Article
Biochemical Research Methods
Joanna von Berg, Michelle ten Dam, Sander W. van der Laan, Jeroen de Ridder
Summary: PolarMorphism is a new method for identifying pleiotropic SNPs from GWAS summary statistics, which is more efficient and powerful than previously published methods. The method can be used to understand relationships between traits and trait domains, and provides more biologically relevant results compared to genetic correlation. Pathway analysis of pleiotropic SNPs discovered using PolarMorphism shows that analyzing more than two traits simultaneously yields better results than pairwise analysis.
Article
Biochemistry & Molecular Biology
Markus Buelow, David Suessmuth, Laurie D. Smith, Omid Aryani, Claudia Castiglioni, Werner Stenzel, Enrico Bertini, Markus Schuelke, Ellen Knierim
Summary: NEDHND is a neurodevelopmental disorder caused by variants in the SPTBN4 gene, leading to severe neurological dysfunction. Clinical features include severe muscular hypotonia, dysphagia, and delayed speech development.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2021)
Review
Cell Biology
Y. Henry Sun, Yueh-Lin Wu, Ben-Yang Liao
Summary: Phenotypic heterogeneity is common in genetic systems and human diseases, and understanding its causes is important for disease diagnosis and treatment. This study emphasizes the role of stochastic fluctuation and regulatory network topology, and proposes a threshold effect as a unifying principle for explaining phenotypic heterogeneity. The study also suggests practical strategies for studying genetic diseases based on the model of ultrasensitivity and identifies the critical factor for manipulation to prevent and treat genetic diseases.
JOURNAL OF BIOMEDICAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Thomas Rolland, Freddy Cliquet, Richard J. L. Anney, Clara Moreau, Nicolas Traut, Alexandre Mathieu, Guillaume Huguet, Jinjie Duan, Varun Warrier, Swan Portalier, Louise Dry, Claire S. Leblond, Elise Douard, Frederique Amsellem, Simon Malesys, Anna Maruani, Roberto Toro, Anders D. Borglum, Jakob Grove, Simon Baron-Cohen, Alan Packer, Wendy K. Chung, Sebastien Jacquemont, Richard Delorme, Thomas Bourgeron
Summary: The prevalence of autism-associated genetic variants in individuals without a diagnosis of autism is explored. These variants are associated with a decrease in fluid intelligence, qualification level, income, and an increase in metrics related to material deprivation. Autism-associated genes have a larger impact on these phenotypic features than other genes with loss-of-function variants.
Article
Biochemistry & Molecular Biology
Thomas Bourinaris, Alkyoni Athanasiou, Stephanie Efthymiou, Sarah Wiethoff, Vincenzo Salpietro, Henry Houlden
Summary: Junctophilin-3 is part of a triprotein junctional complex that regulates neuronal excitability and plays a role in forming junctional membrane structures between voltage-gated ion channels and endoplasmic reticular receptors. Mutations in the JPH3 gene have been associated with the rare late-onset disorder HD-like 2 (HDL2), resembling Huntington disease, and a homozygous truncating variant in JPH3 has been linked to early-onset neurodevelopmental anomalies and dystonia. This study expands the understanding of JPH3-associated mutational spectrum and clinical phenotypes, indicating the involvement of Junctophilin-3 loss in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Hematology
Jenni Maatta, Raisa Serpi, Sohvi Horkko, Valerio Izzi, Johanna Myllyharju, Elitsa Y. Dimova, Peppi Koivunen
Summary: The genetic ablation of P4H-TM was shown to protect against atherosclerosis by potentially modulating immuno-metabolic interactions, including the presence of IgM antibodies to Ox-LDL and increased lipoprotein lipase levels. This mechanism could provide a novel approach for intervention in atherosclerosis pathology by targeting hypertriglyceridemia and promoting protective immune responses.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Praneet K. Gill, Jacqueline S. Dron, Amanda J. Berberich, Jian Wang, Adam D. McIntyre, Henian Cao, Robert A. Hegele
Summary: The genetic profiles of patients with combined hyperlipidemia (CHL) were found to be similar to those with isolated hypertriglyceridemia, showing a significant accumulation of common triglyceride-raising variants. Compared to patients with isolated hypercholesterolemia and isolated HTG, CHL patients did not exhibit significant accumulation of rare variants and polygenic scores related to LDL-C or TG.
