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Your search keyword '"Vujkovic, Marijana [0000-0003-4924-5714]"' showing total 4 results
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4 results on '"Vujkovic, Marijana [0000-0003-4924-5714]"'

1. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Author

Gaziano, Liam, Giambartolomei, Claudia, Pereira, Alexandre C, Gaulton, Anna, Posner, Daniel C, Swanson, Sonja A, Ho, Yuk-Lam, Iyengar, Sudha K, Kosik, Nicole M, Vujkovic, Marijana, Gagnon, David R, Bento, A Patrícia, Barrio-Hernandez, Inigo, Rönnblom, Lars, Hagberg, Niklas, Lundtoft, Christian, Langenberg, Claudia, Pietzner, Maik, Valentine, Dennis, Gustincich, Stefano, Tartaglia, Gian Gaetano, Allara, Elias, Surendran, Praveen, Burgess, Stephen, Zhao, Jing Hua, Peters, James E, Prins, Bram P, Angelantonio, Emanuele Di, Devineni, Poornima, Shi, Yunling, Lynch, Kristine E, DuVall, Scott L, Garcon, Helene, Thomann, Lauren O, Zhou, Jin J, Gorman, Bryan R, Huffman, Jennifer E, O'Donnell, Christopher J, Tsao, Philip S, Beckham, Jean C, Pyarajan, Saiju, Muralidhar, Sumitra, Huang, Grant D, Ramoni, Rachel, Beltrao, Pedro, Danesh, John, Hung, Adriana M, Chang, Kyong-Mi, Sun, Yan V, Joseph, Jacob, Leach, Andrew R, Edwards, Todd L, Cho, Kelly, Gaziano, J Michael, Butterworth, Adam S, Casas, Juan P, VA Million Veteran Program COVID-19 Science Initiative, Epidemiology, Medical Research Council (MRC), Giambartolomei, Claudia [0000-0003-2786-1225], Gaulton, Anna [0000-0003-2634-7400], Posner, Daniel C [0000-0002-3056-6924], Kosik, Nicole M [0000-0003-1384-7035], Vujkovic, Marijana [0000-0003-4924-5714], Gagnon, David R [0000-0002-6367-3179], Bento, A Patrícia [0000-0003-1424-480X], Rönnblom, Lars [0000-0001-9403-6503], Hagberg, Niklas [0000-0003-2064-2716], Lundtoft, Christian [0000-0001-5872-4253], Langenberg, Claudia [0000-0002-5017-7344], Pietzner, Maik [0000-0003-3437-9963], Gustincich, Stefano [0000-0002-2749-2514], Tartaglia, Gian Gaetano [0000-0001-7524-6310], Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Prins, Bram P [0000-0001-5774-034X], Huffman, Jennifer E [0000-0002-9672-2491], O'Donnell, Christopher J [0000-0002-2667-8624], Beltrao, Pedro [0000-0002-2724-7703], Chang, Kyong-Mi [0000-0001-6811-9364], Sun, Yan V [0000-0002-2838-1824], Butterworth, Adam S [0000-0002-6915-9015], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Biochemistry & Molecular Biology, Immunology, Quantitative Trait Loci, Druggability, Genome-wide association study, Receptor, Interferon alpha-beta, Computational biology, Research & Experimental Medicine, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Mendelian randomization, Humans, VA Million Veteran Program COVID-19 Science Initiative, health care economics and organizations, 11 Medical and Health Sciences, Repurposing, Science & Technology, RECEPTOR, SARS-CoV-2, Drug Repositioning, COVID-19, Cell Biology, IN-VITRO, General Medicine, Mendelian Randomization Analysis, Interleukin-10 Receptor beta Subunit, COVID-19 Drug Treatment, Drug repositioning, 030104 developmental biology, Medicine, Research & Experimental, Drug development, 030220 oncology & carcinogenesis, Expression quantitative trait loci, Angiotensin-Converting Enzyme 2, INTERFERON-ALPHA, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10−6; IFNAR2, P = 9.8 × 10−11 and IL-10RB, P = 2.3 × 10−14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Published
2021
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2. Transferability of genetic risk scores in African populations

Author

Kamiza, Abram B, Toure, Sounkou M, Vujkovic, Marijana, Machipisa, Tafadzwa, Soremekun, Opeyemi S, Kintu, Christopher, Corpas, Manuel, Pirie, Fraser, Young, Elizabeth, Gill, Dipender, Sandhu, Manjinder S, Kaleebu, Pontiano, Nyirenda, Moffat, Motala, Ayesha A, Chikowore, Tinashe, Fatumo, Segun, Vujkovic, Marijana [0000-0003-4924-5714], Machipisa, Tafadzwa [0000-0002-4882-9067], Corpas, Manuel [0000-0002-4417-1018], Gill, Dipender [0000-0001-7312-7078], Nyirenda, Moffat [0000-0003-2120-4806], Chikowore, Tinashe [0000-0002-6743-751X], Fatumo, Segun [0000-0003-4525-3362], and Apollo - University of Cambridge Repository

Subjects
Population Groups, Risk Factors, 631/208/212, brief-communication, Black People, Humans, 631/208/1516, Cholesterol, LDL, General Medicine, Brief Communication, General Biochemistry, Genetics and Molecular Biology, Genome-Wide Association Study
Abstract

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.

