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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Juliana Imgenberg-Kreuz
  • Jonas Carlsson Almlöf
  • Dag Leonard
  • Andrei Alexsson
  • Gunnel Nordmark
  • Maija Leena Eloranta
  • Solbritt Rantapää-Dahlqvist
  • Anders A. Bengtsson
  • Andreas Jönsen
  • Leonid Padyukov
  • Iva Gunnarsson
  • Elisabet Svenungsson
  • Christopher Sjöwall
  • Lars Rönnblom
  • Ann Christine Syvänen
  • Johanna K. Sandling
Enheter & grupper
Externa organisationer
  • Uppsala universitet, Historiska institutionen
  • Umeå University
  • Karolinska University Hospital
  • Linköping University
  • Skåne University Hospital
  • Karolinska Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Reumatologi och inflammation

Nyckelord

Originalspråkengelska
Sidor (från-till)736-743
Antal sidor8
TidskriftAnnals of the Rheumatic Diseases
Volym77
Utgåva nummer5
StatusPublished - 2018 maj 1
PublikationskategoriForskning
Peer review utfördJa