Robert A Hegele

Robert A Hegele
The University of Western Ontario | UWO · Robarts Research Institute

MD, FRCPC, Cert. Endo. FACP, FAHA, FCAHS, FCCS

About

1,185
Publications
205,457
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54,938
Citations
Introduction
In collaboration and independently, my laboratory has discovered the genetic basis more than 20 different human diseases. We have implemented next-generation sequencing clinically in the diagnosis of dyslipidemia. We contribute to international initiatives studying the genetic basis of metabolic variables. We have participated in several clinical trials of novel lipid-lowering agents, trained numerous clinicians and graduate students and have helped to write clinical practice guidelines.
Additional affiliations
January 1998 - present
September 1997 - present
London Health Sciences Centre
Position
  • Staff Endocrinologist
August 1997 - May 2016
Robarts Research Institute
Position
  • Scientist, Distinguished University Professor
Education
September 1977 - June 1981
University of Toronto
Field of study

Publications

Publications (1,185)
Article
Background: Genetic variants in LMNA may cause cardiac disease, but population-level contributions of variants to cardiac disease burden are not well-characterized. Objectives: We sought to determine the frequency and contribution of rare LMNA variants to cardiomyopathy and arrhythmia risk among ambulatory adults. Methods: We included 185,990...
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Purpose of Review We reviewed lipid-modifying therapies and the risk of stroke and other cerebrovascular outcomes, with a focus on newer therapies. Recent Findings Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic...
Article
Introduction: Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in plasma causing severe hypertriglyceridemia, typically >10 mmol/L (>875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lower...
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Purpose of Review Common DNA variants with small effects work together to create susceptibility to polygenic hypercholesterolemia. Some clinicians wonder whether patients with polygenic hypercholesterolemia have less severe clinical features compared to patients with monogenic familial hypercholesterolemia (FH) caused by rare deleterious variants....
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Background: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods: Here,...
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Elevated plasma lipoprotein(a) (Lp(a)) is an independent, causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Lp(a) is formed in or on hepatocytes from successive non-covalent and covalent interactions between apo(a) and apoB, although the subcellular location of these interactions and the nature of the...
Article
Objective: Mild to moderate hypertriglyceridemia is a condition often associated with obesity and diabetes, with as yet incomplete knowledge of underlying genetic architecture. The 22q11.2 microdeletion is associated with multimorbidity, including increased risk of obesity and diabetes. In this study, we sought to investigate whether the 22q11.2 mi...
Article
Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and em...
Article
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. This multi‐site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively...
Article
Background: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular...
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There are many metrics to evaluate the performance and status of journals. Among these, the journal impact factor (JIF) has become the dominant metric. The influence of JIF is illustrated by its widespread use to evaluate academic status, compensation, and funding decisions. However, as noted by Clarivate Analytics, the parent company of the web of...
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Complete deficiency of apolipoprotein (apo) B-containing lipoproteins can result from both abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HoHBL), caused by bi-allelic loss-of-function variants in the MTTP and APOB genes encoding microsomal triglyceride transfer protein and apolipoprotein (apo) B, respectively. Both conditions ar...
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Introduction: Homozygous familial hypercholesterolaemia (HoFH) is characterised by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and results from multiple mutations in genes affecting the LDL receptor pathway. Patients are at risk of premature atherosclerotic cardiovascular disease (ASCVD) and premature death. Lomitapide...
Article
Background Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objecti...
Article
Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated p...
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Importance Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. Objective To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3–PL/FFA [CaPre...
Article
Lead Author's Financial Disclosures D.B. has received consulting fees from Amryt. Study Funding Amryt Pharma. Background/Synopsis Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) secondary to bi-allelic pathogenic mutations affecti...
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Rare variants in the LMNA gene encoding nuclear lamin A/C are causal for more than a dozen diverse mendelian disorders. Defining the functional consequences of LMNA variants has been challenging given the pleiotropy of gene functions and potential pathogenic mechanisms. It is essential to develop trustworthy, scalable and rapidly deployable in vitr...
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We evaluated whether low-density lipoprotein cholesterol (LDL-C) levels in familial hypercholesterolemia patients taking triple lipid-lowering therapy would remain below intensification threshold values after withdrawal of ezetimibe. We included 13 heterozygous FH patients with vascular disease who were treated with statin + ezetimibe + evolocumab;...
Article
Plasma triglyceride concentration is easily, inexpensively, and accurately measured, and when elevated is a highly informative disease marker that identifies individuals who frequently have a host of underlying metabolic, inflammatory, and atherogenic risk factors. Although this concept aligns with much that has been discussed regarding the metabol...
Article
Congenital generalized lipodystrophy (CGL) is a rare, heterogeneous, autosomal recessive disorder characterized by near total absence of body fat with increased muscularity noticed at birth or in early infancy. Four distinct genetic subtypes of CGL have been reported to date. Types 1 and 2 are caused by biallelic variants in the 1-acylglycerol-3-ph...
Article
Purpose of review: Lipodystrophies are a group of rare, heterogeneous disorders characterized by a lack or maldistribution of adipose tissue. Treatment focusses on the management of complications, including hypertriglyceridemia, which can be severe. Patients are predisposed to early atherosclerotic cardiovascular disease and acute pancreatitis. Th...
Article
Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administere...
Article
Background Whether LDL receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL-C reductions in HeFH. Methods A total of 615 individuals with H...
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Patients with homozygous familial hypercholesterolemia (HoFH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) with premature atherosclerosis and aortic valve disease. Available drug treatments are inadequate, and even with serial apheresis HoFH patients rarely achieve acceptable LDL-C levels. Evinacumab is a monoclonal...
Article
Purpose In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Cu...
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Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, A1C 11.9%) and led to comprehensive investigation to define the functional, mo...
