Robert Dufour - Academia.edu (original) (raw)

Papers by Robert Dufour

Research paper thumbnail of Loss of Function Variant PCSK9 R46L is Associated with a Reduced Prevalence of Recurrent Cardiovascular Events in Familial Hypercholesterolemia†

Journal of Clinical Lipidology, 2016

Research paper thumbnail of Abstract 19931: Mipomersen, An Apolipoprotein B Synthesis Inhibitor, Reduces Small LDL Particle Number and Increases LDL Particle Size in Patients with Heterozygous Familial Hypercholestrolemia and Coronary Artery Disease

Circulation, Nov 23, 2010

Research paper thumbnail of A tale of 2 cousins: An atypical and a typical case of abetalipoproteinemia

Journal of Clinical Lipidology, 2016

Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP ge... more Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP gene. This disease is characterised by a defect in the lipidation of APO B and the absence of VLDL and chylomicron production. Patients affected by ABL present neurological, hemalogical and gastro-intestinal symptoms due to deficiency in lipophilic vitamins and fat malabsorption. We herein report the case of two cousins, one presenting classical symptoms of abetalipoproteinemia and one presenting a much attenuated phenotype. The proband carried a novel combination of MTTP mutations, the 1867+1G>A and the R540C mutations. This patient never received any vitamin supplements and was relatively free of symptoms despite an undetectable APO B concentration. Her cousin was homozygous for 1867+1G>A MTTP mutation and presented most of the classical symptoms of ABL. In conclusion we report a very unusual kindred where on affected member is strongly symptomatic of ABL whereas the other presents very mostly asymptomatic disease suggesting that ABL can present itself with a very incomplete clinical penetrance.

Research paper thumbnail of A novel nonsense apolipoprotein A-I mutation (apoA-IE136X) causes low HDL cholesterol in French Canadians

Atherosclerosis, Jan 3, 2006

The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency were exami... more The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency were examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a stong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers (n = 17) had marked HDL-C deficiency; among the nine carriers ≥35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14 kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls (n = 3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, <60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD.

Research paper thumbnail of Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer’s Disease Pathology

Journal of Molecular Neuroscience, 2015

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with stat... more 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.

Research paper thumbnail of Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Pharmacogenetics and Genomics, 2015

To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and stati... more To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene. Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01 and P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response. rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s response to statin therapy.

Research paper thumbnail of Inefficiencies in osteoarthritis and chronic low back pain management

The American journal of managed care

Objective: To identify inefficiencies in drug and medical service utilization related to pain man... more Objective: To identify inefficiencies in drug and medical service utilization related to pain management in patients with osteoarthritis and chronic low back pain. Study Design: This retrospective cohort study applied revised measures of pain management inefficiencies to Humana Medicare members with osteoarthritis and/or chronic low back pain. Methods: Subjects had either 2 or more claims for osteoarthritis on different days or 2 or more claims for low back pain 90 or more days apart, from January 1, 2008, to June 30, 2010, with the first occurrence assigned the index date. Inefficiencies were identified for 365 days postindex.Pain-related healthcare costs postindex were compared between members with and without inefficiencies. A generalized linear model calculated adjusted costs per member controlling for age, sex, and comorbidities. Results: Most members diagnosed with osteoarthritis, chronic low back pain, or both (N = 68,453) had at least 1 inefficiency measure (n = 37,863) duri...

