Clinical Characteristics of Patients with High SLE-specific and High Multitrait Polygenic Risk – an Investigation of SLE Risk Loci

Nina Oparina¹, Sarah Reid², Ahmed Sayadi³, Maija-Leena Eloranta⁴, Martina Frodlund⁵, Karoline Lerang⁶, Andreas Jönsen⁷, Solbritt Rantapaa-Dahlqvist⁸, Anders Bengtsson⁷, Anna Rudin⁹, Øyvind Molberg¹⁰, Christopher Sjowall¹¹, Lars Rönnblom⁴ and Dag Leonard⁴, ¹UU, Uppsala, Sweden, ²Uppsala University, Medical Sciences, Uppsala, Sweden, ³Uppsala, Uppsala, Sweden, ⁴Uppsala University, Uppsala, Sweden, ⁵Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden, ⁶Oslo University, Oslo, Norway, ⁷Lund University, Lund, Sweden, ⁸Umeå University, Umeå, Sweden, ⁹Institute of Medicine, University of Gothenburg, Gothenburg, Sweden, ¹⁰Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, ¹¹Linköping University, Linköping, Sweden

Meeting: ACR Convergence 2024

Keywords: autoimmune diseases, genetics, Systemic lupus erythematosus (SLE)

Session Information

Date: Sunday, November 17, 2024

Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Heritability of SLE is high and more than 200 genetically associated SLE risk loci were identified. Part of them are specific and associate with SLE development only while other associate with other diseases, such as type 1 diabetes (T1DM) and rheumatoid arthritis (RA). Our objective: to investigate what clinical phenotype associate with high polygenic scores (PRSs) for SLE-specific and multitrait-associated SLE loci.

Methods: Patients with SLE (ACR-97 or SLICC-12, n=1498) and healthy controls (n=1947) were genotyped using Illumina’s Global Screening Array. SLE-associated single nucleotide variants (SNVs) (European ancestry) at GWAS significance (p< 5×10-8) were identified through the GWAS catalog. After filtering 112 SNVs were identified. SNVs were considered multitrait if associated with ≥1 additional disease. Two PRSs were constructed; one including SLE specific SNVs (n=79) and one including multitrait SNVs (n=33). Groups were compared using logistic regression, adjusting for age and sex. 50% of patients with the highest SLE-specific PRS were selected and from them the 50% with the lowest multitrait PRS were selected. This group (highSLE-lowMultitrait, 25% of total) was then compared with the other patients (75% of total). The same method was used for the highMultitrait-lowSLE group.

Results: Both PRSs were higher in patients in comparison with healthy controls, p< 2×10-6. Besides SLE, the most common diseases associated with the multitrait SNVs were RA (SNV=10), T1DM (SNV=8), multiple sclerosis and ulcerative colitis (SNV=6).

The highSLE-lowMultitrait group had higher prevalence of malar rash (OR 1.28(1.00-1.66), p=0.04), neurologic manifestations (OR 1.44(1.10-2.08), p=0.048), thrombocytopenia (OR 1.47(1.06-2.04), p=0.022), anti-Sm antibodies (OR 1.80(1.12-2.80), p=0.009), low complement (OR 1.70(1.25-2.30), p < 0.001) and lower prevalence of hemolytic anemia (OR 0.55(0.32-0.97), p=0.038) compared with the other group.

The highMultitrait-lowSLE group had higher prevalence of anti-SSA (OR 1.49 (1.14-1.94), p= 0.003) and anti-SSB antibodies (OR 1.79 (1.34-2.39), p < 0.001) and lower prevalence of discoid rash (OR 0.72(0.52-1.0), p=0.038) compared with the other group.

Conclusion: Our results shed light on SLE heterogeneity. Leveraging data for shared genetic associations can be important for determining the genetic background influencing SLE subphenotypes, but also common disease manifestations among autoimmune diseases.

Disclosures: N. Oparina: None; S. Reid: None; A. Sayadi: None; M. Eloranta: None; M. Frodlund: None; K. Lerang: None; A. Jönsen: None; S. Rantapaa-Dahlqvist: None; A. Bengtsson: None; A. Rudin: None; Ø. Molberg: None; C. Sjowall: Bristol-Myers Squibb(BMS), 3; L. Rönnblom: Ampel Biosolutions, 1, AstraZeneca, 1, 6, Bayer, 2, BMS, 1, UCB, 1; D. Leonard: AstraZeneca, 1.

To cite this abstract in AMA style:

Oparina N, Reid S, Sayadi A, Eloranta M, Frodlund M, Lerang K, Jönsen A, Rantapaa-Dahlqvist S, Bengtsson A, Rudin A, Molberg Ø, Sjowall C, Rönnblom L, Leonard D. Clinical Characteristics of Patients with High SLE-specific and High Multitrait Polygenic Risk – an Investigation of SLE Risk Loci [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/clinical-characteristics-of-patients-with-high-sle-specific-and-high-multitrait-polygenic-risk-an-investigation-of-sle-risk-loci/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-characteristics-of-patients-with-high-sle-specific-and-high-multitrait-polygenic-risk-an-investigation-of-sle-risk-loci/