scholarly journals Multiplex Protein Biomarker Profiling in Patients with Familial Hypercholesterolemia

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1599
Author(s):  
Dana Dlouha ◽  
Milan Blaha ◽  
Eva Rohlova ◽  
Jaroslav A. Hubacek ◽  
Vera Lanska ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Plasma Proteins ◽  
Cholesterol Metabolism ◽  
Wide Spectrum ◽  
Combined Therapy ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Plasma ◽  
Protein Biomarkers ◽  
Autosomal Dominant Disorder

Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy (N = 18; men = 8, age 55.4 ± 13.1 years) and patients under combined long-term LDL apheresis/hypolipidemic therapy (N = 14; men = 7; age 58.0 ± 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p < 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p < 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation.

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 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 &gt; C, c.1003 G &gt; 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 &gt; C and c.1003 G &gt; T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G &gt; C and c.1003 G &gt; T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

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 &lt; 2.2 × 10−16). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a &gt;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.

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 A Comprehensive Analysis of Genomics and Metagenomics in a Heterozygote Familial Hypercholesterolemia Family

2021 ◽  
Vol 11 ◽  
Author(s):  
Honghong Liu ◽  
Ye Jin ◽  
Ran Tian ◽  
Siqin Feng ◽  
Shuyang Zhang ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Preventive Treatment ◽  
Whole Exome ◽  
Increased Risk ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
Unclear Etiology

Familial hypercholesterolemia (FH) is an inherited rare disease leading to markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and increased risk for cardiovascular event. Gut microbiota has been implicated as a pivotal contributing factor in hyperlipidemia, however, its role in FH remains elusive. We performed whole-exome and metagenomics sequencing on a family with 22 members in which myocardial infarctions occurred at a young age with unclear etiology. We confirmed the missense mutation of LDLR c.1723C&gt;T accounted for the abnormal cholesterol metabolism in the family through co-segregation analysis. In addition, Prevotella dentalis was found elevated and strongly associated with LDL-C level in FH family members with mutation of LDLR c.1723C&gt;T compared to unaffected members with hyperlipidemia. Overall, our work suggests that whole-exome sequencing can facilitate identification of disease-causing variants and enable preventive treatment of FH. Our metagenomics analysis provides early insights into potential contributions of host-microbe interactions in genetic and common hypercholesterolemia.

scholarly journals Long-Term Follow-up of a Homozygous Familial Hypercholesterolemia Child with Progressive Aortic Stenosis and Coronary Atherosclerosis

2020 ◽  
Author(s):  
Gaojun Cai ◽  
Long Jiang ◽  
Ya Yang ◽  
Liyuan Sun ◽  
Xu Wang ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Familial Hypercholesterolemia ◽  
Coronary Atherosclerosis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Homozygous Mutation ◽  
Autosomal Dominant Disorder ◽  
Long Term Follow Up

Abstract Familial hypercholesterolemia (FH) is a severe autosomal-dominant disorder. We reported a case who firstly admitted to our institution for obvious cutaneous and tendinous xanthomas and high low-density lipoprotein cholesterol when he was 3.7 year old in 2005. DNA sequencing detected the homozygous mutation in LDLR exon9 c.1187-10G>A, a 3' splice acceptor mutation in poly-pyrimidine tract of intron 8. During the long-term follow-up, progressive aortic stenosis and coronary atherosclerosis was found, although given the lipid-lowing drugs. HoFH with c.1187-10G>A mutation in LDLR gene might lead to severe damage in cardiovascular system and unsatisfactory response to conventional lipid-lowing drugs. Other aggressive treatments should be used in HoFH patients with this mutation as early as possible.

Clinical implications and outcomes of the ORION Phase III trials

2020 ◽  
Author(s):  
Julia Brandts ◽  
Kausik K Ray
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phase Iii ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density Lipoprotein Cholesterol ◽  
Clinical Safety ◽  
Phase Iii Trials ◽  
Phase Ii And Iii ◽  
Ongoing Phase

Inclisiran is a siRNA inhibiting hepatic PCSK9 synthesis. As a first-in-class therapy, inclisiran has been assessed within the ORION trial program for its low-density lipoprotein cholesterol (LDL-C) lowering efficacy and clinical safety. Phase II and III trials have shown that inclisiran lowers LDL-C by about 50% with an infrequent dosing schedule in patients with established atherosclerotic cardiovascular disease and those at high risk, including patients with heterozygous familial hypercholesterolemia. Ongoing Phase III trials will provide evidence on longer-term safety and effectiveness, and inclisiran’s efficacy in patients with homozygous familial hypercholesterolemia. Furthermore, the ORION-4 trial will assess inclisiran’s impact on cardiovascular outcomes.

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