Published
2022

3. A missense variant in mitochondrial amidoxime reducing component 1 gene and protection against liver disease

Author

Tuomo Kiiskinen, Matthew J. Bown, Sekar Kathiresan, James G. Wilson, John Danesh, Heribert Schunkert, Krishna G. Aragam, Joshua C. Denny, Million Veteran Program, Diego Ardissino, Danish Saleheen, Marina Serper, Julie A. Lynch, Marijana Vujkovic, Usman Baber, Alexander G. Bick, George Hindy, Amit Khera, Nilesh J. Samani, Connor A. Emdin, Mark J. Daly, Hugh Watkins, Ruth McPherson, Aki S. Havulinna, QiPing Feng, Scott M. Damrauer, Namrata Gupta, Derek Klarin, Roberto Elosua, Juha Karjalainen, Philip S Tsao, B F Voight, Josep M. Mercader, Craig L. Hanis, Kyong-Mi Chang, Mark Chaffin, Wei-Qi Wei, David E. Kaplan, Stacey Gabriel, Lan Jiang, Jeanette Erdmann, Mary E. Haas, Institute for Molecular Medicine Finland, University of Helsinki, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, Emdin, Connor A. [0000-0003-2337-1229], Haas, Mary E. [0000-0002-2816-9268], Khera, Amit V. [0000-0001-6535-5839], Chaffin, Mark [0000-0002-1234-5562], Klarin, Derek [0000-0002-4636-5780], Jiang, Lan [0000-0002-2583-3661], Wei, Wei-Qi [0000-0003-4985-056X], Feng, Qiping [0000-0002-6213-793X], Havulinna, Aki [0000-0002-4787-8959], Kiiskinen, Tuomo [0000-0002-6306-8227], Bick, Alexander [0000-0001-5824-9595], Ardissino, Diego [0000-0003-0410-3528], Schunkert, Heribert [0000-0001-6428-3001], McPherson, Ruth [0000-0002-9087-6107], Erdmann, Jeanette [0000-0002-4486-6231], Chang, Kyong-Mi [0000-0001-6811-9364], Vujkovic, Marijana [0000-0003-4924-5714], Voight, Ben [0000-0002-6205-9994], Damrauer, Scott [0000-0001-8009-1632], Lynch, Julie [0000-0003-0108-2127], Kaplan, David [0000-0002-3839-336X], Serper, Marina [0000-0003-4899-2160], Tsao, Philip [0000-0001-7274-9318], Mercader, Josep [0000-0001-8494-3660], Hanis, Craig [0000-0002-4880-5348], Denny, Joshua [0000-0002-3049-7332], Apollo - University of Cambridge Repository, Emdin, Connor A [0000-0003-2337-1229], Haas, Mary E [0000-0002-2816-9268], and Khera, Amit V [0000-0001-6535-5839]

Subjects
Liver Cirrhosis, Male, Cancer Research, Cirrhosis, Datasets as Topic, PROTEIN, Coronary Artery Disease, QH426-470, Fetge -- Malalties, Biochemistry, Vascular Medicine, Liver disease, chemistry.chemical_compound, 0302 clinical medicine, Sociology, ANGPTL3, Consortia, Liver Cirrhosis, Alcoholic, Loss of Function Mutation, Psychology, Coronary Heart Disease, CONFERS SUSCEPTIBILITY, Genetics (clinical), 0303 health sciences, Liver Diseases, Homozygote, Fatty liver, 1184 Genetics, developmental biology, physiology, Middle Aged, Lipids, Addicts, 3. Good health, Cholesterol, Liver, Alkaline phosphatase, Female, Oxidoreductases, ENZYMES, Colesterol, Research Article, medicine.medical_specialty, Cirrosi hepàtica, Cardiology, Mutation, Missense, Addiction, Gastroenterology and Hepatology, Biology, Social sciences, TM6SF2, Mitochondrial Proteins, 03 medical and health sciences, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alcoholics, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, PNPLA3, 030304 developmental biology, Medicine and health sciences, Biology and life sciences, MORTALITY, Correction, Cholesterol, LDL, medicine.disease, RISK LOCI, Mitochondrial amidoxime reducing component 1, Fatty Liver, Endocrinology, YIELD, chemistry, Alanine transaminase, Genetic Loci, biology.protein, 3111 Biomedicine, Proteïnes, 030217 neurology & neurosurgery
Abstract

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis., Author summary Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease.

Published
2020

4. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program

Author

Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, Assimes, Themistocles L, Gagnon, David R [0000-0002-6367-3179], Chaffin, Mark [0000-0002-1234-5562], Emdin, Connor A [0000-0002-2385-8259], Huffman, Jennifer E [0000-0002-9672-2491], Vujkovic, Marijana [0000-0003-4924-5714], Neale, Benjamin M [0000-0003-1513-6077], Willer, Cristen [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-6724-032X], Assimes, Themistocles L [0000-0003-2349-0009], and Apollo - University of Cambridge Repository

Subjects
Male, Genotype, Black People, Hispanic or Latino, Middle Aged, Lipid Metabolism, Lipids, Polymorphism, Single Nucleotide, White People, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Ethnicity, Humans, Female, Aged, Genome-Wide Association Study, Veterans
Abstract

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

Published
2018

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