JOURNAL OF CLINICAL LIPIDOLOGY
(2021)
Article
Multidisciplinary Sciences
Katalin Mango, Adam Ferenc Kiss, Ferenc Fekete, Reka Erdos, Katalin Monostory
Summary: The CYP2B6 enzyme is a major catalyst for the metabolism of several important drugs, and its function varies greatly among individuals due to both genetic and non-genetic factors. A study found that hepatic CYP2B6 activity is strongly correlated with CYP2B6 mRNA expression, and that both genetic and non-genetic factors can contribute to a mismatch between CYP2B6 genotype and phenotype.
SCIENTIFIC REPORTS
(2022)
Article
Genetics & Heredity
Marilena Nakaguma, Nathalia Garcia Bianchi Pereira Ferreira, Anna Flavia Figueredo Benedetti, Mariana Cotarelli Madi, Juliana Moreira Silva, Jun Z. Li, Qianyi Ma, Ayse Bilge Ozel, Qing Fang, Amanda de Moraes Narcizo, Lais Cavalca Cardoso, Luciana Ribeiro Montenegro, Mariana Ferreira de Assis Funari, Mirian Yumie Nishi, Ivo Jorge Prado Arnhold, Alexander Augusto de Lima Jorge, Berenice Bilharinho de Mendonca, Sally Ann Camper, Luciani R. Carvalho
Summary: In this study, four allelic variants in three genes previously associated with hypopituitarism or related disorders were identified, expanding the understanding of the phenotypic spectrum in patient populations. The discovered variants exhibited varying degrees of phenotypic features in patients, involving both monogenic and polygenic inheritance patterns.
Article
Multidisciplinary Sciences
Jacob Househam, Timon Heide, George D. Cresswell, Inmaculada Spiteri, Chris Kimberley, Luis Zapata, Claire Lynn, Chela James, Maximilian Mossner, Javier Fernandez-Mateos, Alessandro Vinceti, Ann-Marie Baker, Calum Gabbutt, Alison Berner, Melissa Schmidt, Bingjie Chen, Eszter Lakatos, Vinaya Gunasri, Daniel Nichol, Helena Costa, Miriam Mitchinson, Daniele Ramazzotti, Benjamin Werner, Francesco Iorio, Marnix Jansen, Giulio Caravagna, Chris P. Barnes, Darryl Shibata, John Bridgewater, Manuel Rodriguez-Justo, Luca Magnani, Andrea Sottoriva, Trevor A. Graham
Summary: Genetic and epigenetic variation, as well as transcriptional plasticity, contribute to intratumour heterogeneity in colorectal cancer. However, the impact of intratumour genetic variation on gene expression traits and subclonal evolution is limited. Most intratumour gene expression variation is found to be "plastic" rather than strongly heritable. There may exist potential genetic controls on gene expression, but their association with subclone expansions is limited.
Article
Peripheral Vascular Disease
Hyoeun Kim, Chan Joo Lee, Sang-Hyun Kim, Jang Young Kim, Sung Hee Choi, Hyun-Jae Kang, Kyong Soo Park, Byung Ryul Cho, Byung Jin Kim, Ki Chul Sung, In-Kyung Jeong, Jin-Ok Jeong, Jang-Whan Bae, Jung Mi Park, Yunbeom Lee, Ilecheon Jeong, Hyojun Han, Ji Hyun Lee, Sang-Hak Lee
Summary: This study analyzed the phenotypic and genetic features of Korean patients with FH and identified the threshold cholesterol levels for patient differentiation and PV prediction. The results showed that PV rates varied depending on diagnostic criteria and distinctive PV locations.
JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS
(2022)
Article
Genetics & Heredity
Gene S. Fisch
Summary: Genotype-phenotype causal modeling has advanced significantly since its inception, but challenges in research design and statistical complexities in genomewide investigations have hindered the reliability and validity of predictions. Differences in heritability estimates between causal clusters and complex traits among unrelated individuals continue to be a controversial research area.
Review
Peripheral Vascular Disease
German D. Carrasquilla, Malene Revsbech Christiansen, Tuomas O. Kilpelainen
Summary: Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Recent studies have identified over 300 genetic loci associated with triglyceride levels, leading to the understanding that some phenotypes previously attributed to monogenic inheritance may have a polygenic basis. These new genetic discoveries hold promise for the development of more effective triglyceride-lowering treatments and personalized medicine approaches against hypertriglyceridemia.
