Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), CIBERCV, Universidad de Zaragoza, Zaragoza, Spain.
Introduction And Objectives: Approximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members. Read More
Introduction: There is a growing interest in nutraceuticals improving cardiovascular risk factor levels and related organ damage.
Methods: This double-blind, placebo-controlled randomized clinical trial aims to compare the effect of a combined nutraceutical containing red yeast rice (10 mg), phytosterols (800 mg), and L-tyrosol (5 mg) on lipid profile, blood pressure, endothelial function, and arterial stiffness in a group of 60 patients with polygenic hypercholesterolemia resistant to Mediterranean diet.
Results: After 8 weeks of treatment, when compared to the placebo group, the active treated patients experienced a more favorable percentage change in total cholesterol (-16. Read More
J Physiol Anthropol 2017 Jun 14;36(1):25. Epub 2017 Jun 14.
Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Kampar Campus, Jalan Universiti, Bandar Barat, 31900, Kampar, Perak, Malaysia.
Background: Despite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance-collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications. Read More
Hypercholesterolemia is a strong determinant of mortality and morbidity associated with cardiovascular diseases and a major contributor to the global disease burden. Mutations in four genes (LDLR, APOB, PCSK9 and LDLRAP1) account for the majority of cases with familial hypercholesterolemia. However, a substantial proportion of adults with hypercholesterolemia do not have a mutation in any of these four genes. Read More
Background: Familial hypercholesterolemia is a monogenic autosomal dominant dyslipidemia characterized by a permanent and isolated increase of cholesterol carried by low-density lipoproteins. The prevalence of its heterozygous form is estimated between 1/500 and 1/250, and in the absence of specific treatment, this form is responsible for an increase by a factor of 13 of the risk of premature coronary artery disease compared to patients non-affected by the disease.
Objectives: To perform an inventory of the knowledge of heterozygous familial hypercholesterolemia in France for physicians involved in the management of the disease. Read More
Background And Aims: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. Read More
Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. Read More
An Expert Panel convened by the National Lipid Association was charged with updating the recommendations on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy that were provided by the 2015 National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part 2. Recent studies have demonstrated the efficacy of these agents in reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol and have confirmed their excellent safety profile. A cardiovascular outcomes study has shown that these agents reduce incident atherosclerotic cardiovascular disease (ASCVD) events in patents with stable ASCVD and concomitant risk factors. Read More
Introduction: Familial hypercholesterolemia (FH) is a common genetic cause of premature coronary heart disease that is widely underdiagnosed and undertreated. To improve the identification of FH and initiate timely and appropriate treatment strategies, genetic testing is becoming increasingly offered worldwide as a central part of diagnosis. Areas covered: Recent advances have been propelled by an improved understanding of the genetic determinants of FH together with substantially reduced costs of appropriate screening strategies. Read More
aMolecular Diagnostics, Randox Laboratories Ltd., Crumlin bRegional Genetics Centre, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK.
Purpose Of Review: Familial hypercholesterolaemia is a hereditary disorder of lipoprotein metabolism which causes a lifelong increase in LDL-C levels resulting in premature coronary heart disease. The present review looks at some of the recent literature on how molecular methods can be used to assist in the definitive diagnosis of familial hypercholesterolaemia in a range of patient groups.
Recent Findings: Several recent studies have shown that the prevalence of clinical familial hypercholesterolaemia is higher than previously thought at 1/200 to 1/300, and that 2-5% of patients presenting with early myocardial infarction can be found to have a familial hypercholesterolaemia mutation. Read More
Nutrition, Metabolism and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, Québec, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Québec, Canada; Division of Medical Biochemistry, Department of Medicine, McGill University, Québec, Canada. Electronic address:
Background: Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk.
Objective: The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs).
Methods: Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. Read More
Purpose Of Review: Familial hypercholesterolaemia (FH) is an inherited disorder of low-density lipoprotein cholesterol (LDL-C) which is characterised by a raised cholesterol level from birth and a high risk of premature coronary heart disease. In this paper, we review the genetic basis of FH and its impact on the clinical presentation.
Recent Findings: Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH. Read More
Since 2007, the year of their first widespread use, genome-wide association studies (GWAS) have become the "gold standard" for the detection of causal genes and polymorphisms in all fields of human medicine. Cardiovascular disease (CVD), one of the major causes of morbidity and mortality, is no exception. The first GWAS focused on hypercholesterolemia and dyslipidemia as the major CVD determinants. Read More
Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
Introduction And Objectives: The equations used in the general population to calculate cardiovascular risk are not useful in genetic hypercholesterolemia (GH). Carotid plaque detection has proved useful in cardiovascular prediction and risk reclassification but there have been no studies of its usefulness in GH. The aim of this study was to determine the association between the presence of carotid artery plaque and the occurrence of cardiovascular events in patients with GH. Read More
Atherosclerosis and abdominal aortic aneurysms (AAAs) are multifactorial and polygenic diseases with known environmental and genetic risk factors that contribute toward disease development. Atherosclerosis represents an important independent risk factor for AAA, as people with AAA often have atherosclerosis. Studies have shown that comorbidity is usually between ~25% and 55%, but it is still not fully known whether this association is causal or a result of common shared risk profiles. Read More
Objective: To evaluate the effectiveness of criteria based on child-parent assessment in predicting familial hypercholesterolemia (FH)-causative mutations in unselected children with hypercholesterolemia.
