Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified. Notable hypomethylated genes included ETS1, a genetic risk locus for SLE, and PTPN2, a genetic risk locus for other autoimmune diseases. Gene ontology analysis of hypomethylated genes revealed enrichment of genes involved in pregnancy. None of the differentially methylated sites in primary APS were differentially methylated in SLE neutrophils, and there was no demethylation of interferon signature genes in primary APS as is seen in SLE. Hypomethylation within a single probe in the IFI44L promoter (cg06872964) was able to distinguish SLE from primary APS with a sensitivity of 93.3% and specificity of 80.0% at a methylation fraction of 0.329.

Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene

“…DNA and histone modifications act as important signaling mediators between the environment and the genome and can regulate transcription, replication and a number of other intracellular processes [60]. Although little is known about the role of epigenetics for PTPN22 and ARNT, the methylation patterns of PTPN22 are altered in certain cancers [61], in other diseases such as antiphospholipid syndrome [62], and smoking [63]. Methylation patterns in ARNT, also known as HIF1β, are altered in certain cancers such as gastrointestinal stromal tumor [64].…”

Traps N' Clots: NET-Mediated Thrombosis and Related Diseases

“…102 Taken together, functionally diverse neutrophil subsets are apparently attractive targets for "omics" studies that may/will unveil novel anti-inflammatory strategies in several devastating, difficult-to-treat autoimmune thromboinflammatory conditions. [103][104][105][106] For example, RNAseq analysis of whole blood from patients with AAV has previously linked low-density granulocytes (LDGs), a population functionally characterized by high propensity to form NETs, with disease activity and decreased response to treatment. This probably implies that more aggressive treatment and close follow-up are needed in AAV patients with increased frequency of LDGs.…”

“…104 Moreover, genome-wide DNA methylation analysis of neutrophils showed an entirely distinct DNA methylation profile between primary APS and SLE patients. 105 Whether this heterogeneity is related with NETosis or/and therapeutic response in different phenotypes of APS remains to be studied.…”

Neutrophils—Important Communicators in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

“…Of particular importance in SLE is the inhibitory effect ROS has on the production of IFN (103, 104). Interestingly, neutrophils from APS patients demonstrate a proinflammatory signature with overexpression of IFN signaling genes (37, 105) and both mice and CGD patients, which lack NOX2 activity, display an IFN signature and upregulation of STAT1 (106). Deficiency of ROS may oppose tolerance and increase IFN-α, potent in driving the SLE pathogenesis and possibly also APS.…”