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1. Apolipoprotein M and Risk of Type 2 Diabetes

Author

Anne Tybjærg-Hansen, Christina Christoffersen, N. Dalila, Stefan Hajny, M. Christoffersen, and Lars Nielsen

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Genotype, Denmark, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Population, Context (language use), Single-nucleotide polymorphism, Apolipoproteins M, Type 2 diabetes, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Biochemistry, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Risk Factors, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, education, Genetic Association Studies, Aged, education.field_of_study, business.industry, Biochemistry (medical), Hazard ratio, Middle Aged, medicine.disease, Apolipoproteins, 030104 developmental biology, APOM, Diabetes Mellitus, Type 2, Population study, Female, business
Abstract

Context Recent studies have discovered a role of apolipoprotein M (apoM) in energy metabolism, and observational analyses in humans suggest an association with type 2 diabetes. The causal relationship remains however elusive. Objective To investigate whether reduced plasma apoM concentrations are causally linked to increased risk of type 2 diabetes. Design Prospective study design analyzed by Mendelian randomization. Setting and participants Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants from the CCHS with available plasma apoM (n = 725). Genetic analyses included the complete cohorts (n = 102 446). During a median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes. Main outcome measures Plasma apoM concentration, genetic variants in APOM, and type 2 diabetes. Results First, we identified an inverse correlation between plasma apoM and risk of type 2 diabetes in a subset of participants from the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polymorphisms in APOM further revealed a 10.8% (P = 6.2 × 10–5) reduced plasma apoM concentration in participants with variant rs1266078. Third, a meta-analysis including data from 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes. Conclusions The present study does not appear to support a causal association between plasma apoM and risk of type 2 diabetes.

Published
2020
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2. Genetic variants in SUSD2 are associated with the risk of ischemic heart disease

Author

G. Kees Hovingh, Caroline S. Bruikman, Julian C. van Capelleveen, Geesje M. Dallinga-Thie, Laurens C. Huisman, Onno J. de Boer, Anne Tybjærg-Hansen, Jorge Peter, Martine C.M. Willems, Jeffrey Kroon, N. Dalila, Stefan R. Havik, Experimental Vascular Medicine, Graduate School, ACS - Atherosclerosis & ischemic syndromes, Vascular Medicine, ACS - Microcirculation, Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Pulmonary hypertension & thrombosis, Amsterdam Cardiovascular Sciences, Pathology, ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism

Subjects
Adult, Male, medicine.medical_specialty, Heterozygote, Epidemiology, Endocrinology, Diabetes and Metabolism, Population, Nonsense mutation, Myocardial Ischemia, 030204 cardiovascular system & hematology, 03 medical and health sciences, SUSD2, 0302 clinical medicine, Meta-Analysis as Topic, Premature atherosclerosis, Internal medicine, Internal Medicine, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, Allele, education, Aged, education.field_of_study, Nutrition and Dietetics, Membrane Glycoproteins, business.industry, Homozygote, Autosomal dominant trait, Odds ratio, Middle Aged, medicine.disease, Codon, Nonsense, Case-Control Studies, Cardiology, Population study, Female, Cardiology and Cardiovascular Medicine, business, Human
Abstract

Background Genetic factors partly determine the risk for premature myocardial infarction (MI). Objectives We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. Methods Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain–containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N = 105,408) for association with IHD. Results A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87–0.97) in AG heterozygotes and 0.86 (0.62–1.19) in GG homozygotes vs noncarrriers (P-trend = .002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90–0.96) (P = 4.6 × 10−7). Conclusions The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.

Published
2020
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3. Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome

