Lupus (2012) 21, 959–968 http://lup.sagepub.com PAPER Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis HA Martens 1 , HLA Nienhuis 2 , S Gross 3 , G van der Steege 4 , E Brouwer 2 , JHM Berden 5 , RGL de Se´vaux 5 , RHWM Derksen 6 , AE Voskuyl 7 , SP Berger 8 , GJ Navis 3 , IM Nolte 9 , CGM Kallenberg 2 and M Bijl 2 1 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands; 2 Department of Rheumatology and Clinical Immunology, 3 Department of Nephrology, and 4 Department of Genetics, University Medical Center, Groningen, The Netherlands; 5 Department of Nephrology, Radboud University Nijmegen Medical Center, The Netherlands, 6 Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands; 7 Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands; 8 Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; and 9 Department of Epidemiology, University Medical Center, Groningen, The Netherlands Objective: Interaction of advanced glycation end products (AGEs) with their receptors (RAGE) plays an important role in inflammation in auto-immune diseases. Several functional polymorphisms of RAGE have been described. In this study we analysed the role of RAGE polymorphisms in disease susceptibility for systemic lupus erythematosus (SLE). In addition, we investigated whether these polymorphisms in SLE are associated with serum levels of soluble RAGE (sRAGE), renal involvement (lupus nephritis (LN)) and its outcome. Methods: For this cross-sectional study DNA samples of 97 SLE patients, 114 LN patients and 429 healthy controls (HC) were genotyped for four RAGE polymorphisms: 429 T/C, 374 T/A, 2184 A/G and Gly82Ser. Differences in genotype frequencies and allele frequencies were tested between patients and HCs. In SLE patients, sRAGE was measured by enzyme- linked immunosorbent assay (ELISA). In addition, association of genotypes with sRAGE and disease severity in LN was analysed. Results: The C allele of 429 T/C, the T allele of 374 T/ A and the G allele of 2184 A/G were significantly more prevalent in SLE and LN compared with HC. In LN, the C allele of RAGE 429 T/C, the A allele of 374 T/A and the G allele of RAGE 2184 A/G polymorphism were significantly associated with more proteinuria and worse renal function during the first two years of treatment. No association of genotype with sRAGE was found. Conclusion: RAGE polymorphisms are associated with susceptibility to SLE and LN. In addition, some of these polymorphisms are likely to be associated with disease severity and initial response to treatment in LN. Lupus (2012) 21, 959–968. Key words: Receptor for advanced glycation end products; systemic lupus erythematosus; lupus nephritis; polymorphisms; soluble receptor for advanced glycation end products Introduction Systemic lupus erythematosus (SLE) is an auto- immune disease characterized by chronic inflamma- tion. Several factors have been shown to play a role in the pathogenesis of this chronic inflammation, amongst them advanced glycation endproducts (AGEs). AGEs are a class of compounds resulting from glycation of proteins, lipids or nuclear acids, partly under influence of oxidative stress. AGE accumulation is increased and related to acceler- ated atherosclerosis in SLE. 1,2 AGEs may contrib- ute to inflammatory and destructive processes 3 by ligation to their receptor (RAGE). Besides AGEs, other pro-inflammatory ligands like high-mobility group box-1 (HMGB-1) and S100calgranulins also bind to RAGE, resulting in an increased inflamma- tory response. 4 Levels of HMGB-1 are increased in SLE, in particular in patients with active renal dis- ease. 5 It has been postulated that HMGB-1 is Correspondence to: Henk Martens, Department of Rheumatology, Sint Maartenskliniek Nijmegen, PO box 9011, 6500 GM, Nijmegen, The Netherlands Email: h.martens@maartenskliniek.nl Received 7 November 2011; accepted 29 February 2012 ! The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203312444495