Research paper thumbnail of Familial Hypercholesterolemia: PCSK9 InsLEU genetic variant and prediabetes/diabetes risk

Journal of Clinical Lipidology, 2015

Recent meta-analyses have shown a dose-dependent effect of statins therapy on the increased incid... more Recent meta-analyses have shown a dose-dependent effect of statins therapy on the increased incidence of new-onset diabetes. Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are an important group of emerging lipid-lowering therapies. PCSK9 loss-of-function mutations have been associated with low-density lipoprotein cholesterol and cardiovascular risk, but their impact on glucose homeostasis and the risk of diabetes are unclear. We investigated the effect of PCSK9-InsLEU polymorphism on the incidence of prediabetes and diabetes. Genotyping was performed for 724 subjects with familial hypercholesterolemia to detect the PCSK9-InsLEU polymorphism. The primary statistical analysis aimed at investigating the association of this variant with glucose homeostasis/diabetes and secondarily its association with coronary events. In this cohort, 26% of subjects were found to have inherited the PCSK9-InsLEU variant. No significant differences were seen in lipid profiles, but the proportion of coronary events were significantly lower in InsLEU-carriers compared with non-carriers (30.6% vs 22.1%, P = .04). However, a higher proportion of prediabetic and diabetic individuals was seen in the InsLEU-carrier group compared with non-carriers (10% vs 6%, P = .04). Accordingly, carriers had plasma glucose concentrations significantly higher (5.3 vs 5.1 mmol/L, P = .02) and were more often affected with impaired fasting glucose (31.3% vs 14.3%, P &amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) than non-carriers. Familial hypercholesterolemia individuals carry the PCSK9-InsLEU genetic variant benefit of lower risk of coronary events but show an increased occurrence of prediabetes and diabetes. In light of these results, further investigations are needed to better understand the potential long-term metabolic effects of the new PCSK9-lowering therapies and the risk of new-onset diabetes.

Research paper thumbnail of Retrieval of TRAPEASE and OPTEASE Inferior Vena Cava Filters with Extended Dwell Times

Journal of Vascular and Interventional Radiology, 2015

To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60... more To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60 days. A retrospective review was performed of patients who underwent an attempted removal of a TRAPEASE or OPTEASE filter with a greater than 60-day dwell time between 2009 and 2015 at a single institution. Eleven patients within that time span were identified, and 10 were included in the review. One patient was excluded from the study because the date of filter placement was unknown. All filters were successfully retrieved. The average dwell time for removed TRAPEASE filters was 1,273 days (range, 129-3,582 d), with a median of 492 days (n = 5). The average dwell time for OPTEASE filters was 977 days (range, 123-2,584 d), with a median of 661 days (n = 5). The average dwell time of all filters was 1,125 days (range, 123-3,582 d), with a median of 577 days (n = 10). All patients exhibited inferior vena cava (IVC) stenosis after filter retrieval. An IVC pseudoaneurysm was present following retrieval in one case and resolved. In one case, a fractured filter strut was left completely embedded in the caval wall. Two patients reported unilateral leg swelling on clinical follow-up, and the remainder reported no leg swelling or tightness. Initial experience suggests that TRAPEASE and OPTEASE filters can be removed after extended dwell times.

Research paper thumbnail of PCSK9 InsLEU Genetic Variant is Associated with Pre-Diabetes and Diabetes*

Journal of Clinical Lipidology, 2015

Research paper thumbnail of PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study

Arteriosclerosis, thrombosis, and vascular biology, 2014

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipop... more Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross-sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk. We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montréal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with no...

Research paper thumbnail of PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial

The Lancet, 2015

Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more 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 eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.

Research paper thumbnail of CKM and LILRB5 Are Associated With Serum Levels of Creatine Kinase

Circulation: Cardiovascular Genetics, 2014

S tatins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs use... more S tatins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs used in the treatment and prevention of cardiovascular disease. 1,2 Despite reducing clinical cardiovascular events by 20% to 50% 3 and having a positive benefit to risk ratio, statins are underused 4,5 because they can cause muscular side effects ranging from nonspecific myalgia to rhabdomyolysis. The frequency of muscle symptoms was evaluated at 10.5% in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study, an observational study in an unselected hyperlipidemic patient population receiving high-dose statins. 7 Many patients stop statin therapy for aches and pains that are mistakenly thought to be related to their medication, which underscores the relevance of research aiming at the refinement of clinical tools used for the diagnosis of statin-induced myotoxicity.

