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 language | English (US) |
|---|---|
| Pages (from-to) | 242-252 |
| Number of pages | 11 |
| Journal | Annals of the Rheumatic Diseases |
| Volume | 75 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
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ASJC Scopus subject areas
- Rheumatology
- Immunology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Allergy
Cite this
Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. / Zhao, Jian; Giles, Brendan M.; Taylor, Rhonda L.; Yette, Gabriel A.; Lough, Kara M.; Ng, Han Leng; Abraham, Lawrence J.; Wu, Hui; 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; Ceceña, Marco Maradiaga.
In: Annals of the Rheumatic Diseases, Vol. 75, No. 1, 01.01.2016, p. 242-252.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA
AU - Zhao, Jian
AU - Giles, Brendan M.
AU - Taylor, Rhonda L.
AU - Yette, Gabriel A.
AU - Lough, Kara M.
AU - Ng, Han Leng
AU - Abraham, Lawrence J.
AU - Wu, Hui
AU - Kelly, Jennifer A.
AU - Glenn, Stuart B.
AU - Adler, Adam J.
AU - Williams, Adrienne H.
AU - Comeau, Mary E.
AU - Ziegler, Julie T.
AU - Marion, Miranda
AU - Alarcón-Riquelme, Marta E.
AU - Alarcón, Graciela S.
AU - Anaya, Juan Manuel
AU - Bae, Sang Cheol
AU - Kim, Dam
AU - Lee, Hye Soon
AU - Criswell, Lindsey A.
AU - Freedman, Barry I.
AU - Gilkeson, Gary S.
AU - Guthridge, Joel M.
AU - Jacob, Chaim O.
AU - James, Judith A.
AU - Kamen, Diane L.
AU - Merrill, Joan T.
AU - Sivils, Kathy Moser
AU - Niewold, Timothy B.
AU - Petri, Michelle A.
AU - Ramsey-Goldman, Rosalind
AU - Reveille, John D.
AU - Scofield, R. Hal
AU - Stevens, Anne M.
AU - Vilá, Luis M.
AU - Vyse, Timothy J.
AU - Kaufman, Kenneth M.
AU - Harley, John B.
AU - Langefeld, Carl D.
AU - Gaffney, Patrick M.
AU - Brown, Elizabeth E.
AU - Edberg, Jeffrey C.
AU - Kimberly, Robert P.
AU - Ulgiati, Daniela
AU - Tsao, Betty P.
AU - Boackle, Susan A.
AU - Frostegård, Johan
AU - Truedsson, Lennart
AU - De Ramón, Enrique
AU - Sabio, José M.
AU - González-Escribano, María F.
AU - Martin, Javier
AU - Ortego-Centeno, Norberto
AU - Callejas, José Luis
AU - Sánchez-Román, Julio
AU - D'Alfonso, Sandra
AU - Migliarese, Sergio
AU - Sebastiani, Gian Domenico
AU - Galeazzi, Mauro
AU - Witte, Torsten
AU - Lauwerys, Bernard R.
AU - Endreffy, Emoke
AU - Kovács, László
AU - Vasconcelos, Carlos
AU - Da Silva, Berta Martins
AU - Scherbarth, R.
AU - Marino, Pilar C.
AU - Motta, Estela L.
AU - Gamron, Susana
AU - Drenkard, Cristina
AU - Menso, Emilia
AU - Allievi, Alberto
AU - Tate, Guillermo A.
AU - Presas, Jose L.
AU - Palatnik, Simon A.
AU - Abdala, Marcelo
AU - Bearzotti, Mariela
AU - Alvarellos, Alejandro
AU - Caeiro, Francisco
AU - Bertoli, Ana
AU - Paira, Sergio
AU - Roverano, Susana
AU - Graf, Cesar E.
AU - Bertero, Estela
AU - Caprarulo, Cesar
AU - Buchanan, Griselda
AU - Guillerón, Carolina
AU - Grimaudo, Sebastian
AU - Manni, Jorge
AU - Catoggio, Luis J.
AU - Soriano, Enrique R.
AU - Santos, Carlos D.
AU - Prigione, Cristina
AU - Ramos, Fernando A.
AU - Navarro, Sandra M.
AU - Berbotto, Guillermo A.
AU - Jorfen, Marisa
AU - Romero, Elisa J.
AU - Garcia, Mercedes A.
AU - Marcos, Juan C.
AU - Marcos, Ana I.
AU - Perandones, Carlos E.
AU - Eimon, Alicia
AU - Parque, Sanatorio
AU - Battagliotti, Cristina G.
AU - Acevedo, Eduardo
AU - Cucho, Mariano
AU - De La Torre, Ignacio García
AU - Ríos, Mario Cardiel
AU - Moctezuma, José Francisco
AU - Ceceña, Marco Maradiaga
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954322451&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954322451&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2014-205584
DO - 10.1136/annrheumdis-2014-205584
M3 - Article
C2 - 25180293
AN - SCOPUS:84954322451
VL - 75
SP - 242
EP - 252
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 1
ER -