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Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk

Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes invo...

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Autores principales: Lopez, Sonia, Martinez-Perez, Angel, Rodriguez-Rius, Alba, Viñuela, Ana, Brown, Andrew A., Martin-Fernandez, Laura, Vilalta, Noelia, Arús, Marc, Panousis, Nikolaos I., Buil, Alfonso, Sabater-Lleal, Maria, Souto, Juan Carlos, Dermitzakis, Emmanouil T., Soria, Jose Manuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Georg Thieme Verlag KG 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251712/
https://www.ncbi.nlm.nih.gov/pubmed/35272364
http://dx.doi.org/10.1055/s-0041-1742169
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author Lopez, Sonia
Martinez-Perez, Angel
Rodriguez-Rius, Alba
Viñuela, Ana
Brown, Andrew A.
Martin-Fernandez, Laura
Vilalta, Noelia
Arús, Marc
Panousis, Nikolaos I.
Buil, Alfonso
Sabater-Lleal, Maria
Souto, Juan Carlos
Dermitzakis, Emmanouil T.
Soria, Jose Manuel
author_facet Lopez, Sonia
Martinez-Perez, Angel
Rodriguez-Rius, Alba
Viñuela, Ana
Brown, Andrew A.
Martin-Fernandez, Laura
Vilalta, Noelia
Arús, Marc
Panousis, Nikolaos I.
Buil, Alfonso
Sabater-Lleal, Maria
Souto, Juan Carlos
Dermitzakis, Emmanouil T.
Soria, Jose Manuel
author_sort Lopez, Sonia
collection PubMed
description Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project. Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0.26 ( p  = 3.7 × 10 (−6) ), while the GWAS identified a significant association (rs1687391, p  = 3.55 × 10 (−10) ) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood ( p  = 6.14 × 10 (−9) ). Additionally, ORM1 expression correlated with levels of cfDNA ( p  = 4.38 × 10 (−4) ). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association ( ρ (g)  = 0.43, p  = 0.089). All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis.
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spelling pubmed-92517122022-07-05 Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk Lopez, Sonia Martinez-Perez, Angel Rodriguez-Rius, Alba Viñuela, Ana Brown, Andrew A. Martin-Fernandez, Laura Vilalta, Noelia Arús, Marc Panousis, Nikolaos I. Buil, Alfonso Sabater-Lleal, Maria Souto, Juan Carlos Dermitzakis, Emmanouil T. Soria, Jose Manuel Thromb Haemost Plasma cell-free DNA (cfDNA) is a surrogate marker of neutrophil extracellular traps (NETs) that contribute to immunothrombosis. There is growing interest about the mechanisms underlying NET formation and elevated cfDNA, but little is known about the factors involved. We aimed to identify genes involved in the regulation of cfDNA levels using data from the Genetic Analysis of Idiopathic Thrombophilia (GAIT-2) Project. Imputed genotypes, whole blood RNA-Seq data, and plasma cfDNA quantification were available for 935 of the GAIT-2 participants from 35 families with idiopathic thrombophilia. We performed heritability and GWAS analysis for cfDNA. The heritability of cfDNA was 0.26 ( p  = 3.7 × 10 (−6) ), while the GWAS identified a significant association (rs1687391, p  = 3.55 × 10 (−10) ) near the ORM1 gene, on chromosome 9. An eQTL (expression quantitative trait loci) analysis revealed a significant association between the lead GWAS variant and the expression of ORM1 in whole blood ( p  = 6.14 × 10 (−9) ). Additionally, ORM1 expression correlated with levels of cfDNA ( p  = 4.38 × 10 (−4) ). Finally, genetic correlation analysis between cfDNA and thrombosis identified a suggestive association ( ρ (g)  = 0.43, p  = 0.089). All in all, we show evidence of the role of ORM1 in regulating cfDNA levels in plasma, which might contribute to the susceptibility to thrombosis through mechanisms of immunothrombosis. Georg Thieme Verlag KG 2022-03-10 /pmc/articles/PMC9251712/ /pubmed/35272364 http://dx.doi.org/10.1055/s-0041-1742169 Text en The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.
spellingShingle Lopez, Sonia
Martinez-Perez, Angel
Rodriguez-Rius, Alba
Viñuela, Ana
Brown, Andrew A.
Martin-Fernandez, Laura
Vilalta, Noelia
Arús, Marc
Panousis, Nikolaos I.
Buil, Alfonso
Sabater-Lleal, Maria
Souto, Juan Carlos
Dermitzakis, Emmanouil T.
Soria, Jose Manuel
Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title_full Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title_fullStr Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title_full_unstemmed Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title_short Integrated GWAS and Gene Expression Suggest ORM1 as a Potential Regulator of Plasma Levels of Cell-Free DNA and Thrombosis Risk
title_sort integrated gwas and gene expression suggest orm1 as a potential regulator of plasma levels of cell-free dna and thrombosis risk
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251712/
https://www.ncbi.nlm.nih.gov/pubmed/35272364
http://dx.doi.org/10.1055/s-0041-1742169
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