{
  "abstract": "Objectives Systemic lupus erythematosus (SLE) is characterized with diverse clinical manifestations. Genetic predisposition contributes significantly to the pathogenesis of the disease, and higher genetic load is linked to more severe disease. 1 This study aims to elucidate the role of genetic variation in SLE clinical heterogeneity.Methods Scandinavian patients with SLE meeting the 1997 ACR criteria were genotyped using Illumina’s GSA, with clinical data extracted from medical charts. Participants were randomly assigned to a discovery and test cohorts (n=884 and 524). SLE polygenic risk score (SLE-PRS) was calculated using 138 established GWAS non-HLA SLE risk single nucleotide variants (SNVs). Subphenotype-specific PRSs were constructed in the discovery cohort based on 4,088 candidate SNVs associated with immune or inflammatory diseases. Validation in the test cohort was conducted using logistic regression comparing the top quartile to the remainder, adjusting for sex and age. Disease and pathway enrichment analyses were conducted using FUMA 2 and Metascape.3 Results The SLE-PRS was associated with nephritis (OR=1.4, p=1.1×10-5) and photosensitivity (OR=1.1, p=3.6×10-3), but not with other ACR-97 manifestations. Excluding 54 to 75 SNVs not associated with specific SLE subphenotypes enhanced prediction: improved performance for nephritis (OR=1.6, p=4.4×10-6) and serositis (OR=1.3, p=0.02). Next, we constructed subphenotype-specific PRSs (34 SNVs on average). The nephritis-PRS contained the largest fraction of known SLE loci (23%) ( table 1). Several PRSs demonstrated predictive ability: malar rash-PRS (OR=1.3, p=7.1×10-5), nephritis-PRS (OR=1.4, p=4.6×10-12), neurological disorder-PRS (OR=1.1, p=0.02). Enrichment analysis of SNV annotated genes showed association between multiple sclerosis and all PRSs, with the strongest association for neurological disease (p=1.17×10-11). Pathway enrichment analysis showed association between photosensitivity and the Nuclear factor of activated T-cells (NFAT) pathway (p=7.8×10-12) and hematological manifestations with interleukine-27 signaling (p=2.5×10-6).Abstract PO:06:171 Table 1Conclusions The results demonstrate that refined genetic profiles can be associated with specific clinical manifestations of SLE, and that inclusion of non-SLE risk SNVs can enhance predictive power. Functional enrichment analyses further reveal distinct biological pathways underlying different disease features, pointing to potential targets for personalized therapeutic strategies.References Reid S. et al. Ann Rheum Dis. (2019). Watanabe K. et al. Nat. Commun. (2017). Zhou Y. et al. Nat. Commun. (2019).",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Nina Oparina"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Sarah Reid"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Ahmed Sayadi"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Maija-Leena Eloranta"
    },
    {
      "affiliations": [
        "Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping Universit, Linköping, Sweden"
      ],
      "name": "Martina Frodlund"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Karoline Lerang"
    },
    {
      "affiliations": [
        "Department of Clinical Sciences, Lund University, Lund, Sweden"
      ],
      "name": "Andreas Jönsen"
    },
    {
      "affiliations": [
        "Department of Rheumatology, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Øyvind Molberg"
    },
    {
      "affiliations": [
        "Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden"
      ],
      "name": "Solbritt Rantapää-Dahlqvist"
    },
    {
      "affiliations": [
        "Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy of University of Gothen, Gothenburg, Sweden"
      ],
      "name": "Anna Rudin"
    },
    {
      "affiliations": [
        "Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping Universit, Linköping, Sweden"
      ],
      "name": "Christopher Sjöwall"
    },
    {
      "affiliations": [
        "Department of Clinical Sciences, Lund University, Lund, Sweden"
      ],
      "name": "Anders Bengtsson"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Lars Rönnblom"
    },
    {
      "affiliations": [
        "Department of Medical Sciences, Uppsala University, Uppsala, Sweden"
      ],
      "name": "Dag Leonard"
    }
  ],
  "title": "PO:06:171 Clinical heterogeneity in systemic lupus erythematosus: exploring the impact of genetic risk profiles",
  "uid": "34d1ec8f-41d1-5233-9028-215e8cb766e1"
}