Article
Purpose of review: Preprinting, or the sharing of non-peer reviewed, unpublished scholarly manuscripts, has exploded in all fields of science and medicine over the past 5 years. We searched the literature and evaluated the posting and uptake of preprint publications in the field of lipidology in bioRxiv and medRxiv servers. We also contacted the e...
Article
Lipid disorders involving derangements in serum cholesterol, triglycerides or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations and treatment options have necessitated an updated approach to these disorders. Older classification sc...
Article
Purpose of review: : Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified. Recent fi...
Article
BACKGROUND Homozygous familial hypercholesterolemia (HoFH) is an orphan disease characterized by extremely high levels of plasma levels of LDL-C. Affected patients develop clinical atherosclerotic cardiovascular disease (ASCVD) in youth and survival > 30 years of age was unusual until the advent of medications (statins) and extracorporeal LDL filtr...
Preprint
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Computational predictors can help interpret pathogenicity of human genetic variants, especially for the majority of variants where no experimental data are available. However, because we lack a high-quality unbiased test set, identifying the best-performing predictors remains a challenge. To address this issue, we evaluated missense variant effect...
Article
Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the action of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH...
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Background The incidence of severe (S-HTG) and very severe hypertriglyceridemia (VS-HTG) among Canadians is unknown. This study aimed to determine the incidence, characteristics, predictors and care patterns for individuals with VS-HTG. Methods Using linked administrative healthcare databases, a population-based cohort study of Ontario adults was...
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Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also i...
Article
Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial...
Article
Full-text available
Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consi...
Article
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Objective Familial hypercholesterolemia (FH) is associated with a high risk of premature atherosclerotic cardiovascular disease (ASCVD). However, this risk is highly heterogeneous and current risk prediction algorithms for FH suffer from limitations. The primary objective of this study was to develop a score predicting incident ASCVD events over 10...
Article
Introduction Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyce...
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Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revea...
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Familial partial lipodystrophy (FPLD) is a rare Mendelian condition listed in the differential diagnosis of severe hypertriglyceridemia (HTG) and pancreatitis. Here we determined the prevalence of severe HTG and pancreatitis among a cohort of 74 FPLD patients assessed in a lipid clinic. We studied lipid profiles from individuals with either of the...
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Familial hypercholesterolemia (FH), a well-known lipid disease caused by inherited genetic defects in cholesterol uptake and metabolism is underdiagnosed in many countries including Saudi Arabia. The present study aims to identify the molecular basis of severe clinical manifestations of FH patients from unrelated Saudi consanguineous families. Two...
Article
Purpose of review: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming more prominent as a therapeutic choice in diabetes management and their use is being expanded to other indications, such as obesity. Dyslipidemia and cardiovascular disease are common co-morbidities in these populations and understanding the impact of this class o...
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Full-text available
Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the MTTP gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B–containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which...
Article
Background Biomarker measures of contaminant exposure and nutrient status can help increase understanding of the risks and benefits associated with the consumption of traditional foods by Inuit. While gene-environment and gene-nutrient interactions may help explain variations in biomarker measures, the role of genetic polymorphisms is largely under...
Article
Objectives Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible P...
Article
Purpose of review: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antihyperglycemic drugs that show remarkable cardiorenal protective effects in patients with or without type 2 diabetes. Furthermore, they are effective among patients across a wide range of baseline renal and cardiac function. Numerous mechanisms have been evalua...
Article
For many years there has been uncertainty regarding how apolipoprotein E (APOE) E2 and E4 variants may influence overlapping features of neurodegeneration, such as cognitive impairment. We aimed to identify whether the APOE variants are associated with cognitive function across various neurodegenerative and cerebrovascular diagnoses (n = 513). Util...
Preprint
Full-text available
Purpose: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia (FH) Variant Curati...
Article
Full-text available
Aims Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in...
Article
Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translati...
Article
Chylomicronemia is characterized by severe hypertriglyceridemia when chylomicrons persist in plasma despite a fasting state. The recessive monogenic form is due to homozygous or compound heterozygous loss-of-function mutations in the LPL gene or genes involved in the assembly, transport, or function of LPL, including APOC2, APOA5, GP1HBP1, and LMF1...
Article
The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings emerging since the 2016 guidelines. In subjects with clinical atherosclerosis, abdominal aortic aneurysm, most subjects with diabetes or chronic kidney disease, and those with low-density lipoprotein...
Article
Background Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome. Methods The COMPASS trial was a randomised, placebo-contro...
Article
Background: Cockayne syndrome is an autosomal recessive disorder caused by biallelic mutations in ERCC6 or ERCC8 genes. Aims: To study the clinical and mutation spectrum of Cockayne syndrome. Setting and design: Medical Genetics Outpatient Department of Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. This was a prospective...
Article
Purpose of review: The relationship between elevated triglyceride levels (i.e. hypertriglyceridemia) and risk of atherosclerotic cardiovascular disease (ASCVD) has been investigated for decades. Recent genetic studies have sought to resolve the decades-old question of a causal relationship. Recent findings: Genetic studies seem to demonstrate as...
Article
Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative...
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The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank particip...
Article
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Background Polygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in “lone” AF. Methods A total of 186 “lone” AF cases of European anc...
Article
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HDL and its primary receptor, scavenger receptor BI (SR-BI), work together to promote the clearance of excess plasma cholesterol, thereby protecting against atherosclerosis. Human variants of SR-BI have been identified in patients with high HDL-cholesterol levels, and at least one variant has been linked to cardiovascular disease. Therefore, while...