Methylation Risk Score Identifies an Interferon-Driven SLE Subset Distinct from Polygenic Risk

ObjectivesThe aetiopathogenesis of SLE encompasses genetic, environmental and epigenetic factors. We investigated associations between an SLE methylation risk score (MRS), HLA-DRB1*03:01, a non-HLA polygenic risk score (PRS) and clinical and immunological phenotypes. MethodsDNA methylation in whole blood from patients fulfilling [&ge;]4 ACR-82 criteria and controls were investigated using the Illumina HM450K array. The discovery cohort included 311 patients and 400 controls, and the replication cohort comprised 175 patients and 187 controls. Seventeen independent, top differentially methylated CpG sites ({Delta}{beta} of [&ge;]0.1) from case-control comparisons, were used to calculate the MRS. Genotyping was performed using the Immunochip, and the PRS included 57 non-HLA SLE SNVs. Clinical data were collected from patient charts, and serum IFN-2 was measured using Simoa. ResultsHigher MRS was strongly associated with serum IFN-2 levels (p=1.04x10-14). In both cohorts, higher MRS associated with discoid lupus, immunologic involvement, and anti-SSA/SSB/RNP/Sm autoantibodies (all p<0.05), and with higher disease activity in the discovery cohort (p=1.50x10-). MRS was also elevated in patients with multiple autoantibodies (p<1.0x10-15) and in HLA-DRB1*03:01 carriers (p<1.0x10-3). In contrast, higher PRS was associated with nephritis, anti-dsDNA positivity, and lower prevalence of anti-SSB antibodies (all p<0.05). No correlation was observed between the MRS and the PRS (p=0.35). ConclusionThe MRS defines an interferon-high, HLA-DRB1*03:01-linked SLE subset with multiple autoantibodies, partly distinct from PRS-associated nephritis risk, highlighting potentially divergent pathogenic pathways. These findings underscore the value of integrating genetic and epigenetic data to better understand underlying disease mechanisms in SLE. Key MessagesO_LIHigher MRS, but not PRS, correlated with increased levels of serum IFN-. C_LIO_LIThe MRS was associated with discoid rash, hematologic disorder, hypocomplementemia, antibodies including anti-SSA and HLA-DRB1*03:01. C_LIO_LIHigher PRS was linked to nephritis and anti-dsDNA positivity, and did not associate with the MRS. C_LI