Study Design: LDLR, APOB, and PCSK9 genes were sequenced in 78 children and adolescents (mean age 8.4 ± 3. Read More
Hyperlipoproteinemia (HLP) is one of the most common metabolic disorder in childhood. We assume that 20 % of children have a disorder of the lipid metabolism. Some HLP are very common in the population, and moderate, and some are very rare, but are very severe. Read More
Background And Aims: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel.
Methods: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Read More
Familial hypercholesterolemia (FH) is an autosomal codominantly inherited disease. The severity of clinical presentation depends on the zygosity of the mutations in the LDLR, APOB, or PCSK9 genes. The homozygous form (HoFH) is associated with high mortality rate by third decade of life, while individuals with HeFH begin to suffer from premature cardiovascular disease in fourth or fifth decade of life. Read More
Background: A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied.
Objectives: We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH). Read More
Arterioscler Thromb Vasc Biol 2016 Dec 20;36(12):2439-2445. Epub 2016 Oct 20.
From the Robarts Research Institute (J.W., J.S.D., M.R.B., J.F.R., A.D.M., A.A.D., H.C., M.W.H., R.A.H.), Department of Biochemistry (J.S.D., M.A., A.A.D., M.W.H., R.A.H.), and Department of Medicine (P.J.Z., M.W.H., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada; Faculté de Médicine, Université de Montréal, Québec, Canada (M.-P.D., G.L., J.-C.T.); and Montréal Heart institute, Québec, Canada (D.R., C.L.-K., M.-P.D., G.L., J.-C.T.).
Objective: Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic.
Approach And Results: We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5. Read More
Homozygous familial hypercholesterolemia (HoFH) is a polygenic disease arising from defects in the clearance of plasma low-density lipoprotein (LDL), which results in extremely elevated plasma LDL cholesterol (LDL-C) and increased risk of atherosclerosis, coronary heart disease, and premature death. Conventional lipid-lowering therapies, such as statins and ezetimibe, are ineffective at lowering plasma cholesterol to safe levels in these patients. Other therapeutic options, such as LDL apheresis and liver transplantation, are inconvenient, costly, and not readily available. Read More
Familial hypercholesterolaemia (FH) is the most common autosomal dominant condition, with a prevalence of between one in 200 and one in 350 people in the general population. Untreated FH is associated with premature atherosclerotic cardiovascular disease (CVD). The prevalence of homozygous or compound heterozygous FH is now considered to be about one in 300 000 people. Read More
Background: Familial hypercholesterolemia (FH) is caused by mutations in LDLR, APOB, or PCSK9, and in a previous study, we identified a causative mutation in these FH genes in 95% (255 of 269) of children with the FH phenotype. It has been hypothesized that a polygenic form of hypercholesterolemia is present in FH patients in whom no mutation is identified in the 3 FH genes.
Objective: To address whether a polygenic form of hypercholesterolemia, defined as high-weighted effect of low-density lipoprotein cholesterol (LDL-C) raising SNPs expressed as the genetic risk score (GRS), is present in the remaining 14 children. Read More
Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Read More
Background: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population. Read More
Curr Genet Med Rep 2016 7;4(3):130-141. Epub 2016 Jun 7.
Departments of Medicine and Biochemistry, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A - 1151 Richmond Street North, London, ON N6A 5B7 Canada.
Purpose Of Review: Plasma lipids, namely cholesterol and triglyceride, and lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein, serve numerous physiological roles. Perturbed levels of these traits underlie monogenic dyslipidemias, a diverse group of multisystem disorders. We are on the verge of having a relatively complete picture of the human dyslipidemias and their components. Read More
Background: Genome-wide association studies (GWAS) interrogate large-scale whole genome to characterize the complex genetic architecture for biomedical traits. When the number of SNPs dramatically increases to half million but the sample size is still limited to thousands, the traditional p-value based statistical approaches suffer from unprecedented limitations. Feature screening has proved to be an effective and powerful approach to handle ultrahigh dimensional data statistically, yet it has not received much attention in GWAS. Read More
Background: Plasma-oxidized (ox) low-density lipoprotein (LDL) is an atherogenic lipoprotein. The distribution of ox-LDL in plasma LDL subfractions and the effect of statins on this distribution have not been investigated in detail.