Author

Joel T. Haas, Jan Albert Kuivenhoven, Justina C. Wolters, Andrzej J. Rzepiela, Mathilde Varret, Ann Verhaegen, Valérie Carreau, Szymon Stoma, Anne Philippi, Alaa Othman, Jerome Robert, N. Dalila, Belle V. van Rosmalen, An Verrijken, Arnold von Eckardstein, Bart van de Sluis, Silvija Radosavljevic, Paolo Zanoni, Simon F. Norrelykke, Roger Meier, M. Yalcinkaya, Bart Staels, Andreas Geier, Lucia Rohrer, Michael Stebler, Michele Visentin, Antoine Rimbert, Catherine Boileau, Antonio Gallo, Melinde Wijers, Nicolette C. A. Huijkman, Steve E. Humphries, Jonas Weyler, Freerk van Dijk, Michaela Keel, Srividya Velagapudi, Jean-Pierre Rabès, Marieke Smit, Anne Tybjærg-Hansen, Adriaan van der Graaf, Luisa Vonghia, Yara Abou-Khalil, Sven Francque, Grigorios Panteloglou, Marta Futema, Luc Van Gaal, University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Institute for Molecular Systems Biology [ETH Zurich] (IMSB), Department of Biology [ETH Zürich] (D-BIOL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Scientific Center for Optical and Electron Microscopy (ScopeM), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Groningen [Groningen], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), St George's, University of London, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Saint-Joseph de Beyrouth (USJ), University of Copenhagen = Københavns Universitet (UCPH), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP. Université Paris Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), University of Amsterdam [Amsterdam] (UvA), Columbia University [New York], University Hospital of Würzburg, University College of London [London] (UCL), 603091, ANR-10-LABX-46, 2015T068, CVON2017-2020, AOM06024, 2014/267, Pfizer: 24052829, European Molecular Biology Organization, EMBO: ALTF277-2014, Seventh Framework Programme, FP7, Sixth Framework Programme, FP6: LSHM-CT-2005-018734, Fondation Maladies Rares, FMR, International Atherosclerosis Society, IAS, British Heart Foundation, BHF, European Commission, EC, European Research Council, ERC: 694717, ANR 16-RHUS-0006, Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF: 310030-185109, 31003A-160126, Fonds De La Recherche Scientifique - FNRS, FNRS, Fonds Wetenschappelijk Onderzoek, FWO: 1802154 N, PG008/08, RG3008, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO: 184.021.007, Universität Zürich, UZH: FK-20-037, We acknowledge the use of data from BIOS-consortium ( http://wiki.bbmri.nl/wiki/BIOS_bios ) which is funded by BBMRI-NL (NWO project 184.021.007). Flow cytometry was performed with equipment of the flow cytometry facility, University of Zurich., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein’s team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHM-CT-2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children’s FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein's team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Minist?re de l'Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHMCT- 2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children's FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Center for Liver, Digestive and Metabolic Diseases (CLDM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), HAL UVSQ, Équipe, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Spliceosome, Physiology, RNA Splicing, Population, Hypercholesterolemia, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Gene expression, medicine, Humans, education, Gene, 030304 developmental biology, 0303 health sciences, Gene knockdown, education.field_of_study, Intron, Nuclear Proteins, Hep G2 Cells, medicine.disease, Molecular biology, Endocytosis, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Lipoproteins, LDL, Cholesterol, HEK293 Cells, Cardiovascular diseases, Liver, Receptors, LDL, Mutation, LDL receptor, Hepatocytes, Spliceosomes, lipids (amino acids, peptides, and proteins), Human medicine, Cardiology and Cardiovascular Medicine
Abstract

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.

Published
2022
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4. GPR146 gene variants are associated with reduced plasma lipids and cardiovascular health: A novel role for GPR146 in hypolipidemia

Author

A. Rimbert, M. Yeung, N. Dalila, H. Yu, N. Loaiza, F. Oldoni, A. Van Der Graaf, S. Wang, A. Said, L. Blauw, A. Girardeau, L. Bray, A. Caillaud, V. Bloks, M. Marrec, P. Moulin, P. Rensen, B. Van De Sluis, H. Snieder, M. Di Filippo, P. Van Der Harst, A. Tybjærg-Hansen, P. Zimmerman, B. Cariou, and J. Kuivenhoven

Subjects
Cardiology and Cardiovascular Medicine
Published
2022
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6. Identification and Replication of Six Loci Associated With Gallstone Disease

Author

Helene Gellert‐Kristensen, Sune Fallgaard Nielsen, Stefan Stender, Anne Tybjærg-Hansen, N. Dalila, and Børge G. Nordestgaard

Subjects
0301 basic medicine, medicine.medical_specialty, Complex disease, Gallstones, Disease, Danish, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Hepatology, business.industry, Plasma levels, medicine.disease, Biobank, language.human_language, 030104 developmental biology, Increased risk, Genetic Loci, Susceptibility locus, language, 030211 gastroenterology & hepatology, business, Genome-Wide Association Study
Abstract

