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Antithrombin, protein C and protein S: genome and transcriptome wide association studies identify 7 novel loci regulating plasma levels

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Objective Antithrombin, protein C (PC) and protein S (PS) are circulating natural-anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sam...

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Main Authors: Ji, Yuekai (Author) , Temprano-Sagrera, Gerard (Author) , Holle, Lori A. (Author) , Bebo, Allison (Author) , Brody, Jennifer (Author) , Le, Ngoc-Quynh (Author) , Brown, Michael R. (Author) , Martinez-Perez, Angel (Author) , Sitlani, Colleen M. (Author) , Suchon, Pierre (Author) , Kleber, Marcus E. (Author) , Emmert, David B. (Author) , Ozel, Ayse Bilge (Author) , Dobson, Dre’Von A. (Author) , Tang, Weihong (Author) , Llobet, Dolors (Author) , Tracy, Russell P. (Author) , Deleuze, Jean-François (Author) , Delgado Gonzales de Kleber, Graciela (Author) , Gögele, Martin (Author) , Wiggins, Kerri L. (Author) , Souto, Juan Carlos (Author) , Pankow, James S. (Author) , Taylor, Kent D. (Author) , Trégouët, David-Alexandre (Author) , Moissl-Blanke, Angela P. (Author) , Fuchsberger, Christian (Author) , Rosendaal, Frits R. (Author) , Morrison, Alanna C. (Author) , Soria, Jose Manuel (Author) , Cushman, Mary (Author) , Morange, Pierre-Emmanuel (Author) , März, Winfried (Author) , Hicks, Andrew A. (Author) , Desch, Karl C. (Author) , Johnson, Andrew D. (Author) , Vries, Paul S. de (Author) , Wolberg, Alisa S. (Author) , Smith, Nicholas L. (Author) , Sabater-Lleal, Maria (Author)
Format: Article (Journal) Chapter/Article
Language:English
Published: November 02, 2022
In: medRxiv
Year: 2022, Pages: 1-39
DOI:10.1101/2022.11.01.22281689
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1101/2022.11.01.22281689
Verlag, kostenfrei, Volltext: https://www.medrxiv.org/content/10.1101/2022.11.01.22281689v1
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Author Notes:Yuekai Ji, MSc, Gerard Temprano-Sagrera MSc, Lori A Holle PhD, Allison Bebo MSc, Jennifer Brody, Ngoc-Quynh Le MSc, Michael R Brown, Angel Martinez-Perez, Colleen M Sitlani PhD, Pierre Suchon MD PhD, Marcus E Kleber PhD, David B Emmert BA, Ayse Bilge Ozel PhD, Dre'Von A Dobson BS, Weihong Tang PhD, Dolors Llobet PhD, Russell P Tracy PhD, Jean-François Deleuze PhD, Graciela E Delgado MSc, Martin Gögele MSc, Kerri L Wiggins MS, RD, Juan Carlos Souto MD, PhD, James S Pankow PhD, Kent D Taylor PhD, David-Alexandre Trégouët PhD, Angela P Moissl MSc, Christian Fuchsberger PhD, Frits R Rosendaal, Alanna C Morrison PhD, Jose Manuel Soria PhD, Mary Cushman MD, Pierre-Emmanuel Morange MD PhD, Winfried März MD, Andrew A Hicks PhD, Karl C Desch MD, Andrew D Johnson PhD, Paul S de Vries PhD, CHARGE Consortium Hemostasis Working Group, INVENT Consortium, Alisa S Wolberg PhD, Nicholas L Smith PhD, Maria Sabater-Lleal PhD
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Summary:Objective Antithrombin, protein C (PC) and protein S (PS) are circulating natural-anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies (GWAS) of plasma levels of antithrombin, PC, PS free and PS total. - Approach and Results Study participants were of European and African ancestries and genotype data were imputed to TOPMed, a dense multi-ancestry reference panel. Each of 10 studies conducted a GWAS for each phenotype and summary results were meta-analyzed, stratified by ancestry. We also conducted transcriptome-wide association analyses and multi-phenotype analysis to discover additional associations. Novel GWAS findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.GWAS meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (GCKR, BAZ1B, and HP-TXNL4B) and 1 with PS levels (ORM1-ORM2). TWAS identified 3 newly associated genes: 1 with antithrombin level (FCGRT), 1 with PC (GOLM2), and 1 with PS (MYL7). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR, SNX17, and HP genes in antithrombin regulation. - Conclusion The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.
Item Description:Gesehen am 12.11.2025
Physical Description:Online Resource
DOI:10.1101/2022.11.01.22281689

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