Genome-wide profiling identifies associations between lupus nephritis and differential methylation of genes regulating tissue hypoxia and type 1 interferon responses

Abstract

ObjectivePrevious 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.MethodsThe 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.ResultsWe 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.ConclusionsDifferential 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.

Interaction between plasma homocysteine and the MTHFR C.677C > T polymorphism is associated with site‐specific changes in DNA methylation in humans

“…There are, however, robust observational data both supporting and refuting an observational link between 1-CM function-through studies on tHcy, folate, or vitamin B 12 and genetic studies, based on either the MTHFR polymorphism alone (44) or a cassette of genetic markers (45)and aberrant metabolic function (46,47), obesity, or type 2 diabetes (48,49). Results from the current study add further evidence to that literature and motivate future functional work on these identified loci that may allow more robust conclusions to be drawn regarding the role of 1-CM function in the etiology of metabolic disease (41,50,51).…”

Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies

“…Its incidence and severity also vary between patients. Regarding DNA methylation changes, a significantly more robust demethylation of the type I interferon-regulated genes has been observed in naïve CD4 + T cells from SLE patients with renal involvement [34, 35]. In fact, a number of interferon-regulated genes have been observed to be specifically hypomethylated in SLE patients with a history of renal involvement, including IRF7 , a well-known risk locus for SLE susceptibility [36] and IFI44.…”

“…On the other hand, IFI44 is an interferon-inducible gene with an unknown function, but it has been found to be hypomethylated across multiple leukocyte subsets in SLE patients [24–26]. Its hypomethylation in lupus nephritis has been recently confirmed in an independent study [35]. Outside of the interferon pathway, other genes such as TNK2 , DUSP5 , CD47 , or CD247 were found to be differentially methylated only in SLE patients with but not without renal involvement [34].…”

Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

“…Lastly, significant overlap was observed between hypomethylated genes in patients with pSLE and other SLE subgroups, such as adult-onset SLE or patients with lupus nephritis. A number of studies have been performed to investigate the DNAm changes in SLE [11][12][13][14][15][16][17][18][19][20][21][22]. However, the experimental designs are different in terms of the ethnic group, gender, cell types and comparison groups (Supplementary Table 9).…”

“…Diagnosing SLE in children can be more difficult because of the broad range of disease presentations in children and SLE is rarer in children [10]. Previous genome-wide DNAm studies using the Illumina HumanMethylation450 BeadChip have been performed on patients with classical, adult-onset SLE [11][12][13][14][15][16][17], SLE patients with renal involvement or lupus nephritis [18][19][20], patients with autoantibodies [21], and patients with different SLE disease activity index (SLEDAI) [22]. However, no genome-wide DNAm profiling has been performed in patients with pSLE.…”