CURRENT ATHEROSCLEROSIS REPORTS
(2021)
Review
Nutrition & Dietetics
Lene Aasdahl, Tom Ivar Lund Nilsen, Ingebrigt Meisingset, Anne Lovise Nordstoga, Kari Anne I. Evensen, Julie Paulsen, Paul Jarle Mork, Eivind Schjelderup Skarpsno
Summary: Genetic factors play a role in explaining the variation in physical activity and sedentary behavior. High-quality GWAS and consistent replication studies are crucial for establishing robust genetic instruments for physical activity and sedentary behavior. Systematic review highlights the need for more research in this area to improve credibility of genetic variants.
INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY
(2021)
Article
Pharmacology & Pharmacy
Shehan D. Perera, Jian Wang, Adam D. McIntyre, Jacqueline S. Dron, Robert A. Hegele, Cert Endo
Summary: In this study, the longitudinal triglyceride (TG) phenotype of individuals with heterozygous pathogenic LPL variants was evaluated. The results showed that TG levels varied widely among patients and within the same patient. Most patients exhibited mild-to-moderate and severe hypertriglyceridemia (HTG), and the severity likely depended on secondary factors.
JOURNAL OF CLINICAL LIPIDOLOGY
(2023)
Editorial Material
Pathology
Erin O. Jacob, Robert A. Hegele
EXPERT REVIEW OF MOLECULAR DIAGNOSTICS
(2023)
Article
Pharmacology & Pharmacy
Shehan D. Perera, Jian Wang, Adam D. McIntyre, Jacqueline S. Dron, Robert A. Hegele, Cert Endo
Summary: In this study, the longitudinal triglyceride (TG) phenotype of individuals with heterozygous pathogenic LPL variants was evaluated. The results showed that TG levels varied widely among patients and within the same patient. Most patients exhibited mild-to-moderate and severe hypertriglyceridemia (HTG), and the severity likely depended on secondary factors.
JOURNAL OF CLINICAL LIPIDOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Robert A. Hegele
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Pei Jun Zhao, Robert A. Hegele
Summary: The Canadian Society of Clinical Chemists has recommended adopting the more accurate Sampson/US NIH LDL-C equation for cardiovascular disease prevention. Based on the comparison of survey data, it is estimated that approximately 123,000 Canadians who are already taking cholesterol-lowering medications may need to intensify treatment due to the equation change.
Review
Cardiac & Cardiovascular Systems
Marina Cuchel, Frederick J. Raal, Robert A. Hegele, Khalid Al-Rasadi, Marcello Arca, Maurizio Averna, Eric Bruckert, Tomas Freiberger, Daniel Gaudet, Mariko Harada-Shiba, Lisa C. Hudgins, Meral Kayikcioglu, Luis Masana, Klaus G. Parhofer, Jeanine E. Roeters van Lennep, Raul D. Santos, Erik S. G. Stroes, Gerald F. Watts, Albert Wiegman, Jane K. Stock, Lale S. Tokgoezoglu, Alberico L. Catapano, Kausik K. Ray
Summary: This 2023 statement provides updated clinical guidance for the management of homozygous familial hypercholesterolaemia (HoFH), including criteria for diagnosis, genetic testing interpretation, and treatment recommendations. The statement emphasizes the importance of considering both phenotype and genotype in the diagnosis of HoFH, with a LDL-C level >10 mmol/L (>400 mg/dL) being indicative of the condition. Combination therapy targeting LDL-C, including the use of novel therapies like proprotein convertase subtilisin/kexin type 9 inhibitors, is recommended to achieve LDL-C goals and reduce the need for lipoprotein apheresis. To improve HoFH care globally, the statement recommends the implementation of national screening programs, education to increase awareness, and management guidelines adapted to local healthcare systems.
