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DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed) Published
Abstract [en]

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 HLADQB2 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.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP , 2018. Vol. 77, no 5, p. 736-743
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Rheumatology and Autoimmunity
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URN: urn:nbn:se:liu:diva-147784DOI: 10.1136/annrheumdis-2017-212379ISI: 000430492600020PubMedID: 29437559OAI: oai:DiVA.org:liu-147784DiVA, id: diva2:1206505
Note

Funding Agencies|Knut and Alice Wallenberg Foundation [KAW 2011.0073]; Swedish Research Council for Medicine and Health (VR-MH) [521-2014-2263, 521-2013-2830, 521-2014-3954, 2016-01982]; AstraZeneca-Science for Life Laboratory research collaboration grant; Swedish Society for Medical Research; Swedish Rheumatism Association; King Gustaf Vs 80th Birthday Fund; Swedish Research Council postdoc grant (VR) [350-2012-256]; Karolinska University hospital by Swedish Heart-Lung foundation; Stockholm County Council; Science for Life Laboratory; Knut and Alice Wallenberg Foundation; Swedish Research Council (VR-RFI)

Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-05-17

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Sjöwall, Christopher
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Rheumatology
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