Gallstone disease is a common complex disease that confers a substantial economic burden on society. The genetic underpinnings of gallstone disease remain incompletely understood. We aimed to identify genetic associations with gallstone disease using publicly available data from the UK Biobank and two large Danish cohorts. We extracted genetic associations with gallstone disease from the Global Biobank Engine (GBE), an online browser of genome-wide associations in UK Biobank participants (14,940 cases and 322,268 controls). Significant associations (P 2.5 (prevalence 1%) had a 5-fold increased risk of gallstones compared to those with a score

Published
2019
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7. Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans

Author

Bart van de Sluis, Geesje M. Dallinga-Thie, Richard J. Sinke, Federico Oldoni, N. Dalila, Jan Albert Kuivenhoven, Justina C. Wolters, Julian C. van Capelleveen, David Y. Hui, Joerg Heeren, Kees Hovingh, Ruth Frikke-Schmidt, Anne Tybjærg-Hansen, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Diabetes & metabolism, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)

Subjects
0301 basic medicine, CHOLESTEROL EFFLUX, 0302 clinical medicine, TRANSPORTER A1, HDL cholesterol, low-density lipoprotein receptor–related protein 1, lipid metabolism, Prospective Studies, triglycerides, Hypoalphalipoproteinemias, biology, Chemistry, Protein Stability, TANGIER-DISEASE, Scavenger Receptors, Class B, LRP1, 3. Good health, Protein Transport, Phenotype, Biochemistry, Liver, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Low Density Lipoprotein Receptor-Related Protein-1, ATP Binding Cassette Transporter 1, PROTEASE, apolipoprotein, 03 medical and health sciences, Chylomicron remnant, Cell Line, Tumor, Humans, Genetic Predisposition to Disease, TRAFFICKING, low-density lipoprotein receptor-related protein 1, Scavenger receptor, ABCA1-MEDIATED LIPID EFFLUX, Apolipoprotein A-I, Basic Sciences, Cholesterol, HDL, Genetic Variation, Lipid metabolism, Fibroblasts, CATHEPSIN-D, GENE, CHYLOMICRON REMNANTS, 030104 developmental biology, HEK293 Cells, ABCA1, LDL receptor, CELLS, biology.protein, cell membrane, Lipoprotein
Abstract

Supplemental Digital Content is available in the text., Objective— Studies into the role of LRP1 (low-density lipoprotein receptor–related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels. Approach and Results— In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels. Conclusions— This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.

Published
2018
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9. Molybdenum Disulfide (MoS2)/Gold Nanoparticles (AuNPs)-based Field-effect Transistor for C-reactive Protein Detection: Early Diagnosis of Cardiovascular Disease

Author

N. Dalila R., M. K. Md Arshad, Subash C. B. Gopinath, M. Nuzaihan M. N., C. Ibau, and Iswary Letchuman

Subjects
Detection limit, Materials science, Scanning electron microscope, Transistor, law.invention, chemistry.chemical_compound, chemistry, Colloidal gold, law, Microscopy, Field-effect transistor, Spectroscopy, Molybdenum disulfide, Nuclear chemistry
Abstract

C-reactive protein (C-RP), a biomarker for inflammatory validation associated with cardiovascular disease (CVD). Major infection or severe trauma trigger the activation of this protein in the patient's blood. In this paper, the conventional field-effect transistor (FET) is fabricated and followed by direct deposition method of molybdenum disulfide (M O S 2 ) nanosheets. The deposition of MoS 2 nanosheets with the conjugation of 30 nm gold nanoparticles on the 100 µm active channel shows the good response of electrical signals for C-RP detection. Analysis of the MoS 2 and AuNPs was well-supported by atomic force microscopy, scanning electron microscopy, UV-Vis spectroscopy, and high-power microscopy. Finally, the detection limit of 100 fg/mL was attained.

Published
2019
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10. Blood Biomarkers Diagnosis as Primitive Precautionary using Zinc Oxide (ZnO) modified Interdigitated Electrode (IDE)

Author

Iswary Letchumanan, M.K. Md Arshad, Subash C.B. Gopinath, N. Dalila R, and Wan Amirah Basyarah Z. A.

Subjects
Materials science, Scanning electron microscope, Band gap, business.industry, chemistry.chemical_element, Zinc, chemistry, Blood biomarkers, Nano, Interdigitated electrode, Optoelectronics, Electrical measurements, Profilometer, business
Abstract

This paper primarily demonstrates the detection of human blood biomarkers by evaluating the binding event between antigen and antibody. An interdigitated electrode (IDE) was utilized in this work with the bandgap ~100 µm which was modified with antibody (probe) to capture available antigen. Surface analysis was done by atomic force microscope(AFM), scanning electron microscope (SEM) and 3D Nano Profilometer. The electrical measurements was done using linear sweep OV to 2V. The sensitivity attained was 100 fM.

