Daniel Gaudet

Université de Montréal, Montréal, Quebec, Canada

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Publications (369)1838.33 Total impact

  • Monique Tremblay · Diane Brisson · Daniel Gaudet
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    ABSTRACT: Despite the numerous common pathways connecting blood pressure regulation to somatostatin (SST) metabolism, the SST gene has never been seen as a significant blood pressure modulator. The aim of this study was to evaluate the association between a poly-T repeat sequence (rs34872250) in the promoter of the SST gene and blood pressure, according to the obesity status. We genotyped 1918 French-Canadian subjects from a founder population. Analyses were performed according to the length of the poly-T repeat sequence on both alleles and divided into two groups, the 13/13-13/14 group and the 13/15-13/16 group. The effect of age, gender, body mass index, antihypertensive drugs and diabetic status were considered. Systolic, diastolic and mean blood pressures are significantly higher among the 13/15-13/16 group in the whole sample (P<0.05). Whereas the differences remain significant in women, they turn to be non-significant when men are considered alone. The risk of hypertension is increased in the 13/15-13/16 group, particularly among overweight/obese subjects. Systolic blood pressure is significantly higher among overweight/obese carriers of the 13/15-13/16 alleles in the whole sample (P<0.001), in men (P=0.006) and in women (P=0.002), even after correction for age and antihypertensive drugs. These results suggest that the poly-T repeat sequence polymorphism in the promoter of the SST gene is associated with significant variations of blood pressure and could modulate the risk of hypertension, particularly among women.Hypertension Research advance online publication, 28 January 2016; doi:10.1038/hr.2016.4.
    No preview · Article · Jan 2016 · Hypertension Research
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    ABSTRACT: Background/aims: Visceral fat (VF) compared with subcutaneous fat (SF) is more closely associated with cardiometabolic disease. Dietary vitamin A (retinol) may reduce adiposity through its effects on adipogenesis differentially in VF and SF, and this effect may be modulated by retinol-binding protein-4 (RBP4). We investigated whether intake of vitamin A is associated with either VF or SF, and whether this association is moderated by the RBP4 genotype (rs10882272, C/T) previously associated with circulating retinol levels. Methods: This was a cross-sectional association study in a sample of 947 adolescents from a French-Canadian founder population. VF and SF were quantified with magnetic resonance imaging, and vitamin A intake was assessed with a 24-hour food recall. All participants were genotyped to determine their RBP4 variant. Results: Dietary intake of vitamin A was negatively associated with VF; however, it was not associated with SF. These relationships were independent of age, sex, height and energy intake, and were modulated by the RBP4 variant. The T allele promoted adiposity-reducing effects of vitamin A in VF and adiposity-enhancing effects in SF, while the C allele had adiposity-reducing effects in both VF and SF. Conclusions: Dietary vitamin A may reduce abdominal adiposity and promote visceral to subcutaneous body fat redistribution during adolescence in an RBP4-dependent manner. These observational findings provide the basis for future interventional studies, which together with genetic information may inject further causality in the association between dietary vitamin A intake and abdominal adiposity.
    Full-text · Article · Dec 2015 · Journal of Nutrigenetics and Nutrigenomics
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    ABSTRACT: Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS. Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored. Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events. The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. Trial registration ClinicalTrials.gov identifier NCT01146522.
    Preview · Article · Dec 2015 · Lipids in Health and Disease
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    Sylvia Villeneuve · Diane Brisson · Daniel Gaudet
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    ABSTRACT: . Apolipoprotein (Apo) E plays a key role in the handling of lipoprotein particles with ApoE2 and ApoE4 frequently having opposite effects compared to ApoE3. Some individuals simultaneously carry both E2 and E4 alleles. The impact of the ApoE2/4 genotype on lipid concentrations and its consequences on health remain poorly documented. Objective . This study compared the lipid profile between ApoE2/4 carriers and other ApoE genotypes in relation to the waist circumference. Methods . Cholesterol, triglyceride (TG), and ApoB concentrations were measured among 2,680 Caucasians. Multivariate logistic regression models were used to estimate the contribution of ApoE2/4 to various dyslipidemic profiles associated with abdominal obesity. Results . In presence of abdominal obesity, the lipid profile was as deteriorated in ApoE2/4 carriers as in carriers of other ApoE genotypes. There was a more pronounced effect on TG-rich lipoproteins, particularly in ApoE2/2 (a feature of type III dysbetalipoproteinemia), and non-high-density lipoprotein (HDL) cholesterol in ApoE4/4. Compared to ApoE2/2, ApoE2/4 carriers presented lower very-low-density lipoprotein (VLDL) cholesterol concentrations and VLDL-cholesterol/TG ratios, with or without obesity, and higher low-density lipoprotein (LDL) cholesterol concentrations. Conclusion . In presence of abdominal obesity, the influence of the ApoE2 allele could be less pronounced than that of ApoE4 among ApoE2/4 individuals.
    Full-text · Article · Nov 2015
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    ABSTRACT: Aim: To assess the associations between gestational diabetes mellitus (GDM) and DNA methylation levels at genes related to energy metabolism. Patients & methods: Ten loci were selected from our recent epigenome-wide association study on GDM. DNA methylation levels were quantified by bisulfite pyrosequencing in 80 placenta and cord blood samples (20 exposed to GDM) from an independent birth cohort (Gen3G). Results: We did not replicate association between DNA methylation and GDM. However, in normoglycemic women, glucose levels were associated with DNA methylation changes at LRP1B and BRD2 and at CACNA1D and LRP1B gene loci in placenta and cord blood, respectively. Conclusion: These results suggest that maternal glucose levels, within the normal range, are associated with DNA methylation changes at genes related to energy metabolism and previously associated with GDM. Maternal glycemia might thus be involved in fetal metabolic programming.
    No preview · Article · Nov 2015 · Epigenomics
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    Full-text · Poster · Nov 2015
  • J Lachaine · D Gaudet · A Miron · K Tremblay

