{
  "abstract": "Objectives The aetiopathogenesis of SLE encompasses both genetic and epigenetic factors, including hypomethylation of type I interferon (IFN) regulated genes and the HLA-DRB1*03:01 haplotype. This study investigated the relationship between a methylation-based SLE risk score (MRS), a non-HLA SLE polygenic risk score (SLE-PRS), an HLA-DRB1*03:01 tag SNP, serum IFN-α levels, and clinical phenotype.Methods DNA methylation in whole blood from 547 patients fulfilling >=4 ACR-82 criteria was investigated using the Illumina HM450K array. Significant differentially methylated CpGs with a |delta β| of >=0.1 between cases and controls and located at independent genetic loci (n=17) were selected for calculation of the MRS. Genotyping was performed using the Immunochip, and an SLE-PRS including 57 SLE-non-HLA SNVs was calculated for all participants. Clinical data were collected from patient charts. Serum IFN-α2 levels were measured in a subgroup of 85 patients using Simoa. Associations between the MRS, SLE-PRS, the HLA-DRB1*03:01 tag SNP (rs1269852), and clinical variables were assessed applying logistic regression adjusted for age and sex (p<0.05 considered significant).Results The MRS was associated with high disease activity (SLEDAI>4 or SLAM>6 ) (OR=1.01(CI:1.01-1.02), p=2.0×10^-4), higher IFNα levels (Exp(B)=1.03, p=1.0×10^-14) and low complement (OR=1.01(CI:1.00-1.02), p=2.2×10^-3), whereas the SLE-PRS was not (all p>0.05). Further, no significant correlation between the MRS and the SLE-PRS was observed (p=0.35, R 2=0.05). The MRS was associated with discoid rash (OR=1.02(CI:1.01-1.02), p=3.5×10^-4), the hematological disorder criterion (OR=1.02(CI:1.01-1.03), p=1.6×10^-7), and the immunological criterion (OR=1.01(OR:1.01-1.02), p=1.4×10^-4), while the SLE-PRS was associated with the nephritis (OR=1.18(CI:1.00-1.40), p=0.048) and the immunologic criterion (OR=1.40(CI:1.18-1.67), p=1.1×10^-4). Furthermore, the MRS, but not the SLE-PRS, was associated with anti-SSA and anti-RNP antibodies (OR=1.03(CI:1.02-1.03), p=1.1x10^-12 and OR=1.02(CI:1.02-1.03), p=8.2×10^-11). The HLA-DRB1*03:01 tag SNP was significantly associated with higher MRS (B=7.22, p=8.6×10^-4) and with anti-SSA and anti-SSB antibodies (OR 3.09(CI:2.23-4.34) and 4.79(CI:3.28-7.16), both p<1x10^-10).Conclusions The results indicate that the pathogenetic contributions from epigenetic aberrations differ from those of polygenic risk. The significantly higher MRS levels, anti-Ro/La positivity, and hypocomplementaemia in patients with the HLA-DRB1*03:01 risk allele suggests that epigenetic dysregulation may be of particular importance in these individuals, potentially predisposing to increased IFN production.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Holme Vestin"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Nina Oparina"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Maija-Leena Eloranta"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Elisabeth Skoglund"
    },
    {
      "affiliations": [
        "Dept of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden"
      ],
      "name": "Martina Frodlund"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Iva Gunnarsson"
    },
    {
      "affiliations": [
        "Dept of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden"
      ],
      "name": "Christopher Sjöwall"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Elisabet Svenungsson"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Lars Rönnblom"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Juliana Imgenberg-Kreuz"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Dag Leonard"
    }
  ],
  "title": "PT5:03 SLE methylation risk score: divergent associations with SLE features compared to a polygenic risk score and its link to HLA-DRB1*03:01",
  "uid": "23bfec42-f31e-5a35-90b1-b5d11198b212"
}