Published
2019
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13. The U2-spliceosome and its interactors regulate the levels and activity of the LDL receptor in humans

Author

Joost Weyler, Grigorios Panteloglou, B. Van De Sluis, Joel T. Haas, Anne Tybjærg-Hansen, Luisa Vonghia, Ann Verhaegen, Catherine Boileau, Alaa Othman, A. Van Der Graaf, Anne Philippi, Marieke Smit, Sven Francque, Mathilde Varret, Jan Albert Kuivenhoven, Srividya Velagapudi, B.V. Van Rosmalen, L. Van Gaal, Y. Abou Khalil, Justina C. Wolters, Antoine Rimbert, Simon F. Norrelykke, Roger Meier, Bart Staels, Lucia Rohrer, Andrzej J. Rzepiela, Paolo Zanoni, Andreas Geier, Michaela Keel, Valérie Carreau, S.E. Humphries, Michael Stebler, M. Futema, Szymon Stoma, N. Dalila, Melinde Wijers, Nicolette C. A. Huijkman, An Verrijken, Antonio Gallo, Jean-Pierre Rabès, A. von Eckardstein, Silvija Radosavljevic, M. Yalcinkaya, F. van Dijk, and Michele Visentin

Subjects
Spliceosome, Chemistry, LDL receptor, Cardiology and Cardiovascular Medicine, Cell biology
Published
2020
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14. Current and future envision on developing biosensors aided by 2D molybdenum disulfide (MoS

Author

N, Dalila R, M K, Md Arshad, Subash C B, Gopinath, W M W, Norhaimi, and M F M, Fathil

Subjects
Molybdenum, Animals, Humans, Nanotechnology, Biosensing Techniques, Disulfides, Equipment Design, Nanostructures
Abstract

Two-dimensional (2D) layered nanomaterials have triggered an intensive interest due to the fascinating physiochemical properties with the exceptional physical, optical and electrical characteristics that transpired from the quantum size effect of their ultra-thin structure. Among the family of 2D nanomaterials, molybdenum disulfide (MoS

Published
2019

15. A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor

Author

Freerk van Dijk, Bart van de Sluis, Marijn Riemsma, Antoine Rimbert, Justina C. Wolters, Nicolette C. A. Huijkman, Amika Singla, Marieke Smit, Anne Tybjærg-Hansen, N. Dalila, Jan Albert Kuivenhoven, Ydwine T. van der Veen, Ezra Burstein, Niels J. Kloosterhuis, Ruth Frikke-Schmidt, University of Groningen [Groningen], Department of Pediatrics and Laboratory Medicine [Groningen, The Netherlands], University Medical Center Groningen [Groningen] (UMCG), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Pediatrics, Molecular Genetics Section, University of Amsterdam [Amsterdam] (UvA), Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)

Subjects
Candidate gene, Linkage disequilibrium, LOCI, Myocardial Infarction, Vesicular Transport Proteins, Coronary Artery Disease, 030204 cardiovascular system & hematology, DISEASE, PCSK9, Mice, 0302 clinical medicine, WIDE ASSOCIATION, Myocardial infarction, RETROMER, RISK, 0303 health sciences, education.field_of_study, LDL RECEPTORS, Endosomal trafficking, Population study, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, EXPRESSION, medicine.medical_specialty, Cardiovascular mortality, Population, Lower risk, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, Humans, Low-density lipoprotein cholesterol, education, 030304 developmental biology, DECREASES, COMPLEX, business.industry, Cholesterol, LDL, medicine.disease, LDL-receptor, Endocrinology, Receptors, LDL, CCC complex, LDL receptor, business, CCDC93, Genome-Wide Association Study
Abstract

Aims Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR). Methods and results Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10−6 to 8.0 × 10−9), with lower risk of MI (P-trend 0.04–0.002) and lower risk of cardiovascular mortality (P-trend 0.005–0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane. Conclusion This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.

