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A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10−4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

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Acknowledgements

We thank all individuals including the SLE patients and the controls who participated in this study. We are grateful to the research assistants, coordinators and physicians who helped in the recruitment of participants. We would like to express our gratitude to the following individuals for contributing samples genotyped in this study: S D'Alfonso (Italy), R Scorza (Italy), P Junker and H Laustrup (Denmark), M Bijl (Holland), E Endreffy (Hungary), C Vasconcelos and BM da Silva (Portugal), A Suarez and C Gutierrez (Spain), I Rúa-Figueroa (Spain) and C Garcilazo (Argentina); for the Asociación Andaluza de Enfermedades Autoimmunes (AADEA) collaboration: N Ortego-Centeno (Spain), J Jimenez-Alonso (Spain), E de Ramon (Spain) and J Sanchez-Roman (Spain); and for the collaboration on Hispanic populations enriched for Amerindian-European admixture: M Cardiel (Mexico), IG de la Torre (Mexico), M Maradiaga (Mexico), JF Moctezuma (Mexico), E Acevedo (Peru), C Castel and M Busajm (Argentina) and J Musuruana (Argentina). Other participants from the Argentine Collaborative Group are: HR Scherbarth, PC Marino, EL Motta, S Gamron, C Drenkard, E Menso, A Allievi, GA Tate, JL Presas, SA Palatnik, M Abdala, M Bearzotti, A Alvarellos, F Caeiro, A Bertoli, S Paira, S Roverano, CE Graf, E Bertero, C Guillerón, S Grimaudo, J Manni, LJ Catoggio, ER Soriano, CD Santos, C Prigione, FA Ramos, SM Navarro, GA Berbotto, M Jorfen, EJ Romero, MA Garcia, JC Marcos, AI Marcos, CE Perandones, A Eimon and CG Battagliotti. We thank PS Ramos and S Frank for their assistance in genotyping, quality control analyses and clinical data management and the staff of the Lupus Family Registry and Repository (LFRR) for collecting and maintaining SLE samples. Support for this work was obtained from the US National Institutes of Health Grants: R01 AI063274, R01 AR056360, P20 GM103456 (PMG); R01 AR043274 (KLM); N01 AR62277 (KLM and JBH); R37 24717, R01 AR042460, P01 AI083194, R01 DE018209 (JBH); P01 AR49084 (RPK, JCE and EEB); 5UL1 RR025777 (JCE); R01 AR33062 (RPK); P30 AR48311 (EEB); K08 AI083790, LRP AI071651, UL1 RR024999 (TBN); R01 CA141700, RC1 AR058621 (MEAR); R01 AR051545-01A2, ULI RR025014-02 (AMS); U19 AI082714, RC1 AR058554, P30 RR031152, P30 AR053483, N01 AI50026 (JAJ and JMG); R21 AI070304 (SAB); R01 AR43814 (BPT); P60 AR053308, M01 RR-00079 (LAC); R01 AR043727, UL1 RR025005 (MAP), K24 AR002138, P60 2 AR30692, P01 AR49084, UL1 RR025741 (RRG), 1U54 RR23417-01 (JDR), R01 AR043727, UL1 RR025005 (MAP), P60 AR049459 and UL1 RR029882 (DLK). Additional support was obtained from the Alliance for Lupus Research (KLM); Merit Award from the US Department of Veterans Affairs (JBH and GSG); the Swedish Research Council for Medicine, Gustaf Vth-80th Jubilee Fund and Swedish Association Against Rheumatism, Instituto de Salud Carlos III, Oklahoma Center for Advancement of Science and Technology (OCAST) HR09-106 (MEAR); the European Science Foundation funds the BIOLUPUS network (MEAR coordinator); the Barrett Scholarship Fund Oklahoma Medical Research Foundation (OMRF) (CJL); the Korea Healthcare Technology Research and Development Project, Ministry for Health and Welfare, Republic of Korea (A111218-11-GM01, SCB); Lupus Research Institute (TBN); The Alliance for Lupus Research (TBN, LAC and COJ); the Arthritis National Research Foundation Eng Tan Scholar Award (TBN); Arthritis Foundation (PMG and AMS); the Lupus Foundation of Minnesota (PMG and KLM); the Wellcome Trust (TJV); Arthritis Research UK (TJV); Kirkland Scholar Award (LAC); Wake Forest University Health Sciences Center for Public Health Genomics (CDL); and the Federico Wilhelm Agricola Foundation Research grant (BAPE). The work reported on in this publication has been in part financially supported by the ESF, in the framework of the Research Networking Programme European Science Foundation–The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS)' 07-RNP-083.

Author contributions: PMG, CGM, KLM, CJL, JAK, KMK, CDL and JBH selected SNPs and were responsible for the study design. JMG, MEAR, GSA, JMA, SCB, SAB, EEB, MAP, RRG, JDR, LMV, LAC, JCE, BIF, GSG, COJ, JAJ, DLK, RPK, JM, JTM, TBN, BAPE, AMS, BPT, LMV, TJV, JBH, KLM and PMG assisted in the collection and characterization of the SLE cases and controls. AA, KMK and PMG performed the genotyping. SBG, AW, JZ, MEC, MM, JAK, KMK and CDL performed genotyping quality control. IA, SW, GW, CJL, CGM and PMG performed association analyses and imputation. GW, BEW, CL, EKW, SW and PMG performed sequencing. GW, IA, SW, CJL, SBG, CGM and PMG performed sequencing data analysis. SW and PMG performed functional studies. SW, IA, GW, CGM and PMG. prepared the manuscript and all authors approved the final draft.

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Wang, S., Adrianto, I., Wiley, G. et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immun 13, 380–387 (2012). https://doi.org/10.1038/gene.2012.6

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