EUROPEAN HEART JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Brandon Chalazan, Emma Freeth, Arezoo Mohajeri, Krishnan Ramanathan, Matthew Bennett, Jagdeep Walia, Laura Halperin, Thomas Roston, Julieta Lazarte, Robert A. Hegele, Anna Lehman, Zachary Laksman
Summary: This study aims to determine the prevalence of likely pathogenic and pathogenic variants from AF genes in early-onset AF patients. The results suggest a potential clinical utility for offering different screening and treatment regimens in AF patients with a genetic defect.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Review
Pharmacology & Pharmacy
Catherine M. Spagnuolo, Robert A. Hegele
Summary: Mild-to-moderate hypertriglyceridemia (HTG) is associated with atherosclerotic cardiovascular disease (ASCVD) and elevated triglyceride (TG) levels. Apolipoprotein C-III (apo C-III) inhibition is a promising treatment approach for reducing TG levels and ASCVD risk. Biologic agents like volanesorsen, olezarsen, and ARO-APOC3 significantly reduce apo C-III and TG levels, but further study is needed on their impact on cardiovascular outcomes.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Article
Cardiac & Cardiovascular Systems
Gerald F. Watts, Samuel S. Gidding, Robert A. Hegele, Frederick J. Raal, Amy C. Sturm, Laney K. Jones, Mitchell N. Sarkies, Khalid Al-Rasadi, Dirk J. Blom, Magdalena Daccord, Sarah D. de Ferranti, Emanuela Folco, Peter Libby, Pedro Mata, Hapizah M. Nawawi, Uma Ramaswami, Kausik K. Ray, Claudia Stefanutti, Shizuya Yamashita, Jing Pang, Gilbert R. Thompson, Raul D. Santos
Summary: Familial hypercholesterolaemia (FH) is a preventable cause of premature coronary artery disease and death. This guidance article from the International Atherosclerosis Society provides a comprehensive overview of FH care that includes recommendations on the detection and management of patients with FH, as well as strategies to maximize implementation.
NATURE REVIEWS CARDIOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Ahsen Chaudhry, Mark Trinder, Kristin Vesely, Lubomira Cermakova, Linda Jackson, Jian Wang, Robert A. Hegele, Liam R. Brunham
Summary: A study found that approximately 0.9% of patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) actually had homozygous familial hypercholesterolemia (HoFH) based on genetic diagnosis. These patients had higher levels of low-density lipoprotein cholesterol and a higher prevalence of premature cardiovascular disease.
CIRCULATION-GENOMIC AND PRECISION MEDICINE
(2023)
Review
Cardiac & Cardiovascular Systems
Iulia Iatan, G. B. John Mancini, Eunice Yeoh, Robert A. Hegele
Summary: Statins are important for reducing the risk of atherosclerotic cardiovascular disease, but they are underutilized due to concerns about side effects. Statin-associated muscle symptoms are a common cause of intolerance and discontinuation, leading to increased risk of adverse cardiovascular outcomes.
EXPERT REVIEW OF CARDIOVASCULAR THERAPY
(2023)
Article
Health Care Sciences & Services
Jean Lachaine, Jean -Nicolas Charron, Jean C. Gregoire, Robert A. Hegele, Lawrence A. Leiter
Summary: In a cost-utility analysis conducted from a Canadian healthcare payer perspective, icosapent ethyl (IPE) was found to be a cost-effective treatment option for statin-treated patients with elevated triglycerides. Compared to placebo, IPE was associated with a higher number of quality-adjusted life years (QALYs) and an incremental cost-effectiveness ratio (ICER) of $42,797/QALY gained. This analysis highlights the importance of IPE in reducing ischemic cardiovascular events in this patient population and its cost-effectiveness in Canada.
CLINICOECONOMICS AND OUTCOMES RESEARCH
(2023)
Review
Endocrinology & Metabolism
Praneet K. K. Gill, Robert A. A. Hegele
Summary: This article reviews the causes and consequences of hypocholesterolemia resulting from genetic and non-genetic factors, and discusses therapeutic strategies inspired by genetic hypocholesterolemia.
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM
(2023)
Editorial Material
Hematology
Ann Marie Schmidt, Mary G. Sorci-Thomas, Yabing Chen, Robert A. Hegele
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Robert A. Hegele
Article
Genetics & Heredity
Shengjie Ying, Tracy Heung, Bhooma Thiruvahindrapuram, Worrawat Engchuan, Yue Yin, Christina Blagojevic, Zhaolei Zhang, Robert A. Hegele, Ryan K. C. Yuen, Anne S. Bassett
Summary: Elevated TG levels are modifiable risk factors for cardiovascular disease, and this study found that the TG-PRS, along with sex and BMI, were significant predictors of TG levels, especially in individuals with obesity. A combination of TG-PRS, sex, and BMI showed the greatest accuracy in predicting mild-moderate hypertriglyceridemia.
BMC MEDICAL GENOMICS
(2023)
