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Clin Investig Arterioscler 2021 May;33 Suppl 2:43-49

Unidad de Lípidos, Servicio de Medicina Interna, H. U. Gregorio Marañón, Universidad Complutense, Madrid, España.

Familial combined hyperlipidaemia (FCH) is the most prevalent form of familial hyperlipidaemia with a multigenic origin and a complex pattern of inheritance. In this respect, FCH is an oligogenic primary lipid disorder due to interaction of genetic variants and mutations with environmental factors. Patients with FCH are at increased risk of cardiovascular disease and often have other associated metabolic conditions. Read More

J Clin Lipidol 2021 Apr 21. Epub 2021 Apr 21.

Centre for Cardiovascular Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czechia; Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czechia. Electronic address:

We describe the casuistry of a homozygous familial hypercholesterolemia female patient with a biallelic missense variant (NM_000527.4:c.1775G>A, p. Read More

J Hum Genet 2021 May 10. Epub 2021 May 10.

Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. Read More

Curr Opin Lipidol 2021 Jun;32(3):157-162

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital.

Purpose Of Review: Current methods to assess genetic risk of familial hypercholesterolemia and coronary artery disease (CAD) focus on testing monogenic mutations in well known genes. Here we review recent developments in polygenic risk scores (PRSs) for LDL cholesterol and for CAD, and how they may add to current risk prediction algorithms.

Recent Findings: PRSs can identify 10-20 times as many individuals at high polygenic risk compared with monogenic mutations, and PRSs can modulate the effect of a monogenic variant on risk. Read More

J Am Heart Assoc 2021 May 23;10(9):e018932. Epub 2021 Apr 23.

Department of Translational and Precision Medicine "Sapienza" University of Rome Rome Italy.

Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH-causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long-term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low-density lipoprotein-rising genetic risk score >0. Read More

NPJ Genom Med 2021 Apr 14;6(1):28. Epub 2021 Apr 14.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8. Read More

Cardiol Rev 2021 Mar 19. Epub 2021 Mar 19.

Department of Medicine Division of Cardiovascular Medicine Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA.

Genetic testing for cardiovascular (CV) disease has had a profound impact on the diagnosis and evaluation of monogenic causes of CV disease, such as hypertrophic and familial cardiomyopathies, long QT syndrome, and familial hypercholesterolemia (FH). The success in genetic testing for monogenic diseases has prompted special interest in utilizing genetic information in the risk assessment of more common diseases such as atherosclerotic cardiovascular disease (ASCVD). Polygenic risk scores (PRS) have been developed to assess the risk of coronary artery disease (CAD) that now include millions of single-nucleotide polymorphisms (SNPs) that have been identified through genome-wide association studies (GWAS). Read More

Front Genet 2021 11;12:625959. Epub 2021 Feb 11.

Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.

Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the genes, as well as a part of the gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Read More

Vasc Health Risk Manag 2021 17;17:59-67. Epub 2021 Feb 17.

Department of Cardiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. Read More

Sci Rep 2021 Feb 15;11(1):3801. Epub 2021 Feb 15.

University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, 1749-016, Lisboa, Portugal.

Familial hypercholesterolaemia increases circulating LDL-C levels and leads to premature cardiovascular disease when undiagnosed or untreated. Current guidelines support genetic testing in patients complying with clinical diagnostic criteria and cascade screening of their family members. However, most of hyperlipidaemic subjects do not present pathogenic variants in the known disease genes, and most likely suffer from polygenic hypercholesterolaemia, which translates into a relatively low yield of genetic screening programs. Read More

Curr Opin Lipidol 2021 Apr;32(2):112-116

Department of Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.

Purpose Of Review: The current review describes the development, clinical relevance and potential caveats of polygenic risk scores (PRS) for LDL cholesterol (LDL-C).

Recent Findings: In recent years, a large number of common variants have been shown to have a small effect on LDL-C levels. The aggregate effect of all of these variants on LDL-C levels can be captured in a PRS and an elevated number of LDL-C increasing common variants is considered to be a cause of high LDL-C levels in patients with familial hypercholesterolemia (FH) without a large effect, rare mutation. Read More

PLoS One 2021 4;16(2):e0246538. Epub 2021 Feb 4.

Personal Genomics Institute, Genome Research Foundation, Ulsan, Republic of Korea.

Background: The polygenic risk score (PRS) developed for coronary artery disease (CAD) is known to be effective for classifying patients with CAD and predicting subsequent events. However, the PRS was developed mainly based on the analysis of Caucasian genomes and has not been validated for East Asians. We aimed to evaluate the PRS in the genomes of Korean early-onset AMI patients (n = 265, age ≤50 years) following PCI and controls (n = 636) to examine whether the PRS improves risk prediction beyond conventional risk factors. Read More

Circ Genom Precis Med 2021 Feb 13;14(1):e003106. Epub 2021 Jan 13.

Department of Epidemiology, Biostatistics, and Occupational Health (H.W., S.Z., S.R.B., J.B.R.), Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada.

Background: The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH).

Methods: We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Read More

Psychol Med 2021 Jan 12:1-11. Epub 2021 Jan 12.

Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.

Background: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.