Published
2018
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16. Silicon-on-insulator FET biosensor for dengue DNA complementation

Author

N. Dalila R., M. F. Azman, M. Rajaahmoorthi, M. K. Md Arshad, M. F. M. Fathil, M. Nuzaihan M. N., and N. A. Parmin

Subjects
Analyte, Materials science, business.industry, Transistor, Silicon on insulator, Dengue virus, medicine.disease_cause, law.invention, Transducer, law, medicine, Optoelectronics, Wafer, Photolithography, business, Biosensor
Abstract

In this paper, a label-free approach utilizing field-effect transistor (FET) biosensor is presented and demonstrated for deoxyribonucleic acid (DNA) detection related to dengue virus. The biologically active element (in this case for DNA) will have a reaction with a physical transducer (i.e. channel area that connecting the source and drain) and transforms the reaction into a quantifiable signal. This event occurs when an analyte is bound to the recognition element after surface modification, the charge distribution at the surface resulting in current flow across the channel. The field-effect transistor was fabricated using the conventional photolithography approach on thin silicon-on-insulator (SOI) wafer. The source and drain are either doped or undoped (as it initial intrinsic impurity is 1x1015 cm−3). The fabricated device of FET was then observed under scanning electron microscope (SEM), atomic force microscope (AFM), and 3D nano-profilometer to characterize the surface morphology. In addition, the electrical characterization was also performed using Keithley 6487 picoammeter to examine and analyze the bare device. Lastly, the diagnosis of dengue fever is performed by functionalizing the bio-receptor at the channel of the FET which is served as a molecular gate by the binding of a target DNA and monitoring electrical response to the concentrations of dengue virus. The device was tested repeatedly by using different concentrations of DNA target dengue. This step was performed to detect the sensitivity of the device. The device shows a wide-range of detection capability for detection of DNA dengue. The demonstrated results show that the FET has excellent properties for detection of dengue virus with outstanding sensitivity and selectivity properties.

Published
2018
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20. A Common Variant In Ccdc93 Decreases Ldl-C And Protects Against Myocardial Infarction By Regulating Endosomal Trafficking Of Ldl-Receptor

Author

F. van Dijk, Marieke Smit, Nicolette C. A. Huijkman, Niels J. Kloosterhuis, Y. van der Veen, Ruth Frikke-Schmidt, T.H. Tybjaerg-Hansen, E. Burtsein, Antoine Rimbert, B. Van De Sluis, Amika Singla, Justina C. Wolters, M. Riemsma, N. Dalila, and Jan Albert Kuivenhoven

Subjects
medicine.medical_specialty, Endocrinology, Chemistry, Endosome, Internal medicine, LDL receptor, medicine, Myocardial infarction, Cardiology and Cardiovascular Medicine, medicine.disease
Published
2019
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21. A Regulatory Role of the Endosomal Sorting Machinery in Controlling Plasma LDL Cholesterol Levels and Atherosclerosis in Mice and Humans

Author

Marieke Smit, Niels J. Kloosterhuis, Alina Fedoseienko, Bart van de Sluis, Anne Tybjærg-Hansen, K. Wolters, Nicolette C. A. Huijkman, Marten H. Hofker, Daphne Dekker, Antoine Rimbert, Han Levels, Ezra Burstein, Daniel D. Billadeau, Jan Albert Kuivenhoven, N. Dalila, Jan M. van Deursen, Melinde Wijers, and Jay D. Horton

Subjects
Ldl cholesterol, Chemistry, Endosome, Internal Medicine, Sorting, General Medicine, Cardiology and Cardiovascular Medicine, Cell biology
Published
2018
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23. Silicon-on-Insulator FET Biosensor for Dengue DNA Complementation.

Author

R., N. Dalila, Azman, M. F., Rajaahmoorthi, M., Md Arshad, M. K., Fathil, M. F . M ., M. N., M. Nuzaihan, and Parmin, N . A .

Subjects
DENGUE viruses, FIELD-effect transistors, ELECTRIC insulators & insulation, SILICON-on-insulator technology, PHOTOLITHOGRAPHY, DOPING agents (Chemistry)
Abstract

