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

Thromb Haemost. 2016 Jul 4;116(1):115-23. doi: 10.1160/TH15-12-0947. Epub 2016 Apr 21.


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, β2glycoprotein 1 (anti-β2GPI), and IgG against domain 1 of β2GPI (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-β2GPI 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-β2GPI antibodies. Expression analysis confirmed increased expression of TNFα 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; cohort study; gene expression; genome-wide association study; monocytes.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Antiphospholipid / blood*
  • Antiphospholipid Syndrome / blood
  • Antiphospholipid Syndrome / genetics*
  • Antiphospholipid Syndrome / immunology*
  • Cohort Studies
  • Female
  • Gene Expression
  • Genome-Wide Association Study
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Pregnancy
  • Prospective Studies
  • RNA / blood
  • RNA / genetics


  • Antibodies, Antiphospholipid
  • Membrane Proteins
  • NAV3 protein, human
  • Nerve Tissue Proteins
  • RNA