[Show abstract][Hide abstract] ABSTRACT: Objectives: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C levels, limited response to conventional lipid-lowering therapies, and high risk of premature CVD. Severe atherosclerosis, believed related to LDL-C levels, may be evident by the second decade of life. Clinicians have traditionally identified HoFH based upon LDL-C levels: untreated >500mg/dL or treated ≥300mg/dL. Recent studies suggest that the clinical presentation of HoFH may be more variable. We examined baseline treated LDL-C levels in a cohort of patients with genetically confirmed HoFH to assess the relevance of traditional identification.
Methods: Baseline characteristics of 29 HoFH patients from a multinational Phase 3 study were collected. All subjects were ≥18 years and met the diagnosis of HoFH based on: untreated TC >500 mg/dL and both parents with documented untreated TC >250mg/dL; documented genetic mutations of genes known to affect LDLR functionality; or skin fibroblast LDLR activity <20% normal.
Results: All patients had confirmed mutations in both alleles of LDLR (n=28) or LDLRAP1 (n=1) gene. Age ranged from 18-55 years; 93% of patients had a history of CVD, 35% had undergone CABG, and 10% each had undergone coronary angioplasty, aortic valve replacement, or mitral valve replacement/repair. Patients were receiving statins (93%; 76% with ezetimibe) and apheresis (62%). Treated LDL-C levels ranged from 152-564mg/dL; 38% had LDL-C <300mg/dL and 14% <200mg/dL (Table). There was no difference between levels of subjects receiving apheresis treatment or not.
Conclusion: Contrary to conventional viewpoints, and consistent with recent studies, this cohort of patients provides further evidence of the heterogeneity of treated LDL-C values in genetically defined HoFH patients. Diagnosis of HoFH should not be excluded based on treated levels <300 mg/dL, but must also include other supportive clinical or genetic evidence.
The 2nd World Congress of Clinical Lipidology, Vienna, Austria; 12/2014
[Show abstract][Hide abstract] ABSTRACT: The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.
New England Journal of Medicine 12/2014; 371(23):2200-6. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychiatric conditions contribute the most to global health burden.•Developmental cascades provide a framework for understanding causes and consequences.•Multi-generational design enables studies of virtual health trajectories.•Saguenay Youth Study is a multi-generational and multi-system cohort designed along these lines.
[Show abstract][Hide abstract] ABSTRACT: Background
Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.
This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18–80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918.
Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4–65·1], monthly dose: 61·3% reduction [53·6–69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5–65·8] and 65·6% reduction [59·8–71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]).
In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.
[Show abstract][Hide abstract] ABSTRACT: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled phase 2 studies of 8 or 12 weeks duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, NCT01288443). Data were available for 102/108 patients who received alirocumab 150 mg Q2W and 74/77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (–30.3% versus –0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that less than 5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C). In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of LDL-C lowering.
The American Journal of Cardiology 09/2014; · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction.
[Show abstract][Hide abstract] ABSTRACT: Personalized medicine uses various individual characteristics to guide medical decisions. Apolipoprotein (ApoE), the most studied polymorphism in humans, has been associated with several diseases. The purpose of this review is to elucidate the potential role of ApoE polymorphisms in personalized medicine, with a specific focus on neurodegenerative diseases, by giving an overview of its influence on disease risk assessment, diagnosis, prognosis, and therapy. This review is not a systematic inventory of the literature, but rather a summary and discussion of novel, influential and promising works in the field of ApoE research that could be valuable for personalized medicine. Empirical evidence suggests that ApoE genotype informs pre-symptomatic risk for a wide variety of diseases, is valuable for the diagnosis of type III dysbetalipoproteinemia, increases risk of dementia in neurodegenerative diseases, and is associated with a poor prognosis following acute brain damage. ApoE status appears to influence the efficacy of certain drugs, outcome of clinical trials, and might also give insight into disease prevention. Assessing ApoE genotype might therefore help to guide medical decisions in clinical practice.