In this paper, a label-free approach utilizing field-effect transistor (FET) biosensor is presented and demonstrated for deoxyribonucleic acid (DNA) detection related to dengue virus. The biologically active element (in this case for DNA) will have a reaction with a physical transducer (i.e. channel area that connecting the source and drain) and transforms the reaction into a quantifiable signal. This event occurs when an analyte is bound to the recognition element after surface modification, the charge distribution at the surface resulting in current flow across the channel. The field-effect transistor was fabricated using the conventional photolithography approach on thin silicon-on-insulator (SOI) wafer. The source and drain are either doped or undoped (as it initial intrinsic impurity is 1x1015 cm-3). The fabricated device of FET was then observed under scanning electron microscope (SEM), atomic force microscope (AFM), and 3D nano-profilometer to characterize the surface morphology. In addition, the electrical characterization was also performed using Keithley 6487 picoammeter to examine and analyze the bare device. Lastly, the diagnosis of dengue fever is performed by functionalizing the bio-receptor at the channel of the FET which is served as a molecular gate by the binding of a target DNA and monitoring electrical response to the concentrations of dengue virus. The device was tested repeatedly by using different concentrations of DNA target dengue. This step was performed to detect the sensitivity of the device. The device shows a wide-range of detection capability for detection of DNA dengue. The demonstrated results show that the FET has excellent properties for detection of dengue virus with outstanding sensitivity and selectivity properties. [ABSTRACT FROM AUTHOR]

Published
2018
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25. Polygenic risk of high LDL cholesterol and ischemic heart disease in the general population.

Author

Eyrich TM, Dalila N, Christoffersen M, Tybjærg-Hansen A, and Stender S

Subjects
Humans, Male, Female, Middle Aged, Denmark epidemiology, Aged, Heterozygote, Risk Assessment, Risk Factors, Adult, Phenotype, Biomarkers blood, Cholesterol, LDL blood, Myocardial Ischemia genetics, Myocardial Ischemia blood, Myocardial Ischemia epidemiology, Genetic Predisposition to Disease, Multifactorial Inheritance, Receptors, LDL genetics, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II blood, Hyperlipoproteinemia Type II epidemiology, Coronary Artery Disease genetics, Coronary Artery Disease blood, Coronary Artery Disease epidemiology, Apolipoprotein B-100 genetics, Apolipoprotein B-100 blood
Abstract

Background and Aims: We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population., Methods: We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH)., Results: Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38-0.88) and 1.83 (95 % CI, 1.33-2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41-0.92) and 2.06 (95 % CI, 1.49-2.85)., Conclusions: The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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26. Plasma TSH and cardiovascular disease in the general population: A Mendelian randomization study of 105,224 individuals.

Author

Dalila N, Frikke-Schmidt R, Nordestgaard BG, and Tybjærg-Hansen A

Subjects
Humans, Thyrotropin, Prospective Studies, Mendelian Randomization Analysis, Risk Factors, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases genetics, Myocardial Infarction epidemiology, Myocardial Infarction genetics, Myocardial Infarction complications, Heart Failure epidemiology, Heart Failure genetics, Heart Failure complications, Atrial Fibrillation complications, Aortic Valve Stenosis epidemiology, Stroke diagnosis, Stroke epidemiology, Stroke genetics
Abstract

Background and Aims: The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal., Methods: We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal., Results: Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00-1.26) for stroke to 1.27 (1.11-1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08-1.52) for AF, 1.35 (1.06-1.71) for MI, 1.06 (0.89-1.26) for stroke, 1.19 (0.94-1.52) for HF, 1.53 (1.03-2.26) for AVS, and 1.09 (0.97-1.23) for MACE., Conclusions: In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. AT-H reports consultancies or talks sponsored by Akcea, Amgen, AstraZeneca, Draupnir Bio, Novartis, Regeneron, Sanofi, and Silence Therapeutics. BGN reports consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutics. RF-S reports consultancy sponsored by Novo Nordisk. ND had no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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27. Concurrent Inhibition of Akt and ERK Using TIC-10 Can Overcome Venetoclax Resistance in Mantle Cell Lymphoma.

Author

Granau AM, Andersen PA, Jakobsen T, Taouxi K, Dalila N, Mogensen JB, Kristensen LS, Grønbæk K, and Dimopoulos K

Abstract

Venetoclax, a BCL-2 inhibitor, has proven to be effective in several hematological malignancies, including mantle cell lymphoma (MCL). However, development of venetoclax resistance is inevitable and understanding its underlying molecular mechanisms can optimize treatment response. We performed a thorough genetic, epigenetic and transcriptomic analysis of venetoclax-sensitive and resistant MCL cell lines, also evaluating the role of the stromal microenvironment using human and murine co-cultures. In our model, venetoclax resistance was associated with abrogated TP53 activity through an acquired mutation and transcriptional downregulation leading to a diminished apoptotic response. Venetoclax-resistant cells also exhibited an upregulation of the PI3K/Akt pathway, and pharmacological inhibition of Akt and ERK with TIC-10 led to cell death in all venetoclax-resistant cell lines. Overall, we highlight the importance of targeted therapies, such as TIC-10, against venetoclax resistance-related pathways, which might represent future therapeutic prospects.

