BackgroundSystemic lupus erythematosus (SLE) has been associated with more than 100 genetic loci. This parallels positively to the clinical diversity that is reflected by the classification of SLE.ObjectivesWe aimed to investigate associations between disease manifestations of SLE and risk gene variants relevant to Danish subjects of European ancestry.MethodsWe included 427 SLE patients of European ancestry similar to previous reports.[1] We also included 89,699 controls from the Danish Blood Donor Study Genomic Cohort. SLE risk loci in this population were identified by genome-wide association methodology and hereafter correlated to cumulative occurrence of SLE classification items.ResultsFourteen variants mapped to the following genes: NCF2, STAT4, TNPO3/TPI1P2, IRF5, and ITGAM, were significantly associated (p<5E-8) with SLE.The five lead variants were associated (p<0.05) with the following manifestations; NCF2: proteinuria and anti-phospholipid antibodies, STAT4: arthritis, serositis, neurologic disorder, lymphopenia, and anti-Smith antibodies, IRF5: seizures and proteinuria, TNPO3: proteinuria, and ITGAM: photosensitivity (Table 2).ConclusionOur findings support the future use of select, relevant genetic markers in predicting various SLE phenotypes.References[1]Leffers HCB, Troldborg A, Voss A, et al. Smoking associates with distinct clinical phenotypes in patients with systemic lupus erythematosus: a nationwide Danish cross-sectional study. Lupus Sci Med 2021;8(1).Table 1.Associations between five SLE risk loci and specific disease manifestations in 427 Danish patients with SLE*.NCF2STAT4IRF5TNPO3ITGAMrs17849502_Trs7574865_Trs4728142_Ars13239597_Ars11860650_TN (%)Malar rash233 (55%)1.28 (0.84-1.96)0.83 (0.62-1.11)1.01 (0.74-1.38)1.44 (0.97-2.12)1.14 (0.80-1.61)Discoid rash46 (11%)1.49 (0.81-2.73)0.90 (0.56-1.45)1.01 (0.62-1.66)1.16 (0.63-2.12)0.76 (0.42-1.41)Photosensitivity219 (51%)0.96 (0.63-1.46)1.09 (0.81-1.47)0.98 (0.71-1.34)0.84 (0.57-1.25)0.67 (0.47-0.97)Oral ulcers132 (31%)0.96 (0.61-1.50)0.90 (0.65-1.23)0.83 (0.60-1.16)1.30 (0.87-1.96)1.43 (0.99-2.05)Non-erosive Arthritis342 (80%)0.84 (0.52-1.37)1.49 (1.02-2.18)0.93 (0.63-1.36)1.04 (0.64-1.68)1.16 (0.74-1.80)Serositis-Pleuritis124 (29%)0.63 (0.38-1.05)1.38 (1.01-1.89)1.22 (0.87-1.72)0.85 (0.56-1.29)0.84 (0.57-1.24)-Pericarditis72 (17%)0.75 (0.41-1.40)1.35 (0.93-1.96)1.05 (0.70-1.58)1.15 (0.70-1.89)1.09 (0.70-1.72)Persistent proteinuria158 (37%)1.63 (1.07-2.49)1.08 (0.80-1.46)0.68 (0.49-0.94)1.74 (1.16-2.61)1.09 (0.76-1.57)Neurologic disorder-Seizures23 (5%)1.58 (0.75-3.35)1.49 (0.80-2.76)2.10 (1.04-4.25)0.61 (0.26-1.44)0.93 (0.42-2.06)-Psychosis8 (2%)0.76 (0.097-5.87)2.77 (0.94-8.15)0.35 (0.10-1.23)0 (0)2.96 (0.85-10.3)Haematologic disorder-Haemolytic anaemia38 (9%)0.78 (0.34-1.76)1.37 (0.85-2.22)0.75 (0.44-1.29)1.11 (0.57-2.19)1.24 (0.70-2.20)-Leukopenia130 (30%)1.04 (0.67-1.61)1.19 (0.87-1.63)1.00 (0.72-1.39)0.90 (0.60-1.37)0.94 (0.64-1.37)-Lymphopenia228 (53%)0.95 (0.63-1.44)1.35 (1.01-1.81)0.95 (0.70-1.29)1.16 (0.79-1.70)1.09 (0.77-1.54)-Thrombocytopenia102 (24%)1.42 (0.91-2.22)0.84 (0.60-1.18)0.83 (0.58-1.18)1.35 (0.86-2.11)0.91 (0.60-1.37)Immunologic disorder-anti-DNA ab.330 (77%)0.69 (0.44-1.09)1.02 (0.72-1.44)0.94 (0.65-1.35)0.97 (0.62-1.53)1.08 (0.71-1.65)-anti-Smith ab.44 (10%)1.44 (0.79-2.64)1.58 (1.00-2.49)1.23 (0.73-2.07)1.47 (0.80-2.69)1.07 (0.61-1.84)-anti-phospholipid ab.183 (43%)1.63 (1.07-2.49)1.05 (0.79-1.41)0.84 (0.61-1.14)1.14 (0.77-1.68)1.14 (0.80-1.62)* Logistic regression models for each manifestation included all five lead variants (multivariate) and were adjusted for age and sexDisclosure of InterestsHenrik Leffers: None declared, David Westergaard: None declared, Saedis Saevarsdottir: None declared, Ingileif Jonsdottir: None declared, Ole Birger Pedersen: None declared, Anne Troldborg: None declared, Anne Voss: None declared, Salome Kristensen: None declared, Jesper Lindhardsen: None declared, Prabhat Kumar: None declared, Asta Linauskas: None declared, Lars Juul: None declared, Niels Steen Krogh: None declared, Bent Deleuran: None declared, Lene Dreyer Speakers bureau: Speakers bureau: Eli Lilly, Galderma and Janssen, Grant/research support from: from BMS outside the present work, Michael Schwinn: None declared, Lise wegner Thørner: None declared, Lotte Hindhede: None declared, Christian Erikstrup: None declared, Henrik Ullum: None declared, Søren Brunak Shareholder of: SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, Kari Stefansson: None declared, Karina Banasik: None declared, Søren Jacobsen: None declared