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Thromb Haemost 2016; 116(01): 115-123
DOI: 10.1160/TH15-12-0947
Blood Cells, Inflammation and Infection
Schattauer GmbH

Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression

Nadine Müller-Calleja   *
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
Heidi Rossmann   *
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
Christian Müller   *
2   Clinic of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
3   Deutsches Zentrum für Herzkreislaufforschung (DZHK), Partner Site Hamburg Lübeck Kiel, Hamburg, Germany
,
Philipp Wild
4   Department of Medicine 2, University Medical Center Mainz, Mainz, Germany
5   Deutsches Zentrum für Herzkreislaufforschung (DZHK), partner site RhineMain, Mainz, Germany
6   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
,
Stefan Blankenberg
2   Clinic of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
3   Deutsches Zentrum für Herzkreislaufforschung (DZHK), Partner Site Hamburg Lübeck Kiel, Hamburg, Germany
,
Norbert Pfeiffer
7   Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany
,
Harald Binder
8   Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Mainz Germany
,
Manfred E. Beutel
9   Department of Psychosomatic Medicine and Psychotherapy, University Medical Center Mainz, Mainz, Germany
,
Davit Manukyan
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
,
Tanja Zeller
2   Clinic of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
3   Deutsches Zentrum für Herzkreislaufforschung (DZHK), Partner Site Hamburg Lübeck Kiel, Hamburg, Germany
,
Karl J. Lackner
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
› Author Affiliations
Further Information

Publication History

Received: 11 December 2015

Accepted after major revision: 15 March 2016

Publication Date:
27 November 2017 (online)

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Summary

The antiphospholipid syndrome (APS) is characterised by venous and/ or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, D2glycoprotein 1 (antiD2GPI), and IgG against domain 1 of D2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-D2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-D2GPI antibodies. Expression analysis confirmed increased expression of TNFD in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS.

Keywords

Antiphospholipid antibodies - genome-wide association study - gene expression - monocytes - cohort study

* These authors contributed equally to the manuscript.


 

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