    No preview · Article · Nov 2015 · Value in Health

  • No preview · Article · Nov 2015 · Value in Health
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    ABSTRACT: Background Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension.Objectives Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence.Methods In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges.ResultsMales vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm3 of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP.Conclusions Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.
    No preview · Article · Oct 2015 · Pediatric Obesity
  • Daniel Gaudet · Diane Brisson

    No preview · Article · Oct 2015 · Current Opinion in Lipidology
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    ABSTRACT: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis. We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline. A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study. We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).
    No preview · Article · Jul 2015 · New England Journal of Medicine
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    ABSTRACT: DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative-trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3kb). Here we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300-kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300-kb region. The meQTL was identified in four samples (p=2.8x10(-17), p=3.1x10(-31), 4.0x10(-71), 5.2x10(-199)), comprising a total of 2,796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300-kb region (p=7.1x10(-18)-1.0x10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: p=2.4×10(-13)-7.1×10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (p=0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Jul 2015 · Human Molecular Genetics

  • No preview · Article · Jul 2015 · Atherosclerosis

  • No preview · Article · Jul 2015 · Atherosclerosis
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    ABSTRACT: Despite current standard-of-care, many patients at high cardiovascular disease (CVD) risk still have elevated low-density lipoprotein cholesterol (LDL-C). Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). To compare LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies. Design, Patients, Interventions: Patients (n=355) with CVD and LDL-C levels ≥70 mg/dL, or CVD risk factors and LDL-C ≥100 mg/dL, on baseline atorvastatin 20 or 40 mg, were randomized to: (1) add-on alirocumab 75 mg every 2 weeks (Q2W) subcutaneously; (2) add-on ezetimibe 10 mg/day; (3) double atorvastatin dose; (4) for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg. For patients not achieving protocol-defined LDL-C goals, alirocumab dose was increased (blinded) at week 12 to 150 mg Q2W. Primary endpoint was % change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). Among atorvastatin 20 and 40 mg regimens respectively, add-on alirocumab reduced LDL-C levels by 44.1% and 54.0% (p<0.001 vs all comparators); add-on ezetimibe, 20.5% and 22.6%; doubling of atorvastatin dose, 5.0% and 4.8%; and switching atorvastatin 40 mg to rosuvastatin 40 mg, 21.4%. Most alirocumab-treated patients (87.2% and 84.6%) achieved their LDL-C goals. Most alirocumab-treated patients (86%) maintained their 75 mg Q2W regimen. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients, vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data pooled). Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin, and enabled greater LDL-C goal achievement.
    No preview · Article · Jun 2015 · The Journal of Clinical Endocrinology and Metabolism

