. Glueck ◽  
R. C. Tsang ◽  
R. W. Fallat ◽  
M. Mellies
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cholesterol Level ◽  
Ldl Cholesterol ◽  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasma Cholesterol Level ◽  
Drug Adherence ◽  
Cholesterol Levels ◽  
Childhood Diet

In 16 children heterozygous for familial hypercholesterolemia, two- to three-year therapy with diet and cholestyramine resin (16 gm/day) was assessed in terms of effectiveness, practicality, and safety. All 16 children had previously taken a low-cholesterol (< 300 mg/day), polyunsaturate-rich (P/S ratio, 1.5:1) diet and cholestyramine resin (12 gm/day) for 12 months. In this study, the cholestyramine resin dose was increased to 16 gm/day, and follow-up was maintained through months 13 through 18, 19 through 24, 25 through 30, and 31 through 36. Eleven children had good drug adherence (four packs of cholestyramine per day) and five children had fair adherence (two to three packs per day). Plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not significantly lowered on the drug-plus-diet regimen as compared to diet alone in five children with fair drug adherence. For children with good drug adherence. mean plasma cholesterol level was lowered below levels achieved on diet alone by 13% (months 13 through 18), 12% (months 19 through 24), 12% (months 25 through 30), and 11% (months 31 through 36) (P < .05). Reduction in plasma cholesterol level was no greater with 16 than with 12 gm of cholestyramine per day. There were no group changes in mean plasma triglyceride levels. Cholestyramine resin, when added to diet and maintained for two to three years, effects a significant reduction in total and LDL cholesterol levels in about 60% of children heterozygous for familial hypercholesterolemia. Continued reinforcelnent of both diet and drug adherence is necessary in the face of gradual increments in plasma cholesterol level with time.

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.

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