Research paper thumbnail of Pain Conditions Ranked by Healthcare Costs for Members of a National Health Plan

Pain Practice, 2014

Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concer... more Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concern, as increasing dollar amounts are spent on pain-related conditions. Understanding which pain conditions drive the highest utilization and cost burden to the healthcare system would enable providers and payers to better target conditions to manage pain adequately and efficiently. The current study focused on 36 noncancer chronic and 14 noncancer acute pain conditions and measured the HCRU and costs per member over 365 days. These conditions were ranked by per-member costs and total adjusted healthcare costs to determine the most expensive conditions to a national health plan. The top 5 conditions for the commercial line of business were back pain, osteoarthritis (OA), childbirth, injuries, and non-hip, non-spine fractures (adjusted annual total costs for the commercial members were 119million,119 million, 119million,98 million, 69million,69 million, 69million,61 million, and 48million,respectively).Thetop5conditionsforMedicarememberswereOA,backpain,hipfractures,injuries,andnon−hip,non−spinefractures(adjustedannualcostsfortheMedicarememberswere48 million, respectively). The top 5 conditions for Medicare members were OA, back pain, hip fractures, injuries, and non-hip, non-spine fractures (adjusted annual costs for the Medicare members were 48million,respectively).Thetop5conditionsforMedicarememberswereOA,backpain,hipfractures,injuries,andnon−hip,non−spinefractures(adjustedannualcostsfortheMedicarememberswere327 million, 218million,218 million, 218million,117 million, 82million,and82 million, and 82million,and67 million, respectively). The conditions ranked highest for both per-member and total healthcare costs were hip fractures, childbirth, and non-hip, non-spine fractures. Among these, hip fractures in the Medicare member population had the highest mean cost per member (adjusted per-member cost was $21,058). Further examination specific to how pain is managed in these high-cost conditions will enable providers and payers to develop strategies to improve patient outcomes through appropriate pain management.

Research paper thumbnail of PO5-109 Identification of Two New Large Deletions in the Low Density Lipoprotein Receptor (LDLR) Gene in the French Canadian Population

Atherosclerosis Supplements, 2007

Research paper thumbnail of Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue

The Journal of Lipid Research, 2013

This article is available online at http://www.jlr.org among the most common is reduced triglycer... more This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).

Research paper thumbnail of Insulin Infusion Acutely Downregulates Circulating PCSK9 in Human*

Journal of Clinical Lipidology, 2014

Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the... more Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.

Research paper thumbnail of A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care

Diabetes, Obesity and Metabolism, 2013

To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals ... more To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients &amp;amp;gt;40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) ≤7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the &amp;amp;lt;130/80 mmHg target, whereas 60% of those without met the &amp;amp;lt;140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification.

Research paper thumbnail of The effect of insulin on circulating PCSK9 in postmenopausal obese women

Clinical Biochemistry, 2014

Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the... more Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.

Research paper thumbnail of Lab Tests Online and consumer understanding of laboratory testing

Clinica Chimica Acta, 2013

Lab Tests Online is a "peer-reviewed, non-commercial, patient-centered" resource where patients a... more Lab Tests Online is a "peer-reviewed, non-commercial, patient-centered" resource where patients and their relatives and caregivers can learn about the tests used to screen for, diagnose, and manage disease. Consumers are becoming increasingly involved in the management of their own health care and increasingly have access to their laboratory results through electronic health records. Research has shown that consumers have difficulty with health literacy in general and with numerical data in particular. The Lab Tests Online global websites are an important step toward helping consumers understand the complexity of the pathology process, the expertise of the people involved and the meaning of the results provided to them and their healthcare professionals.