  • No preview · Article · Jun 2015 · Pancreatology
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    ABSTRACT: Background and objectives • Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels, inadequate response to conventional drug therapy and premature-onset cardiovascular disease.1 • HoFH is most commonly caused by the occurrence of two LDL–receptor (LDL-R) gene (LDLR) mutations but can also be caused by mutations in other genes which directly or indirectly affect the LDL-C/LDL-R pathway, including the genes encoding apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL-receptor adapter protein 1 (LDLRAP1) (Figure 1).1 • The genotype and clinical phenotype of HoFH patients varies, and depending on the type of mutations, patients can present with untreated LDL-C levels as low as 4.4 mmol/L.1, 2 • To further explore the variability of HoFH, we examined the phenotype, genotype and baseline-treated LDL-C levels in a cohort of patients with genetically confirmed HoFH enrolled in a clinical trial.
    Full-text · Conference Paper · May 2015
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    ABSTRACT: Homozygous familial hypercholesterolemia features a wide range of LDL-C levels Abstract nr. 389 Author Stefanutti , Claudia, ‘Sapienza’ University of Rome, Rome, Italy Co-author(s) - Blom , Dirk Co-author(s) - Averna , Maurizio Co-author(s) - Meagher , Emma Co-author(s) - Theron , Hendrik du toit Co-author(s) - Marais , David Co-author(s) - Hegele , Robert Co-author(s) - Sirtori , Cesare Co-author(s) - Shah , Prediman Co-author(s) - Gaudet , Daniel Co-author(s) - Vigna , Giovanni Co-author(s) - Du Plessis , Anne Co-author(s) - Bloedon , LeAnne Co-author(s) - Rader , Daniel Co-author(s) - Cuchel , Marina Topic Dyslipidemia; Lipids, Lipoproteins and Apolipoproteins Keywords Familial Hypercholesterolemia,Genetics,Hypolipidemic Drugs,LDL Objectives: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by highly elevated LDL-C levels, limited response to conventional lipid-lowering therapies, and increased risk of premature CVD. Severe atherosclerosis may develop before the age of 30. Traditionally, HoFH has been diagnosed according to untreated plasma LDL-C levels >500mg/dL; or treated levels ≥300mg/dL. More recently, studies suggest that the range of LDL-C levels in HoFH may be more variable. To explore this, we analyzed baseline LDL-C levels in a group of treated clinical trial subjects with genetically confirmed HoFH. 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 range was 18-55 years. Nearly all patients (93%) had a history of CVD: CABG, 35%; coronary angioplasty, 10%; aortic valve replacement, 10%; mitral valve replacement/repair, 10%. Therapy included statins (93%; 76% with ezetimibe) and apheresis (62%). Treated LDL-C levels were in the range 152-564mg/dL; 38% had LDL-C <300mg/dL and 14% <200mg/dL (Table). There were no differences in LDL-C levels between subjects who were receiving apheresis treatment and those who were not. Conclusion: Consistent with other recent studies, this analysis provides additional evidence of the heterogeneity of on-treatment LDL-C values in patients with genetically defined HoFH. Diagnosis of HoFH should not rely solely on treated LDL-C >300 mg/dL, but should also include other clinical or genetic factors. Table of baseline characteristics Subdivision 3. Clinical Studies Presentation Preference Electronic poster presentation
    Full-text · Conference Paper · May 2015

  • No preview · Article · May 2015 · Journal of Clinical Lipidology

  • No preview · Article · May 2015 · Journal of Clinical Lipidology

Publication Stats

9k Citations
1,838.33 Total Impact Points


  • 2001-2015
    • Université de Montréal
      • Department of Medicine
      Montréal, Quebec, Canada
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
  • 2014
    • Centre hospitalier affilié universitaire de Québec (CHA)
      Quebec City, Quebec, Canada
    • AVACO AG, Switzerland
      Basel-Landschaft, Switzerland
  • 2010-2014
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
    • University of Nottingham
      • Brain and Body Centre
      Nottigham, England, United Kingdom
  • 2013
    • Université de Sherbrooke
      Sherbrooke, Quebec, Canada
  • 1997-2013
    • University of Québec in Chicoutimi
      • Department of Health Sciences
      Saguenay, Quebec, Canada
  • 2006
    • Institute of Heart Sciences
      Valladolid, Castille and León, Spain
  • 1997-2006
    • Laval University
      • Department of Food and Nutrition Sciences
      Quebec City, Quebec, Canada
  • 2005
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • New York State
      New York City, New York, United States
  • 2002-2004
    • Philadelphia ZOO
      Filadelfia, Pennsylvania, United States
  • 2003
    • University of Toronto
      Toronto, Ontario, Canada
    • Children's Hospital of Eastern Ontario
      Ottawa, Ontario, Canada
  • 2000-2002
    • Medical College of Wisconsin
      • Department of Medicine
      Milwaukee, Wisconsin, United States
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • Fonds de recherche du Québec
      Montréal, Quebec, Canada
  • 1989
    • Centre Hospitalier de Laval
      Лаваль, Pays de la Loire, France