Published
2023
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28. Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.

Author

Rimbert A, Yeung MW, Dalila N, Thio CHL, Yu H, Loaiza N, Oldoni F, van der Graaf A, Wang S, Said MA, Blauw LL, Girardeau A, Bray L, Caillaud A, Bloks VW, Marrec M, Moulin P, Rensen PCN, van de Sluis B, Snieder H, Di Filippo M, van der Harst P, Tybjaerg-Hansen A, Zimmerman P, Cariou B, and Kuivenhoven JA

Subjects
Animals, Apolipoproteins B genetics, C-Reactive Protein, Cholesterol, HDL, Cholesterol, LDL, Humans, Mice, Pharmaceutical Preparations, Receptors, G-Protein-Coupled genetics, Atherosclerosis genetics, Atherosclerosis prevention & control, Hypobetalipoproteinemias genetics
Abstract

Background: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown., Methods: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants., Results: In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease ( P =0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels., Conclusions: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.

Published
2022
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29. Chlamydia Infection as a Risk Factor for Cervical Cancer: A Systematic Review and Meta-Analysis.

Author

Bhuvanendran Pillai A, Mun Wong C, Dalila Inche Zainal Abidin N, Fazlinda Syed Nor S, Fathulzhafran Mohamed Hanan M, Rasidah Abd Ghani S, Afzan Aminuddin N, and Safian N

Abstract

Background: We reviewed studies on the prevalence of Chlamydia infection as a risk factor for developing cervical cancer in a meta-analysis studies published in that subject area., Methods: Cochrane Library and PubMed databases were systematically searched for articles (observational and randomized controlled trials) published from 2008-2018. A meta-analysis of studies was performed to analyse the association between chlamydia infection and cervical cancer., Results: Five articles were included in the final analysis (N=5271). All five articles were case-control studies, of which three studies sampled from population-based registries. All studies involved with sexually active women with minimum 15 years old. Three studies reported the association of C. trachomatis infection cervical cancers, two other studies reported C. trachomatis-HPV co-infection in association with cervical cancer. Result showed C. trachomatis has an overall prevalence of 31.9%, pooled OR 1.96, 95% CI 1.05 to 3.67, OR 2.13, 95% CI 1.78 to 2.54 among cervical cancer. There was a mild publication bias detected at 3.0 effect estimation. Heterogeneity detected from clinical and methodological diversities particularly from C. trachomatis-HPV co-infection subgroup analysis, including sampling bias, geographical strain diversity, and different outcome endpoint measured., Conclusion: C. trachomatis infection was significantly associated with the development of cervical cancer. Co-infection of C. trachomatis-HPV with cervical cancer is plausibly sound but temporality of C. trachomatis-HPV with the development of cervical cancer need to be proven in future prospective cohort studies., Competing Interests: Conflict of interests Non-declared., (Copyright © 2022 Pillai et al. Published by Tehran University of Medical Sciences.)

Published
2022
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30. Current and future envision on developing biosensors aided by 2D molybdenum disulfide (MoS 2 ) productions.

Author

Dalila R N, Md Arshad MK, Gopinath SCB, Norhaimi WMW, and Fathil MFM

Subjects
Animals, Biosensing Techniques instrumentation, Disulfides chemical synthesis, Equipment Design, Humans, Nanostructures ultrastructure, Nanotechnology instrumentation, Biosensing Techniques methods, Disulfides chemistry, Molybdenum chemistry, Nanostructures chemistry, Nanotechnology methods
Abstract

Two-dimensional (2D) layered nanomaterials have triggered an intensive interest due to the fascinating physiochemical properties with the exceptional physical, optical and electrical characteristics that transpired from the quantum size effect of their ultra-thin structure. Among the family of 2D nanomaterials, molybdenum disulfide (MoS 2 ) features distinct characteristics related to the existence of direct energy bandgap, which significantly lowers the leakage current and surpasses other 2D materials. In this overview, we expatiate the novel strategies to synthesize MoS 2 that cover techniques such as liquid exfoliation, chemical vapour deposition, mechanical exfoliation, hydrothermal reaction, and Van Der Waal epitaxial growth on the substrate. We extend the discussion on the recent progress in biosensing applications of the produced MoS 2 , highlighting the important surface-to-volume of ultrathin MoS 2 structure, which enhances the overall performance of the devices. Further, envisioned the missing piece with the current MoS 2 -based biosensors towards developing the future strategies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Published
2019
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31. Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1.

