Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

Jian Zhao, Brendan M. Giles, Rhonda Taylor, Gabriel A. Yette, Kara M. Lough, Han Leng Ng, Lawrence J. Abraham, Hui Wu, Jennifer A. Kelly, Stuart B. Glenn, Adam J. Adler, Adrienne H. Williams, Mary E. Comeau, Julie T. Ziegler, Miranda Marion, Marta E. Alarcón-Riquelme, Graciela S. Alarcón, Juan Manuel Anaya, Sang Cheol Bae, Dam KimHye Soon Lee, Lindsey A. Criswell, Barry I. Freedman, Gary S. Gilkeson, Joel M. Guthridge, Chaim O. Jacob, Judith A. James, Diane L. Kamen, Joan T. Merrill, Kathy Moser Sivils, Timothy B. Niewold, Michelle A. Petri, Rosalind Ramsey-Goldman, John D. Reveille, R. Hal Scofield, Anne M. Stevens, Luis M. Vilá, Timothy J. Vyse, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Patrick M. Gaffney, Elizabeth E. Brown, Jeffrey C. Edberg, Robert P. Kimberly, Daniela Ulgiati, Betty P. Tsao, Susan A. Boackle, Johan Frostegård, Lennart Truedsson, Enrique De Ramón, José M. Sabio, María F. González-Escribano, Javier Martin, Norberto Ortego-Centeno, José Luis Callejas, Julio Sánchez-Román, Sandra D'Alfonso, Sergio Migliarese, Gian Domenico Sebastiani, Mauro Galeazzi, Torsten Witte, Bernard R. Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins Da Silva, R. Scherbarth, Pilar C. Marino, Estela L. Motta, Susana Gamron, Cristina Drenkard, Emilia Menso, Alberto Allievi, Guillermo A. Tate, Jose L. Presas, Simon A. Palatnik, Marcelo Abdala, Mariela Bearzotti, Alejandro Alvarellos, Francisco Caeiro, Ana Bertoli, Sergio Paira, Susana Roverano, Cesar E. Graf, Estela Bertero, Cesar Caprarulo, Griselda Buchanan, Carolina Guillerón, Sebastian Grimaudo, Jorge Manni, Luis J. Catoggio, Enrique R. Soriano, Carlos D. Santos, Cristina Prigione, Fernando A. Ramos, Sandra M. Navarro, Guillermo A. Berbotto, Marisa Jorfen, Elisa J. Romero, Mercedes A. Garcia, Juan C. Marcos, Ana I. Marcos, Carlos E. Perandones, Alicia Eimon, Sanatorio Parque, Cristina G. Battagliotti, Eduardo Acevedo, Mariano Cucho, Ignacio García De La Torre, Mario Cardiel Ríos, José Francisco Moctezuma, Marco Maradiaga Ceceña, BIOLUPUS and GENLES Networks

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4 Citations (Scopus)

Abstract

Objectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10-4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10-7, OR 0.71; case-only pmeta=1.9×10-4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.

Original languageEnglish
Pages (from-to)242-252
Number of pages11
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number1
DOIs
Publication statusPublished - 2014

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