Familial defective apolipoprotein B-100: A review

Andersen, Lars Højsgaard; Miserez, André R.; Ahmad, Zahid; Andersen, Rolf

doi:10.1016/j.jacl.2016.09.009

Cited by 73 publications

(48 citation statements)

References 52 publications

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“…ApoB-100 maintains the structural integrity of the LDL particle and allows the binding of LDL to LDL-receptor [12]. Few mutations in the APOB gene causing defective binding of LDL to LDL-receptor and causing FH have been described, and p.3527 (earlier reported as p.3500) was described as the ‘mutation hotspot’ of APOB gene because genetic mutations in majority of patients with FH due to defective apoB were observed at this location [13]. Multiple SNVs associated with serum lipid traits, frequently the LDL-C level were recognized by many GWAS [14–26], and the association of some of these variants (rs693, rs562338, rs506585, rs515135, rs1367117, rs7575840) were replicated in more than one study.…”

Section: Genetic Basis Of Polygenic Hypercholesterolemia – the Genesmentioning

confidence: 99%

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

2017

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Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. This indicates the probability of having other genes with a causative or contributory role in the pathogenesis of hypercholesterolemia and suggests a polygenic inheritance of this condition. Here in, we review the recent evidence of association of the genetic variants with hypercholesterolemia and the three lipid traits; total cholesterol (TC), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C), their biological pathways and the associated pathogenetic mechanisms. Nearly 80 genes involved in lipid metabolism (encoding structural components of lipoproteins, lipoprotein receptors and related proteins, enzymes, lipid transporters, lipid transfer proteins, and activators or inhibitors of protein function and gene transcription) with single nucleotide variants (SNVs) that are recognized to be associated with hypercholesterolemia and serum lipid traits in genome-wide association studies and candidate gene studies were identified. In addition, genome-wide association studies in different populations have identified SNVs associated with TC, HDL-C and LDL-C in nearly 120 genes within or in the vicinity of the genes that are not known to be involved in lipid metabolism. Over 90% of the SNVs in both these groups are located outside the coding regions of the genes. These findings indicates that there might be a considerable number of unrecognized processes and mechanisms of lipid homeostasis, which when disrupted, would lead to hypercholesterolemia. Knowledge of these molecular pathways will enable the discovery of novel treatment and preventive methods as well as identify the biochemical and molecular markers for the risk prediction and early detection of this common, yet potentially debilitating condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-017-0488-4) contains supplementary material, which is available to authorized users.

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Section: Genetic Basis Of Polygenic Hypercholesterolemia – the Genesmentioning

confidence: 99%

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

2017

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“…26 For example, when intracellular cholesterol levels are depleted, SREBP regulation of cholesterol synthesis, LDLR, and PCSK9 expression leads to the upregulation of both LDLR and PCSK9 expression. 9,27 Therefore, one potential hypothesis could be that as the Arg3500Gln:APOB LOFm variant has reduced affinity with the LDLR, 6,28 leading to reduced intracellular LDL-C concentrations; this may result in upregulation of both LDLR and PCSK9 expression, and hence an increase in the PCSK9 production rate in APOB LOFm vs PCSK9 GOFm groups. The observation of greater baseline total PCSK9 concentrations in the APOB LOFm group compared with the PCSK9 GOFm group (0.77 mg/L vs 0.50 mg/L, respectively), as well as relatively higher total PCSK9 concentrations over time, lends support to this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

Hopkins

Krempf

Bruckert

et al. 2019

Journal of Clinical Lipidology

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BACKGROUND: Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). OBJECTIVE: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. METHODS: Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C $70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. RESULTS: At Week 8, mean 6 standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 6 1.81 vs 16.74 6 2.53 mg/L). APOB LOFm carriers had higher mean 6 SE total PCSK9 (6.56 6 0.73 mg/L) and lower mean 6 SE free PCSK9 (0.025 6 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 6 0.35 and 0.11 6 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean 6 SE percent LDL-C reduction was lower in APOB LOFm (55.3 6 1.0%) compared with PCSK9 GOFm carriers (73.1 6 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group.

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“…Despite the large size of the protein (over 500 kDa), all pathogenic variants have been found at the same coding region, facilitating a more targeted testing approach in the pre‐NGS era compared with LDLR . Most cases are caused by the p.Arg3527Gln substitution (rs5742904; often referred to as R3500Q), with p.Arg3500Trp (rs1444467873; R3500W) and other variants less commonly seen . However, the expansion of the clinical application of NGS has led to the discovery of further functional and benign variants in APOB .…”

Section: Pathophysiology and Molecular Geneticsmentioning

confidence: 99%

“…Most cases are caused by the p.Arg3527Gln substitution (rs5742904; often referred to as R3500Q), with p.Arg3500Trp (rs1444467873; R3500W) and other variants less commonly seen. 21 However, the expansion of the clinical application of NGS has led to the discovery of further functional and benign variants in APOB. 22 An integrated in vitro and in vivo approach to the investigation of variants suspected to be pathogenic, as outlined in relation to LDLR, is also important for APOB.…”

Section: Variants In Apob -An Infrequent Cause Of Fhmentioning

confidence: 99%

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

2019

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Familial hypercholesterolaemia (FH) is caused by pathogenic variants in LDLR, APOB or PCSK9. Impaired low‐density lipoprotein (LDL) receptor function leads to decreased LDL catabolism and premature atherosclerotic cardiovascular disease (ASCVD). Thousands of LDLR variants are known, but assignation of pathogenicity requires accurate phenotyping, family studies and assessment of LDL receptor function. Precise, genetic diagnosis of FH using targeted next generation sequencing allows for optimal treatment, distinguishing FH from pathogenically distinct disorders requiring different treatment. Polygenic hypercholesterolaemia resulting from an accumulation of LDL cholesterol‐raising single nucleotide polymorphisms (SNPs) could also be suspected by this approach. Similarly, ASCVD risk could be estimated by broader sequencing of cholesterol and non‐cholesterol‐related genes. Both of these areas require further research. The clinical management of FH, focusing on the primary or secondary prevention of ASCVD, has been boosted by PCSK9 inhibitor therapy. The efficacy of PCSK9 inhibitors in homozygous FH may be partly predicted by the LDLR variants. While expanded genetic testing in FH is clinically useful in providing an accurate diagnosis and enabling cost‐effective testing of relatives, further research is needed to establish its value in improving clinical outcomes.

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Familial defective apolipoprotein B-100: A review

Cited by 73 publications

References 52 publications

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

Genetic determinants of inherited susceptibility to hypercholesterolemia – a comprehensive literature review

Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

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