Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of ...definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation.
Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out.
No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.
Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels ...of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol.
In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18F-FDG PET/CT to quantify arterial wall inflammation.
A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm2, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks.
In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.
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•This randomized clinical trial evaluated HDL mimetic CER-001 in patients with familial hypoalphalipoproteinemia (FHA).•FHA is characterized by very low HDL-c levels and diminished cholesterol efflux capacity.•CER-001 did not reduce carotid artery wall dimensions or arterial wall inflammation after 24 weeks of infusions.•HDL mimetics have been unsuccessful in regressing atherosclerosis in randomized clinical trials.
Familial hypercholesterolaemia (FH) is commonly caused by mutations in the LDLR, APOB or PCSK9 genes, with untreated mean low density lipoprotein-cholesterol (LDL-C) concentrations being elevated in ...APOB mutation carriers, even higher in LDLR mutation and highest in those with a PCSK9 mutation. Here we examine this in children with FH from Norway, UK, The Netherlands, Belgium, Czech Republic, Austria, Portugal and Greece.
Differences in characteristics and pre- and post-treatment lipid concentrations in those with different molecular causes were compared by standard statistical tests.
Data were obtained from 2866 children, of whom 2531 (88%) carried a reported LDLR/APOB/PCSK9 variant. In all countries, the most common cause of FH was an LDLR mutation (79% of children, 297 different), but the prevalence of the APOB p.(Arg3527Gln) mutation varied significantly (ranging from 0% in Greece to 39% in Czech Republic, p < 2.2 × 10−16). The prevalence of a family history of premature CHD was significantly higher in children with an LDLR vs APOB mutation (16% vs 7% p=0.0005). Compared to the LDLR mutation group, mean (±SD) concentrations of pre-treatment LDL-C were significantly lower in those with an APOB mutation (n = 2260 vs n = 264, 4.96 (1.08)mmol/l vs 5.88 (1.41)mmol/l, p < 2.2 × 10−16) and lowest in those with a PCSK9 mutation (n = 7, 4.71 (1.22)mmol/l).
The most common cause of FH in children from eight European countries was an LDLR mutation, with the prevalence of the APOB p.(Arg3527Gln) mutation varying significantly across countries. In children, LDLR-FH is associated with higher concentrations of LDL-C and family history of CHD compared to those with APOB-FH.
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•LDLR mutations are the most common cause of familial hypercholesterolaemia (FH) in children from 8 European countries.•Overall, 279 different LDLR mutations were found in 2531 FH children.•The frequency of APOB p.(Arg3527Gln) varied significantly over the 8 countries.•APOB-FH was less severe than LDLR-FH for low density lipoprotein-cholesterol (LDL-C) concentration and family onset of coronary heart disease (CHD).
Summary
Objectives
To put data from our recent systematic review of phase 3 studies of anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice.
...Methods
Data from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non‐systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti‐PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long‐term clinical trials of anti‐PCSK9 antibodies and from extrapolations derived from correlation between low‐density lipoprotein cholesterol (LDL‐C) reduction and CV benefit with other lipid‐lowering therapies (LLTs).
Results
Rapid (within 1‐2 weeks) and persistent (8‐74 weeks) reductions in LDL‐C levels were achieved with anti‐PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL‐C goal achievement were observed (41%‐87% with alirocumab and 63%‐100% with evolocumab). In long‐term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL‐C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high–very high risk (15%‐60% absolute 10‐year CVE risk) and elevated LDL‐C despite maximally tolerated statins, the 10‐year number needed to treat with an anti‐PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL‐C levels and residual absolute CVE risk.
Conclusions
Anti‐PCSK9 antibodies effectively lower LDL‐C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL‐C goal and require substantial reductions in LDL‐C.
Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of ...premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH. This article aims to describe a feasible strategy to facilitate the detection and management of FH among patients hospitalized for CVD.
A multidisciplinary national panel of lipidologists, cardiologists, endocrinologists and cardio-geneticists developed a three-step diagnostic algorithm, each step including three key aspects of diagnosis, treatment and family care.
A sequence of tasks was generated, starting with the process of suspecting FH amongst affected patients admitted for CVD, treating them to LDL-C target, finally culminating in extensive cascade-screening for FH in their family. Conceptually, the pathway is broken down into 3 phases to provide the treating physicians with a time-efficient chain of priorities.
We emphasize the need for optimal collaboration between the various actors, starting with a "vigilant doctor" who actively develops the capability or framework to recognize potential FH patients, continuing with an "FH specialist", and finally involving the patient himself as ”FH ambassador” to approach his/her family and facilitate cascade screening and subsequent treatment of relatives.
•A strategy to facilitate the detection and management of FH among patients hospitalized for CVD.