Frontiers in Aging Neuroscience 07/2014; 6:154. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The combination of hypertriglyceridemia (hyperTG) and hyperapobetalipoproteinemia (hyperapoB) is associated with an increased coronary artery disease (CAD) risk. Apolipoprotein (apo) E and lipoprotein lipase (LPL) genes are involved in the catabolism of triglycerides (TG)-rich apoB-containing lipoproteins (VLDL). Several apoE and LPL gene variants affecting CAD risk, plasma TG or apoB concentrations have an allelic frequency of >5% in the general population. This study examined the combined effect of frequent apoE and LPL gene polymorphisms on the expression of hyperTG and hyperapoB. ApoE (E2, E3, and E4) and LPL (D9N, N291S, G188E, and P207L) were genotyped and fasting lipid profiles were assessed among 1,441 French-Canadian subjects. Multivariate analyses were performed to estimate the relationship between apoE and LPL gene variants and the risk of hyperTG (TG>1.7 mmol/l) and hyperapoB (apoB>0.9 g/l). Compared to apoE3 carriers, the apoE4 allele significantly increased the risk of expressing the "hyperTG/hyperapoB" phenotype [odds ratio (OR)=1.95; p=0.014]. This risk was significantly exacerbated (OR=4.69; p=0.017) by the presence of frequent deleterious LPL gene variants in this population. The apoE2 allele was negatively associated with hyperTG/hyperapoB (OR=0.49; p=0.002) in the absence of a deleterious LPL gene variant. These results suggest that epistasis is a phenomenon to consider while assessing the CAD risk associated with gene variants or the effect of frequent alleles on high-risk lipid profiles.
Journal of endocrinological investigation 07/2014; 30(7):551-7. · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Patients suffering from HoFH are characterized by extreme atherosclerosis progression, leading to premature death. HDL has been shown to exert anti-atherogenic effects. We set out to investigate the effect of infusions of CER-001, an engineered pre-beta HDL mimetic, on atherosclerosis by carotid 3T MRI.
82nd Congress of the European-Atherosclerosis-Society (EAS), Madrid, SPAIN; 05/2014
[Show abstract][Hide abstract] ABSTRACT: Placental lipoprotein lipase (LPL) is crucial for placental lipid transfer. Impaired LPL gene expression and activity were reported in pregnancies complicated by gestational diabetes mellitus (GDM) and intra-uterine growth restriction. We hypothesized that placental LPL DNA methylation is altered by maternal metabolic status and could contribute to fetal programming. The objective of this study was thus to assess whether placental LPL DNA methylation is associated with GDM and both maternal and newborn lipid profiles. Placenta biopsies were sampled at delivery from 126 women including 27 women with GDM diagnosed following a post 75 g-oral glucose tolerance test (OGTT) between weeks 24 and 28 of gestation. Placental LPL DNA methylation and expression levels were determined using bisulfite pyrosequencing and quantitative real-time PCR, respectively. DNA methylation levels within LPL proximal promoter region (CpG1) and intron 1 CpG island (CpGs 2 and 3) were lower in placenta of women with GDM. DNA methylation levels at LPL-CpG1 and CpG3 were also negatively correlated with maternal glucose (2-h post OGTT; r=–0.22; P=0.02) and HDL-cholesterol levels (third trimester of pregnancy; r=–0.20; p=0.03), respectively. Moreover, we report correlation between LPL-CpG2 DNA methylation and cord blood lipid profile. DNA methylation levels within intron 1 CpG island explained up to 26% (r⩽–0.51; P<0.001) of placental LPL mRNA expression variance. Overall, we showed that maternal metabolic profile is associated with placental LPL DNA methylation dysregulation. Our results suggest that site-specific LPL epipolymorphisms in the placenta are possibly functional and could potentially be involved in determining the future metabolic health of the newborn.