Author

Seitz T, Stalmann R, Dalila N, Chen J, Pojar S, Dos Santos Pereira JN, Krätzner R, Brockmöller J, and Tzvetkov MV

Abstract

Background: The organic cation transporter OCT1 (SLC22A1) mediates the uptake of vitamin B1, cationic drugs, and xenobiotics into hepatocytes. Nine percent of Caucasians lack or have very low OCT1 activity due to loss-of-function polymorphisms in OCT1 gene. Here we analyzed the global genetic variability in OCT1 to estimate the therapeutic relevance of OCT1 polymorphisms in populations beyond Caucasians and to identify evolutionary patterns of the common loss of OCT1 activity in humans., Methods: We applied massively parallel sequencing to screen for coding polymorphisms in 1,079 unrelated individuals from 53 populations worldwide. The obtained data was combined with the existing 1000 Genomes data comprising an additional 1,092 individuals from 14 populations. The identified OCT1 variants were characterized in vitro regarding their cellular localization and their ability to transport 10 known OCT1 substrates. Both the population genetics data and transport data were used in tandem to generate a world map of loss of OCT1 activity., Results: We identified 16 amino acid substitutions potentially causing loss of OCT1 function and analyzed them together with five amino acid substitutions that were not expected to affect OCT1 function. The variants constituted 16 major alleles and 14 sub-alleles. Six major alleles showed improper subcellular localization leading to substrate-wide loss in activity. Five major alleles showed correct subcellular localization, but substrate-specific loss of activity. Striking differences were observed in the frequency of loss of OCT1 activity worldwide. While most East Asian and Oceanian individuals had completely functional OCT1, 80 % of native South American Indians lacked functional OCT1 alleles. In East Asia and Oceania the average nucleotide diversity of the loss-of-function variants was much lower than that of the variants that do not affect OCT1 function (ratio of 0.03) and was significantly lower than the theoretically expected heterozygosity (Tajima's D = -1.64, P < 0.01)., Conclusions: Comprehensive genetic analyses showed strong global variations in the frequency of loss of OCT1 activity with selection pressure for maintaining OCT1 activity in East Asia and Oceania. These results not only enable pharmacogenetically-based optimization of drug treatment worldwide, but may help elucidate the functional role of human OCT1.

Published
2015
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32. Impact of mineralocorticoid receptor polymorphisms on urinary electrolyte excretion with and without diuretic drugs.

Author

Dalila N, Brockmöller J, Tzvetkov MV, Schirmer M, Haubrock M, and Vormfelde SV

Subjects
Adolescent, Adult, Bumetanide pharmacology, Cross-Over Studies, Furosemide pharmacology, Genetic Association Studies, Humans, Hydrochlorothiazide pharmacology, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Potassium urine, Receptors, Mineralocorticoid drug effects, Single-Blind Method, Sodium Chloride urine, Sulfonamides pharmacology, Torsemide, Triamterene pharmacology, Young Adult, Diuretics pharmacology, Electrolytes urine, Polymorphism, Genetic genetics, Receptors, Mineralocorticoid genetics
Abstract

Aim: Polymorphisms in the mineralocorticoid receptor may affect urinary sodium and potassium excretion. We investigated polymorphisms in the MR gene in relation to urinary electrolyte excretion in two separate studies., Patients & Methods: The genotype-phenotype association was studied in healthy volunteers after single doses of bumetanide, furosemide, torsemide, hydrochlorothiazide, triamterene and after NaCl restriction., Results: High potassium excretion under all conditions except torsemide, and high NaCl excretion after bumetanide and furosemide were associated with the A allele of the intron-3 polymorphism (rs3857080). This polymorphism explained 5-10% of the functional variation and in vitro, rs3857080 affected DNA binding of the transcription factor LHX4., Conclusion: rs3857080 may be a promising new candidate for research in cardiac and renal disorders and on antialdosteronergic drugs like spironolactone.

Published
2015
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