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

Imgenberg-Kreuz, Juliana; Almlöf, Jonas Carlsson; Leonard, Dag; Alexsson, Andrei; Nordmark, Gunnel; Eloranta, Maija Leena; Rantapää-Dahlqvist, Solbritt; Bengtsson, Anders A. LU ; Jönsen, Andreas LU and Padyukov, Leonid, et al. (2018) In Annals of the Rheumatic Diseases 77(5). p.736-743
Abstract

Objectives Systemic 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. Methods DNA 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... (More)

Objectives Systemic 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. Methods DNA 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. Results We 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. Conclusions Our 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.

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publication status
published
subject
keywords
gene polymorphism, systemic lupus erythematosus
in
Annals of the Rheumatic Diseases
volume
77
issue
5
pages
8 pages
publisher
British Medical Association
external identifiers
  • scopus:85046359601
ISSN
0003-4967
DOI
10.1136/annrheumdis-2017-212379
language
English
LU publication?
yes
id
8d4134d1-f32f-47fd-8b0a-4f41497de2b8
date added to LUP
2018-05-15 14:05:35
date last changed
2018-08-19 04:42:44
@article{8d4134d1-f32f-47fd-8b0a-4f41497de2b8,
  abstract     = {<p>Objectives Systemic 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. Methods DNA 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. Results We 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. Conclusions Our 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.</p>},
  author       = {Imgenberg-Kreuz, Juliana and Almlöf, Jonas Carlsson and Leonard, Dag and Alexsson, Andrei and Nordmark, Gunnel and Eloranta, Maija Leena and Rantapää-Dahlqvist, Solbritt and Bengtsson, Anders A. and Jönsen, Andreas and Padyukov, Leonid and Gunnarsson, Iva and Svenungsson, Elisabet and Sjöwall, Christopher and Rönnblom, Lars and Syvänen, Ann Christine and Sandling, Johanna K.},
  issn         = {0003-4967},
  keyword      = {gene polymorphism,systemic lupus erythematosus},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {736--743},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2017-212379},
  volume       = {77},
  year         = {2018},
}