1. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA
- Author
-
Zhao, Jian, Giles, Brendan M., Taylor, Rhonda L., Yette, Gabriel A., Lough, Kara M., Han Leng, Ng, Abraham, Lawrence J., Hui, Wu, Kelly, Jennifer A., Glenn, Stuart B., Adler, Adam J., Williams, Adrienne H., Comeau, Mary E., Ziegler, Julie T., Marion, Miranda, Alarcón Riquelme, Marta E., Alarcón, Graciela S., Anaya, Juan Manuel, Bae, Sang Cheol, Kim, Dam, Lee, Hye Soon, Criswell, Lindsey A., Freedman, Barry I., Gilkeson, Gary S., Guthridge, Joel M., Jacob, Chaim O., James, Judith A., Kamen, Diane L., Merrill, Joan T., Sivils, Kathy Moser, Niewold, Timothy B., Petri, Michelle A., Ramsey Goldman, Rosalind, Reveille, John D., Scofield, R. Hal, Stevens, Anne M., Vilá, Luis M., Vyse, Timothy J., Kaufman, Kenneth M., Harley, John B., Langefeld, Carl D., Gaffney, Patrick M., Brown, Elizabeth E., Edberg, Jeffrey C., Kimberly, Robert P., Ulgiati, Daniela, Tsao, Betty P., Boackle, Susan A., Frostegård, Johan, Truedsson, Lennart, De Ramón, Enrique, Sabio, José M., González Escribano, María F., Martin, Javier, Ortego Centeno, Norberto, Callejas, José Luis, Sánchez Román, Julio, D'Alfonso, Sandra, Migliarese, Sergio, Sebastiani, Gian Domenico, Galeazzi, Mauro, Witte, Torsten, Lauwerys, Bernard R., Endreffy, Emoke, Kovács, László, Vasconcelos, Carlos, Da Silva, Berta Martins, Scherbarth, R., Marino, Pilar C., Motta, Estela L., Gamron, Susana, Drenkard, Cristina, Menso, Emilia, Allievi, Alberto, Tate, Guillermo A., Presas, Jose L., Palatnik, Simon A., Abdala, Marcelo, Bearzotti, Mariela, Alvarellos, Alejandro, Caeiro, Francisco, Bertoli, Ana, Paira, Sergio, Roverano, Susana, Graf, Cesar E., Bertero, Estela, Caprarulo, Cesar, Buchanan, Griselda, Guillerón, Carolina, Grimaudo, Sebastian, Manni, Jorge, Catoggio, Luis J., Soriano, Enrique R., Santos, Carlos D., Prigione, Cristina, Ramos, Fernando A., Navarro, Sandra M., Berbotto, Guillermo A., Jorfen, Marisa, Romero, Elisa J., Garcia, Mercedes A., Marcos, Juan C., Marcos, Ana I., Perandones, Carlos E., Eimon, Alicia, Parque, Sanatorio, Battagliotti, Cristina G., Acevedo, Eduardo, Cucho, Mariano, De La Torre, Ignacio García, Ríos, Mario Cardiel, Moctezuma, José Francisco, and Ceceña, Marco Maradiaga more...
- Subjects
Genetics and Molecular Biology (all) ,CR1 protein, human ,Anti-nuclear antibody ,Intron ,Pathogenesis ,Complement receptor ,Real time polymerase chain reaction ,Procedures ,Biochemistry ,Haplotype ,Basic and Translational Research ,Systemic lupus erythematosus ,Messenger RNA ,3. Good health ,Blood ,Human ,Genotype ,Immunology ,Case control study ,B-Lymphocyte Subsets ,Single-nucleotide polymorphism ,Major clinical study ,Biosynthesis ,Risk Assessment ,Article ,General Biochemistry, Genetics and Molecular Biology ,Double stranded DNA antibody ,03 medical and health sciences ,Gene Polymorphism ,Rheumatology ,Genetics ,Humans ,Polymorphism ,Autoantibodies ,B cells ,Genetic predisposition ,Systemic ,Genetic Variation ,DNA ,medicine.disease ,030104 developmental biology ,Case-Control Studies ,Receptors, Complement 3b ,Receptors, Complement 3d ,Complement component C3b receptor ,Transcription factor ,Transcription Factors ,0301 basic medicine ,Unclassified drug ,Complement receptor 2 ,Systemic Lupus Erythematosus ,Adolescent ,Adult ,Antibodies, Antinuclear ,Genetic Predisposition to Disease ,Haplotypes ,Lupus Erythematosus, Systemic ,Middle Aged ,Phenotype ,Polymorphism, Single Nucleotide ,Young Adult ,Immunology and Allergy ,Medicine (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Complement receptor 1 ,Antinuclear ,Receptors ,Flow cytometry ,Middle aged ,Priority journal ,Risk assessment ,Allele ,biology ,Single Nucleotide ,Complement component C3d receptor ,Chromatin immunoprecipitation ,Transcription factor CTCF ,Antibodies ,DNA protein complex ,Antinuclear antibody ,medicine ,Genetic variation ,Lupus erythematosus ,B lymphocyte ,Lupus Erythematosus ,Complement 3d ,Complement 3b ,Molecular biology ,Single nucleotide polymorphism ,Minor allele frequency ,Metabolism ,Genetic association ,Genetic variability ,Gel mobility shift assay ,biology.gene ,Controlled study - 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. more...
- Published
- 2016
- Full Text
- View/download PDF