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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(06): 1027-1039
DOI: 10.1055/s-0041-1742169
Stroke, Systemic or Venous Thromboembolism

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

Sonia Lopez 
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
,
Angel Martinez-Perez 
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
,
Alba Rodriguez-Rius
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
,
Ana Viñuela
2   Biosciences Institute, Faculty of Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom
,
Andrew A. Brown
3   Population Health and Genomics, University of Dundee, Dundee, Scotland, United Kingdom
,
Laura Martin-Fernandez
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
4   Fundación Española de Trombosis y Hemostasia (FETH), Madrid, Spain
5   Congenital Coagulopathies Laboratory, Banc de Sang i Teixits, Barcelona, Spain
6   Transfusional Medicine, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
,
Noelia Vilalta
7   Haemostasis and Thrombosis Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Marc Arús
7   Haemostasis and Thrombosis Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Nikolaos I. Panousis
8   Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, South Cambridgeshire, United Kingdom
9   Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
,
Alfonso Buil
10   Institute of Biological Psychiatry, Mental Health Sct. Hans Hospital, Roskilde, Denmark
,
Maria Sabater-Lleal
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
11   Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
,
Juan Carlos Souto
7   Haemostasis and Thrombosis Unit, Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
,
Emmanouil T. Dermitzakis
9   Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
,
Jose Manuel Soria
1   Genomics of Complex Diseases Unit, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain
› Author Affiliations Funding This study was supported by grants of the Spanish Government Instituto de Salud Carlos III and Fondo de Investigación Sanitaria (ISCIII-FIS) (PI14/00582, PI17/00059, J.M.S. and S.L.), Grupo Consolidado Generalitat de Catalunya (SGR 1736, J.M.S.), CERCA Programme/Generalitat de Catalunya, Fundación Española de Trombosis y Hemostasia (FETH; L.M-.F.), and the nonprofit association Activa'TT por la Salud. A.R-.R. was supported by a predoctoral fellowship of the Catalonia Government Agència de Gestió d'ajuts Universitaris i de Recerca (AGAUR) (FI2017B_00673). M.S-.L. is supported by a Miguel Servet contract from the ISCIII (CP17/00142) and co-financed by the European Social Fund.
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Abstract

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.

Keywords

immunothrombosis - neutrophil extracellular traps - α-1-acid glycoprotein 1 - expression quantitative trait loci

Ethical Approval

The study was performed in compliance with the Helsinki Declaration. The Ethical Committee at Hospital de la Santa Creu i Sant Pau approved the GAIT-2 study. Adult participants provided informed consent for themselves and for their minor children.


Supplementary Material



Publication History

Received: 17 March 2021

Accepted: 20 October 2021

Article published online:
10 March 2022

© 2022. 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/)

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