Methods: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Read More

J Transl Med 2021 01 6;19(1):19. Epub 2021 Jan 6.

Department of Clinical and Experimental Medicine, Nutrition Unit, University Magna Grecia, 88100, Catanzaro, Italy.

Background: Most studies focused on the benefits of lycopene on serum lipids but no studies have been specifically designed to assess the role of a tomato sauce from vine-ripened tomatoes on patients affected by polygenic hypercholesterolemia. The aim of this study was to compare the lipid-lowering effect of a novel functional tomato sauce with a well-known functional food with a lipid-lowering effect, i.e. Read More

Curr Opin Lipidol 2021 Apr;32(2):103-111

Centre for Heart Lung Innovation, University of British Columbia.

Purpose Of Review: Contemporary polygenic scores, which summarize the cumulative contribution of millions of common single-nucleotide variants to a phenotypic trait, can have effects comparable to monogenic mutations. This review focuses on the emerging use of 'genome-wide' polygenic scores for plasma lipoproteins to define the etiology of clinical dyslipidemia, modify the severity of monogenic disease, and inform therapeutic options.

Recent Findings: Polygenic scores for low-density lipoprotein cholesterol (LDL-C), triglycerides, and high-density lipoprotein cholesterol are associated with severe hypercholesterolemia, hypertriglyceridemia, or hypoalphalipoproteinemia, respectively. Read More

Front Genet 2020 3;11:554931. Epub 2020 Dec 3.

Hospital Universitario Miguel Servet, Instituto de Investigacion Sanitaria Aragon (IIS Aragn), Zaragoza, Spain.

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (, or ), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Read More

J Clin Lipidol 2021 Jan-Feb;15(1):79-87. Epub 2020 Nov 24.

Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada. Electronic address:

Background: Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear.

Objective: To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG). Read More

Molecules 2020 Nov 4;25(21). Epub 2020 Nov 4.

Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.

Hypercholesterolemia is a major cause of atherosclerosis development and premature cardiovascular disease (CVD). It leads to inflammation, which further accelerates atherosclerosis progression. Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated serum LDL-c from birth, due to a disease-causing variant in one of the causative genes (, , ). Read More

Front Genet 2020 7;11:574474. Epub 2020 Oct 7.

3rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University, Prague, Czechia.

Familial hypercholesterolemia (FH) is one of the most common monogenic diseases, leading to an increased risk of premature atherosclerosis and its cardiovascular complications due to its effect on plasma cholesterol levels. Variants of three genes (, and ) are the major causes of FH, but in some probands, the FH phenotype is associated with variants of other genes. Alternatively, the typical clinical picture of FH can result from the accumulation of common cholesterol-increasing alleles (polygenic FH). Read More

Res Social Adm Pharm 2020 Oct 28. Epub 2020 Oct 28.

Cruzeiro do Sul University, Sao Paulo, Brazil. Electronic address:

Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide.

Objectives: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH).

Methods: FH patients will be enrolled at six research centers in Brazil. Read More

Circ Genom Precis Med 2020 10 13;13(5):515-523. Epub 2020 Aug 13.

Centre for Heart Lung Innovation (M.T., L.R.B.), University of British Columbia, Vancouver.

Background: Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH. Read More

Biomedicines 2020 Sep 15;8(9). Epub 2020 Sep 15.

Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain.

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (), apolipoprotein B (), and proprotein convertase subtilisin/kexin 9 () genes. A pathological variant has not been identified in 30-70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. Read More

Arch Cardiol Mex 2020 ;90(2):130-136

Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Universidad de Buenos Aires, Laboratorio de Lípidos y Aterosclerosis, INFIBIOCUBA. Buenos Aires, Argentina.

Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. Read More

Nat Commun 2020 08 20;11(1):3635. Epub 2020 Aug 20.

Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Read More

Clin Genet 2020 11 2;98(5):457-467. Epub 2020 Sep 2.

Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. Read More

Arterioscler Thromb Vasc Biol 2020 09 30;40(9):1970-1981. Epub 2020 Jul 30.

Department of Biochemistry (R.A.H., J.S.D.), Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Dyslipidemias include both rare single gene disorders and common conditions that have a complex underlying basis. In London, ON, there is fortuitous close physical proximity between the Lipid Genetics Clinic and the London Regional Genomics Centre. For >30 years, we have applied DNA sequencing of clinical samples to help answer scientific questions. Read More

Curr Atheroscler Rep 2020 06 18;22(8):32. Epub 2020 Jun 18.

Section of Cardiology, Baylor College of Medicine, Houston, TX, USA.

Purpose Of Review: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC).

Recent Findings: The studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). Read More

Curr Opin Lipidol 2020 08;31(4):187-193

Departments of Biochemistry and Medicine, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.

Purpose Of Review: The aim of this study was to evaluate the potential role of genetic testing, particularly next-generation DNA sequencing, in diagnosing and managing dyslipidaemias, particularly monogenic dyslipidaemias.

Recent Findings: Targeted DNA sequencing of the genes causing monogenic dyslipidaemias is becoming more accessible. Some societies' position statements advise selective utilization of DNA testing in combination with clinical and biochemical assessment. Read More