Objective: We examined the distribution of cholesterol and ox-LDL in 3 ultracentrifugally separated plasma LDL subfractions and investigated the effects of a statin, rosuvastatin, on the levels of these lipoproteins. Read More
The main guidelines for cardiovascular disease prevention suggest that nutraceuticals could be an efficacious tool to improve lipid pattern. Our aim was to carry out a clinical trial comparing the metabolic effects of a combined nutraceutical containing both red yeast rice and polyunsaturated fatty acids (PUFAs) and a phytosterol-based approach in a setting of clinical practice. This was a multicenter open study with parallel control. Read More
Background/objective: Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians. Read More
Background: Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions.
Objective: We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). Read More
aPublic Health Department, Corporate Services, Hampshire County Council, Winchester, Hampshire bSolutions for Public Health, Oxford Business Park South, Cowley, Oxfordshire cCentre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
Purpose Of Review: Many international recommendations for the management of familial hypercholesterolaemia propose the use of cascade testing using the family mutation to unambiguously identify affected relatives. In the current economic climate DNA information is often regarded as too expensive. Here, we review the literature and suggest strategies to improve cost-effectiveness of cascade testing. Read More
Background: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. Read More
J Med Genet 2014 Aug 1;51(8):537-44. Epub 2014 Jul 1.
British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, the Rayne Building University College London, London, UK.
Background: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. Read More
Purpose Of Review: Genome-Wide Association Studies have provided robust identification of approximately 100 genetic loci determining plasma lipid parameters. Using these multiple common genetic lipid-determining variants in a 'gene score' has thrown new light on the mode of inheritance of familial lipid disorders.
Recent Findings: Different hypertriglyceridaemia states have been explained by the polygenic coinheritance of triglyceride-raising alleles. Read More
Background: GWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. Severe LDLR mutations are responsible for familial hypercholesterolemia (FH). However, most primary hypercholesterolemias are polygenic diseases. Read More
Purpose Of Review: The purpose of this review is to describe advances in the diagnosis, cause, metabolism, risk factors for atherosclerosis, and treatment of familial hypercholesterolemia.
Recent Findings: Heterozygous familial hypercholesterolemia is almost four-fold more frequent than previously thought and is associated with 10-fold to 13-fold risk of cardiovascular disease comparing with normolipidemics. LDL receptor (LDLR) dysfunction and LDL-cholesterol (LDL-C) accumulation disturb the metabolism of other lipoprotein classes, such as chylomicrons and remnants and HDL. Read More
J Am Coll Cardiol 2014 May 12;63(19):1935-47. Epub 2014 Mar 12.
Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address:
The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor, apolipoprotein B (APOB), or proprotein convertase subtilisin kexin type 9 (PCSK9) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. Read More
J Lipid Res 2014 May 13;55(5):947-55. Epub 2014 Mar 13.
Unidade de Investigação & Desenvolvimento, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
The distinction between a monogenic dyslipidemia and a polygenic/environmental dyslipidemia is important for the cardiovascular risk assessment, counseling, and treatment of these patients. The present work aims to perform the cardiovascular risk assessment of dyslipidemic children to identify useful biomarkers for clinical criteria improvement in clinical settings. Main cardiovascular risk factors were analyzed in a cohort of 237 unrelated children with clinical diagnosis of familial hypercholesterolemia (FH). Read More
Cardiovascular disease, particularly coronary artery disease (CAD), is the leading cause of death in the United States. Dyslipidemia, including elevated low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and low high density lipoprotein cholesterol (HDL-C), is a well-established risk factor for CAD and is influenced by both genetic and lifestyle factors, including the diet and dietary fat in particular. Major strides in elucidating the genetic basis for dyslipidemia have been made in recent years, and the quest to clarify how genetic differences influence lipid response to dietary intervention continues. Read More
Objective: There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes.
Approach And Results: We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). Read More
There is no convincing evidence regarding radiation-induced heritable risks of adult-onset multifactorial diseases in humans, although it is important from the standpoint of protection and management of populations exposed to radiation. The objective of the present study was to examine whether parental exposure to atomic-bomb (A-bomb) radiation led to an increased risk of common polygenic, multifactorial diseases-hypertension, hypercholesterolaemia, diabetes mellitus, angina pectoris, myocardial infarction or stroke-in the first-generation (F1) offspring of A-bomb survivors. A total of 11,951 F1 offspring of survivors in Hiroshima or Nagasaki, conceived after the bombing, underwent health examinations to assess disease prevalence. Read More
Background: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. Read More
The TALLYHO/Jng (TH) mouse is an inbred polygenic model for type 2 diabetes (T2D) with moderate obesity. Both male and female TH mice are characterized by increased body and fat pad weights, hyperleptinemia, hyperinsulinemia, and hyperlipidemia. Glucose intolerance and hyperglycemia are exhibited only in males. Read More
Background And Aim: The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c. Read More
Aim: Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. Read More
Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Read More