Abstract Background Despite international standardization programs for LDLc and HDLc measurements, results vary significantly with methods from different manufacturers. We aimed to simulate the ...impact of analytical error and hypertriglyceridemia on HDLc- and LDLc-based cardiovascular risk classification. Methods From the Dutch National EQA-2012 external quality assessment of 200 clinical laboratories, we examined data from normotriglyceridemic (∼1 mmol/l) and hypertriglyceridemic (∼7 mmol/l) serum pools with lipid target values assigned by the Lipid Reference Laboratory in Rotterdam. HDLc and LDLc were measured using direct methods of Abbott, Beckman, Siemens, Roche, Olympus, or Ortho Clinical Diagnostics. We simulated risk reclassification using HDL- and sex-specific SCORE multipliers considering two fictitious moderate-risk patients with initial SCORE 4% (man) and 3% (woman). Classification into high-risk treatment groups (LDLc >2.50 mmol/l) was compared between calculated LDLc and direct LDLc methods. Results Overall HDLc measurements in hypertriglyceridemic serum showed negative mean bias of −15%. HDL-multipliers falsely reclassified 70% of women and 43% of men to a high-risk (SCORE >5%) in hypertriglyceridemic serum ( P < 0.0001 vs. normotriglyceridemic serum) with method-dependent risk reclassifications. Direct LDLc in hypertriglyceridemic serum showed positive mean bias with Abbott (+16%) and Beckman (+14%) and negative mean bias with Roche (−7%). In hypertriglyceridemic serum, 57% of direct LDLc measurements were above high-risk treatment goal (2.50 mmol/l) vs. 29% of direct LDLc (33% of calculated LDLc) in normotriglyceridemic sera. Conclusion LDLc and HDLc measurements are unreliable in severe hypertriglyceridemia, and should be applied with caution in SCORE risk classification and therapeutic strategies.
Abstract Familial hypercholesterolemia (FH) is a co-dominantly inherited disorder of plasma lipoprotein metabolism. The prevalence of heterozygous FH (HeFH) is between 1/500 and 1/200 whereas that of ...homozygous form (HoFH) is about 1/1,000,000. Diagnosis is based on cutaneous xanthomas and untreated levels of LDL-cholesterol over 500 mg/dl before 10 years of age. Life expectancy, without treatment, does not exceed 20 years of age. The aim of this study is to characterise in details a cohort of 8 HoFH paediatric patients in order to illustrate all the current therapeutic options and to add some clinical and genetic information about this rare disease. We collected demographic, clinical, biological, imaging and genotype details. Furthermore, clinical and biochemical response to different treatment methods was retrospectively evaluated. All patients had genetically proven HoFH. All patients were subject to a lipid-lowering diet and medical treatment (except one), three patients underwent a liver transplant and one an hepatocytes infusion. Medical treatment was well tolerated with a median reduction of 44% and 47% in LDL-Cholesterol and Total Cholesterol respectively. The hepatocytes transplant produced a further, though slight, decrease in cholesterol levels as opposed to medical therapy alone. Transplanted patients normalized their cholesterol levels. Since the very high cardiovascular risk, HoFH requires immediate diagnosis, treatment and monitoring. Nowadays, the use of statins remains the cornerstone of medical therapy and liver transplantation is the possibly curative therapy. Besides, high hopes are pinned in new drugs (antibody targeting PCSK9, Mipomersen and Lomitapide) and stem cells.
Evolving concepts on the management of dyslipidaemia Descamps, Olivier S.; Verhaegen, Ann; Demeure, Fabien ...
Acta clinica belgica (English ed. Online),
01/2020, Letnik:
75, Številka:
1
Journal Article, Web Resource
Recenzirano
Odprti dostop
It has been well established that low-density lipoproteins (LDL) and other apolipoprotein B-containing lipoproteins are causally related to atherosclerotic cardiovascular disease (ASCVD) and that ...lowering these lipoproteins reduces the risk of ASCVD. By lowering LDL particles as much as possible, ASCVD can be prevented. There seems to be no LDL-cholesterol (LDL-C) threshold below which no further ASCVD prevention can be achieved. Furthermore, a low (an even very low) LDL-C appears to be safe. The new ESC/EAS guidelines based on these concepts are a step towards a benefit-based strategy by focusing on the clinical benefit that can be achieved by treating the cause of ASCVD. It is recommended to lower LDL-C as much as possible to prevent ASCVD, especially in high and very high-risk patients. With these new recommendations come recognition of the importance of combination therapies in high and very high-risk patients, first with statins and ezetimibe, and if needed with a PCSK9 inhibitor. The present paper is a review of some new concepts arising during the past 10 years in the field of lipidology and the description of what is new in the 2019 EAS/ESC guidelines.
Does FTO have a paradoxical effect in fetal life? Descamps, Olivier S; Tarantino, Eric; Guilmot, Pierre-Francois
BMC Genetics,
2014-Dec-24, 2014-12-24, 20141224, Letnik:
15, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Low weight at birth is associated with obesity in later life. One hypothesis to explain such an association is that genetic variants that increase the risk of obesity also reduce fetal weight. ...Recently, obesity in adults was found to be associated with common variants of the fat mass and obesity-associated (FTO) gene. We examined the association between FTO polymorphisms and birth weight in a singleton, full-term birth cohort of 494 newborn-mother pairs without any complications.
The risk alleles for obesity ("A" allele for the rs9939609 FTO variant and "G" allele for the rs9930506 FTO variant) were associated with low weight at birth. The mean differences per risk allele were -79 g (95% CI: -129 to -30; p = 0.002) for rs9939609 and -84 g (95% CI: -131 to -36; P < 0.001) for rs9930506. The level of association remained statistically significant after adjustment for the maternal risk allele and for variables usually associated with birth weight (-50 g, 95% CI: -99 to 0; p = 0.05 for rs9939609 and -48 g, 95% CI: -100 to 0; p = 0.05 for rs9930506). In the follow-up, the allelic difference in weight was attenuated over time.
The FTO variants that confer a predisposition to obesity later in life appear to be associated with low weight at birth. This finding favors the hypothesis of a common genetic denominator that predisposes to a low weight at birth and obesity in adults.
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