Research paper thumbnail of Loss of Function Variant PCSK9 R46L is Associated with a Reduced Prevalence of Recurrent Cardiovascular Events in Familial Hypercholesterolemia†

Journal of Clinical Lipidology, 2016

Research paper thumbnail of Abstract 19931: Mipomersen, An Apolipoprotein B Synthesis Inhibitor, Reduces Small LDL Particle Number and Increases LDL Particle Size in Patients with Heterozygous Familial Hypercholestrolemia and Coronary Artery Disease

Circulation, Nov 23, 2010

Research paper thumbnail of A tale of 2 cousins: An atypical and a typical case of abetalipoproteinemia

Journal of Clinical Lipidology, 2016

Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP ge... more Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by mutations of the MTTP gene. This disease is characterised by a defect in the lipidation of APO B and the absence of VLDL and chylomicron production. Patients affected by ABL present neurological, hemalogical and gastro-intestinal symptoms due to deficiency in lipophilic vitamins and fat malabsorption. We herein report the case of two cousins, one presenting classical symptoms of abetalipoproteinemia and one presenting a much attenuated phenotype. The proband carried a novel combination of MTTP mutations, the 1867+1G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A and the R540C mutations. This patient never received any vitamin supplements and was relatively free of symptoms despite an undetectable APO B concentration. Her cousin was homozygous for 1867+1G&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;A MTTP mutation and presented most of the classical symptoms of ABL. In conclusion we report a very unusual kindred where on affected member is strongly symptomatic of ABL whereas the other presents very mostly asymptomatic disease suggesting that ABL can present itself with a very incomplete clinical penetrance.

Research paper thumbnail of A novel nonsense apolipoprotein A-I mutation (apoA-IE136X) causes low HDL cholesterol in French Canadians

Atherosclerosis, Jan 3, 2006

The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency were exami... more The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency were examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a stong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers (n = 17) had marked HDL-C deficiency; among the nine carriers ≥35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14 kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls (n = 3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, <60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD.

Research paper thumbnail of Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer’s Disease Pathology

Journal of Molecular Neuroscience, 2015

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with stat... more 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.

Research paper thumbnail of Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Pharmacogenetics and Genomics, 2015

To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and stati... more To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene. Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01 and P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response. rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s response to statin therapy.

Research paper thumbnail of Inefficiencies in osteoarthritis and chronic low back pain management

The American journal of managed care

Objective: To identify inefficiencies in drug and medical service utilization related to pain man... more Objective: To identify inefficiencies in drug and medical service utilization related to pain management in patients with osteoarthritis and chronic low back pain. Study Design: This retrospective cohort study applied revised measures of pain management inefficiencies to Humana Medicare members with osteoarthritis and/or chronic low back pain. Methods: Subjects had either 2 or more claims for osteoarthritis on different days or 2 or more claims for low back pain 90 or more days apart, from January 1, 2008, to June 30, 2010, with the first occurrence assigned the index date. Inefficiencies were identified for 365 days postindex.Pain-related healthcare costs postindex were compared between members with and without inefficiencies. A generalized linear model calculated adjusted costs per member controlling for age, sex, and comorbidities. Results: Most members diagnosed with osteoarthritis, chronic low back pain, or both (N = 68,453) had at least 1 inefficiency measure (n = 37,863) duri...

Research paper thumbnail of Familial Hypercholesterolemia: PCSK9 InsLEU genetic variant and prediabetes/diabetes risk

