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Extended report
DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
  1. Juliana Imgenberg-Kreuz1,2,
  2. Jonas Carlsson Almlöf1,
  3. Dag Leonard2,
  4. Andrei Alexsson2,
  5. Gunnel Nordmark2,
  6. Maija-Leena Eloranta2,
  7. Solbritt Rantapää-Dahlqvist3,
  8. Anders A Bengtsson4,
  9. Andreas Jönsen4,
  10. Leonid Padyukov5,
  11. Iva Gunnarsson5,
  12. Elisabet Svenungsson5,
  13. Christopher Sjöwall6,
  14. Lars Rönnblom2,
  15. Ann-Christine Syvänen1,
  16. Johanna K Sandling1,2
  1. 1 Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  2. 2 Section of Rheumatology, Department of Medical Sciences, Uppsala University, Upssala, Sweden
  3. 3 Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
  4. 4 Department of Clinical Sciences, Section of Rheumatology, Lund University, Skane University Hospital, Lund, Sweden
  5. 5 Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  6. 6 Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, Linköping, Sweden
  1. Correspondence to Dr Johanna K Sandling, Department of Medical Sciences, Uppsala University, Rudbeck Laboratory, Uppsala 751 85, Sweden; johanna.sandling{at}


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.

  • systemic lupus erythematosus
  • gene polymorphism

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  • Handling editor Josef S Smolen

  • Contributors JI-K, A-CS, JKS designed the study and drafted the manuscript. DL, GN, M-LE, SR-D, AAB, AJ, LP, IG, ES, CS and LR collected patient and control material and clinical data. JI-K and JKS performed the experiments. JI-K, JKS, AA and JCA analysed the data. All authors read and provided critical review and accepted the final version of the manuscript.

  • Funding This study was supported by grants from the Knut and Alice Wallenberg Foundation (KAW 2011.0073), the Swedish Research Council for Medicine and Health (VR-MH Dnr 521-2014-2263 to ACS, Dnr 521-2013-2830 to LR, Dnr 521-2014-3954 to ES and Dnr 2016-01982 to GN), an AstraZeneca-Science for Life Laboratory research collaboration grant (to LR), the Swedish Society for Medical Research (to CS), the Swedish Rheumatism Association (to CS and DL), King Gustaf V’s 80th Birthday Fund (to DL) and a Swedish Research Council postdoc grant (VR Dnr 350-2012-256 to JKS). Funding to collect samples and characterise patients/controls from the Karolinska University hospital was provided by the Swedish Heart-Lung foundation (ES), Stockholm County Council (ALF) (ES and IG), King Gustaf V’s 80th Birthday Fund (ES and IG) and the Swedish Rheumatism Association (ES and IG). The SNP&SEQ Technology Platform is supported by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation and the Swedish Research Council (VR-RFI).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Regional Ethics board in Uppsala with Dnr 00-227 and 2016/155.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Normalised or raw intensity data of the HM450k BeadChips are available upon request from the authors on a collaborative basis.

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