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Genetics
Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses
  1. Amanda Mok1,
  2. Olivia Solomon1,
  3. Renuka R Nayak2,
  4. Patrick Coit3,
  5. Hong L Quach1,
  6. Joanne Nititham2,
  7. Amr H Sawalha3,4,
  8. Lisa F Barcellos1,
  9. Lindsey A Criswell2 and
  10. Sharon A Chung2
  1. 1Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, California, USA
  2. 2Russell/Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, California, USA
  3. 3Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Sharon A Chung; Sharon.chung{at}ucsf.edu

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 in HIF3A, IFI44 and PRR4 were 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.

  • Systemic Lupus Erythematosus
  • Lupus Nephritis
  • DNA methylation
  • Epigenetics

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/lupus-2016-000183

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    Footnotes

    • Contributors Conceived and designed the experiments: SAC, LFB and LAC. Performed the experiments: HLQ, PC, AHS and LFB. Analysed the data: AM, OS, RRN, JN and SAC. Contributed reagents/materials/analysis tools: PC, HLQ, AHS, LFB and LAC. Wrote the paper: AM, OS and SAC.

    • Funding The work was supported by the following NIH (http://www.nih.gov) grants: R01 AR052300 (LAC), K24 AR02175 (LAC), P60 AR053308 (LAC), R01 AI097134 (AHS), UCSF-CTSI KL2 RR024130 (SAC), UCSF-CTSI UL1 TR000004 (SAC) and K23 AR063126 (SAC); Alliance for Lupus Research (http://www.lupusresearch.org, LAC); Mary Kirkland Scholar Award (http://www.hss.edu/mary-kirkland-scholar-program.asp, LAC); Rheumatology Research Foundation (AM), the Irene Perstein Award (https://medschool.ucsf.edu/school-medicine-irene-perstein-award/, SAC), and the Russell/Engleman Rheumatology Research Center (https://russellenglemancenter.ucsf.edu/, RRN, JN, LAC and SAC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

    • Competing interests None declared.

    • Ethics approval Institutional Review Board, University of California, San Francisco, USA.

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

    • Data sharing statement Methylation data for the study participants are available at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000947.v1.p1. Additional phenotype data is available to academic investigators by contacting SAC, the corresponding author.