Journal of Clinical Lipidology, 2015

Recent meta-analyses have shown a dose-dependent effect of statins therapy on the increased incid... more Recent meta-analyses have shown a dose-dependent effect of statins therapy on the increased incidence of new-onset diabetes. Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are an important group of emerging lipid-lowering therapies. PCSK9 loss-of-function mutations have been associated with low-density lipoprotein cholesterol and cardiovascular risk, but their impact on glucose homeostasis and the risk of diabetes are unclear. We investigated the effect of PCSK9-InsLEU polymorphism on the incidence of prediabetes and diabetes. Genotyping was performed for 724 subjects with familial hypercholesterolemia to detect the PCSK9-InsLEU polymorphism. The primary statistical analysis aimed at investigating the association of this variant with glucose homeostasis/diabetes and secondarily its association with coronary events. In this cohort, 26% of subjects were found to have inherited the PCSK9-InsLEU variant. No significant differences were seen in lipid profiles, but the proportion of coronary events were significantly lower in InsLEU-carriers compared with non-carriers (30.6% vs 22.1%, P = .04). However, a higher proportion of prediabetic and diabetic individuals was seen in the InsLEU-carrier group compared with non-carriers (10% vs 6%, P = .04). Accordingly, carriers had plasma glucose concentrations significantly higher (5.3 vs 5.1 mmol/L, P = .02) and were more often affected with impaired fasting glucose (31.3% vs 14.3%, P &amp;amp;amp;amp;amp;amp;amp;amp;lt; .01) than non-carriers. Familial hypercholesterolemia individuals carry the PCSK9-InsLEU genetic variant benefit of lower risk of coronary events but show an increased occurrence of prediabetes and diabetes. In light of these results, further investigations are needed to better understand the potential long-term metabolic effects of the new PCSK9-lowering therapies and the risk of new-onset diabetes.

Research paper thumbnail of Retrieval of TRAPEASE and OPTEASE Inferior Vena Cava Filters with Extended Dwell Times

Journal of Vascular and Interventional Radiology, 2015

To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60... more To demonstrate that OPTEASE and TRAPEASE filters can be removed after dwell times greater than 60 days. A retrospective review was performed of patients who underwent an attempted removal of a TRAPEASE or OPTEASE filter with a greater than 60-day dwell time between 2009 and 2015 at a single institution. Eleven patients within that time span were identified, and 10 were included in the review. One patient was excluded from the study because the date of filter placement was unknown. All filters were successfully retrieved. The average dwell time for removed TRAPEASE filters was 1,273 days (range, 129-3,582 d), with a median of 492 days (n = 5). The average dwell time for OPTEASE filters was 977 days (range, 123-2,584 d), with a median of 661 days (n = 5). The average dwell time of all filters was 1,125 days (range, 123-3,582 d), with a median of 577 days (n = 10). All patients exhibited inferior vena cava (IVC) stenosis after filter retrieval. An IVC pseudoaneurysm was present following retrieval in one case and resolved. In one case, a fractured filter strut was left completely embedded in the caval wall. Two patients reported unilateral leg swelling on clinical follow-up, and the remainder reported no leg swelling or tightness. Initial experience suggests that TRAPEASE and OPTEASE filters can be removed after extended dwell times.

Research paper thumbnail of PCSK9 InsLEU Genetic Variant is Associated with Pre-Diabetes and Diabetes*

Journal of Clinical Lipidology, 2015

Research paper thumbnail of PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study

Arteriosclerosis, thrombosis, and vascular biology, 2014

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipop... more Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross-sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk. We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montréal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with no...

Research paper thumbnail of PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial

The Lancet, 2015

Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more 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 eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder.

Research paper thumbnail of CKM and LILRB5 Are Associated With Serum Levels of Creatine Kinase

Circulation: Cardiovascular Genetics, 2014

S tatins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs use... more S tatins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs used in the treatment and prevention of cardiovascular disease. 1,2 Despite reducing clinical cardiovascular events by 20% to 50% 3 and having a positive benefit to risk ratio, statins are underused 4,5 because they can cause muscular side effects ranging from nonspecific myalgia to rhabdomyolysis. The frequency of muscle symptoms was evaluated at 10.5% in the Prediction of Muscular Risk in Observational Conditions (PRIMO) study, an observational study in an unselected hyperlipidemic patient population receiving high-dose statins. 7 Many patients stop statin therapy for aches and pains that are mistakenly thought to be related to their medication, which underscores the relevance of research aiming at the refinement of clinical tools used for the diagnosis of statin-induced myotoxicity.