Journal of Developmental Origins of Health and Disease 04/2014; FirstView:1-10. · 0.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims: To determine whether placental IGF1R, IGFBP3, INSR and IGF1 DNA methylation and mRNA levels were dysregulated when exposed to maternal impaired glucose tolerance (IGT) and investigate whether the epigenetic profile is associated with feto-placental developmental markers. Patients & methods: The IGT diagnosis was made according to the WHO criteria (IGT: n = 34; normal glucose tolerance [NGT]: n = 106). DNA methylation and mRNA levels were quantified using bisulfite pyrosequencing and qRT-PCR, respectively. Results: IGF1R and IGFBP3 DNA methylation levels were lower in placentas exposed to IGT compared with NGT (-4.3%; p = 0.021 and -2.5%; p = 0.006 respectively) and correlated with 2-h post-oral glucose tolerance test (OGTT) glycemia (r = -0.23; p = 0.010 and r = -0.20; p = 0.028, respectively). IGF1R mRNA levels were associated with newborns' growth markers (e.g., birth weight; r = 0.20; p = 0.032). Conclusion: These results support the growth-promoting role of the IGF system in placental/fetal development and suggest that the IGF1R and IGFBP3 DNA methylation profiles are dysregulated in IGT, potentially affecting the fetal metabolic programming.
[Show abstract][Hide abstract] ABSTRACT: Gene polymorphisms associated so far with plasma lipid concentrations explain only a fraction of their heritability, which can reach up to 60%. Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of this missing heritability. We therefore assessed whether the DNA methylation of key lipoprotein metabolism genes is associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels in patients with familial hypercholesterolemia (FH). Untreated FH patients (61 men and 37 women) were recruited for the measurement of blood DNA methylation levels at the ABCG1, LIPC, PLTP and SCARB1 gene loci using bisulfite pyrosequencing. ABCG1, LIPC and PLTP DNA methylation was significantly associated with HDL-C, LDL-C and triglyceride levels in a sex-specific manner (all P<0.05). FH subjects with previous history of coronary artery disease (CAD) had higher LIPC DNA methylation levels compared with FH subjects without CAD (P = 0.02). Sex-specific multivariable linear regression models showed that new and previously reported epipolymorphisms (ABCG1-CpGC3, LIPC-CpGA2, mean PLTP-CpGC, LPL-CpGA3, CETP-CpGA2, and CETP-CpGB2) significantly contribute to variations in plasma lipid levels (all P<0.001 in men and P<0.02 in women), independently of traditional predictors such as age, waist circumference, blood pressure, fasting plasma lipids and glucose levels. These results suggest that epigenetic perturbations of key lipoprotein metabolism genes are associated with plasma lipid levels, contribute to the interindividual variability and might partially explain the missing heritability of plasma lipid levels, at least in FH.
Epigenetics: official journal of the DNA Methylation Society 02/2014; 9(5). · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:ADRB3 DNA hypermethylation was recently associated with dyslipidemia in familial hypercholesterolemia (FH). In this study, we verified whether ADRB3 DNA methylation in blood and visceral adipose tissue (VAT) was associated with obesity and its related complications. Methods: DNA methylation levels were measured in the blood of 61 FH men, and the blood and VAT of 30 severely obese men. Common ADRB3 polymorphisms were genotyped in all subjects. Results: Higher ADRB3 DNA methylation levels were significantly associated with lower low-density lipoprotein cholesterol levels (r = -0.40; p = 0.01) in FH, and with a lower waist-to-hip ratio (r = -0.55; p = 0.01) and higher blood pressure (r = 0.43; p = 0.05) in severely obese men. ADRB3 g.-843C>T and p.W64R polymorphisms were found to be strongly associated (p < 0.001) with ADRB3 DNA methylation and mRNA levels. Conclusion: Although further studies are needed, these results suggest that epigenetic changes at the ADRB3 gene locus might be involved in the development of obesity and its related metabolic complications.