Michel W P Tsang-A-Sjoe1, Sietse Q Nagelkerke2, Irene E M Bultink3, Judy Geissler2, Michael W T Tanck4, Carline E Tacke5, Justine A Ellis6, Werner Zenz7, Marc Bijl8, Johannes H Berden9, Karina de Leeuw10, Ronald H Derksen11, Taco W Kuijpers12, Alexandre E Voskuyl3. 1. Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center, m.tsangasjoe@vumc.nl. 2. Sanquin Research, and Landsteiner Laboratory, University of Amsterdam. 3. Department of Rheumatology, Amsterdam Rheumatology and immunology Center, VU University Medical Center. 4. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center. 5. Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Department of Paediatrics, University of Melbourne, VIC, Australia. 7. Department of General Paediatrics, Medical University of Graz, Austria. 8. Department of Internal Medicine and Rheumatology, Martini Hospital, Groningen. 9. Division of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen. 10. Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen and. 11. Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. 12. Sanquin Research, and Landsteiner Laboratory, University of Amsterdam, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.
OBJECTIVE: To determine relevant Fc-gamma receptor (FcγR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcγRII and FcγRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLEpatients and 919 healthy Caucasian controls. Expression of FcγRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (including FCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23), FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype of FCGR2B (OR 1.59; 95% CI: 1.13, 2.24), but not FCGR2C open reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcγRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcγRII and FcγRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcγRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcγRs in the pathogenesis of SLE and LN.
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