Research paper thumbnail of Pain Conditions Ranked by Healthcare Costs for Members of a National Health Plan

Pain Practice, 2014

Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concer... more Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concern, as increasing dollar amounts are spent on pain-related conditions. Understanding which pain conditions drive the highest utilization and cost burden to the healthcare system would enable providers and payers to better target conditions to manage pain adequately and efficiently. The current study focused on 36 noncancer chronic and 14 noncancer acute pain conditions and measured the HCRU and costs per member over 365 days. These conditions were ranked by per-member costs and total adjusted healthcare costs to determine the most expensive conditions to a national health plan. The top 5 conditions for the commercial line of business were back pain, osteoarthritis (OA), childbirth, injuries, and non-hip, non-spine fractures (adjusted annual total costs for the commercial members were 119million,119 million, 119million,98 million, 69million,69 million, 69million,61 million, and 48million,respectively).Thetop5conditionsforMedicarememberswereOA,backpain,hipfractures,injuries,andnon−hip,non−spinefractures(adjustedannualcostsfortheMedicarememberswere48 million, respectively). The top 5 conditions for Medicare members were OA, back pain, hip fractures, injuries, and non-hip, non-spine fractures (adjusted annual costs for the Medicare members were 48million,respectively).Thetop5conditionsforMedicarememberswereOA,backpain,hipfractures,injuries,andnon−hip,non−spinefractures(adjustedannualcostsfortheMedicarememberswere327 million, 218million,218 million, 218million,117 million, 82million,and82 million, and 82million,and67 million, respectively). The conditions ranked highest for both per-member and total healthcare costs were hip fractures, childbirth, and non-hip, non-spine fractures. Among these, hip fractures in the Medicare member population had the highest mean cost per member (adjusted per-member cost was $21,058). Further examination specific to how pain is managed in these high-cost conditions will enable providers and payers to develop strategies to improve patient outcomes through appropriate pain management.

Research paper thumbnail of PO5-109 Identification of Two New Large Deletions in the Low Density Lipoprotein Receptor (LDLR) Gene in the French Canadian Population

Atherosclerosis Supplements, 2007

Research paper thumbnail of Low density lipoprotein delays clearance of triglyceride-rich lipoprotein by human subcutaneous adipose tissue

The Journal of Lipid Research, 2013

This article is available online at http://www.jlr.org among the most common is reduced triglycer... more This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).

Research paper thumbnail of Insulin Infusion Acutely Downregulates Circulating PCSK9 in Human*

Journal of Clinical Lipidology, 2014

Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the... more Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.

Research paper thumbnail of A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care

Diabetes, Obesity and Metabolism, 2013

To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals ... more To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients &amp;amp;gt;40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) ≤7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the &amp;amp;lt;130/80 mmHg target, whereas 60% of those without met the &amp;amp;lt;140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification.

Research paper thumbnail of The effect of insulin on circulating PCSK9 in postmenopausal obese women

Clinical Biochemistry, 2014

Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the... more Background: PCSK9 (proprotein convertase subtilisin/kexin type 9) promotes the degradation of the LDLR (LDL receptor) in hepatocytes, leading to an increase in plasma LDL-C (LDL cholesterol). Previous animal studies have shown that insulin stimulates PCSK9 transcription and observational human studies showed a positive correlation between plasma PCSK9 concentration and fasting insulinemia.

Research paper thumbnail of Lab Tests Online and consumer understanding of laboratory testing

Clinica Chimica Acta, 2013

Lab Tests Online is a "peer-reviewed, non-commercial, patient-centered" resource where patients a... more Lab Tests Online is a "peer-reviewed, non-commercial, patient-centered" resource where patients and their relatives and caregivers can learn about the tests used to screen for, diagnose, and manage disease. Consumers are becoming increasingly involved in the management of their own health care and increasingly have access to their laboratory results through electronic health records. Research has shown that consumers have difficulty with health literacy in general and with numerical data in particular. The Lab Tests Online global websites are an important step toward helping consumers understand the complexity of the pathology process, the expertise of the people involved and the meaning of the results provided to them and their healthcare professionals.