DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus

Abstract

ObjectivesSystemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.MethodsDNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.ResultsWe identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.ConclusionsOur results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

“…While most epigenetic studies in lupus have been performed in T cells, there is evidence to suggest reduced DNA methylation levels in multiple cell types in this disease. For example, a robust demethylation signature in interferon-regulated genes in lupus is wide-spread and characteristic of the disease [4][5][6].…”

Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus

“…However, elucidating the causal genes underlying GWAS hits remains challenging given the complexities of a typical genome-wide significant locus and the regulatory process. [25][26][27] Our study identified hundreds of DNA methylations that were associated with SLE. On the other hand, although traditional case-control studies have identified DNA methylations 25 and gene expressions [19][20][21][22] implicated in the pathogenesis of SLE, the power is very limited because of the small sample size.…”

“…Laboratory-based evaluation of all of the genes in the associated regions is costly and hard to achieve at this stage. 26 These methylations were supposed to affect UBE2L3 expression (needs to be proven). Moreover, traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which genetic, epigenetic and other factors directly influence SLE.…”

Association of IRF5 rs2004640 polymorphism and systemic lupus erythematosus: A meta‐analysis

“…One of these cytokines is IFN‐α, a multipotent type of IFN, characterized by disrupting immune tolerance, activating autoreactive T and B cells and enhancing the autoimmune response . Human interferon regulatory factor (IRF)5 gene is mapped to the chromosome 7q32 . There are nine exons in the IRF5 gene.…”

“…3 Human interferon regulatory factor (IRF)5 gene is mapped to the chromosome 7q32. 4 There are nine exons in the IRF5 gene. It has a CpG island, encompassing exons 1A and 1B.…”