title: Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses.
abstract: OBJECTIVE
  Previous studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE.
  
  
  METHODS
  The methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome-wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis.
  
  
  RESULTS
  We identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites inHIF3A,IFI44andPRR4were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE.
  
  
  CONCLUSIONS
  Differential methylation of genes regulating the response to tissue hypoxia and interferon-mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE.
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mok
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Solomon
authors.affiliation: Russell/Engleman Rheumatology Research Center, University of California, San Francisco , San Francisco, California , USA.
authors.forename: Renuka R
authors.initials: RR
authors.lastname: Nayak
authors.affiliation: Division of Rheumatology, Department of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Coit
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Hong L
authors.initials: HL
authors.lastname: Quach
authors.affiliation: Russell/Engleman Rheumatology Research Center, University of California, San Francisco , San Francisco, California , USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Nititham
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.affiliation: Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.affiliation: Russell/Engleman Rheumatology Research Center, University of California, San Francisco , San Francisco, California , USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Russell/Engleman Rheumatology Research Center, University of California, San Francisco , San Francisco, California , USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
keywords: DNA methylation; Epigenetics; Lupus Nephritis; Systemic Lupus Erythematosus