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

Jian Zhao, Brendan M. Giles, Rhonda L. 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

Resultado de la investigación: Contribución a RevistaArtículo

2 Citas (Scopus)

Resumen

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. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.
Idioma originalEnglish (US)
PublicaciónAnnals of the Rheumatic Diseases
DOI
EstadoPublished - sep 1 2014

Huella dactilar

Complement 3d Receptors
Electrophoretic mobility
Alleles
Association reactions
Autoantibodies
Chromatin
Antibodies
Assays
DNA
Cells
Chromatin Immunoprecipitation
Complement Receptors
Electrophoretic Mobility Shift Assay
Nuclear Antigens
Messenger RNA
Proteins
Flow cytometry
Gene expression
B-Lymphocytes
Introns

Citar esto

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. / Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. En: Annals of the Rheumatic Diseases. 2014.
@article{be8c7106d7b6450487e6782c729d06a8,
title = "Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA",
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. {\circledC} 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.",
author = "Jian Zhao and Giles, {Brendan M.} and Taylor, {Rhonda L.} and Yette, {Gabriel A.} and Lough, {Kara M.} and Ng, {Han Leng} and Abraham, {Lawrence J.} and Hui Wu and Kelly, {Jennifer A.} and Glenn, {Stuart B.} and Adler, {Adam J.} and Williams, {Adrienne H.} and Comeau, {Mary E.} and Ziegler, {Julie T.} and Miranda Marion and Alarc{\'o}n-Riquelme, {Marta E.} and Alarc{\'o}n, {Graciela S.} and Anaya, {Juan Manuel} and Bae, {Sang Cheol} and Dam Kim and Lee, {Hye Soon} and Criswell, {Lindsey A.} and Freedman, {Barry I.} and Gilkeson, {Gary S.} and Guthridge, {Joel M.} and Jacob, {Chaim O.} and James, {Judith A.} and Kamen, {Diane L.} and Merrill, {Joan T.} and Sivils, {Kathy Moser} and Niewold, {Timothy B.} and Petri, {Michelle A.} and Rosalind Ramsey-Goldman and Reveille, {John D.} and Scofield, {R. Hal} and Stevens, {Anne M.} and Vil{\'a}, {Luis M.} and Vyse, {Timothy J.} and Kaufman, {Kenneth M.} and Harley, {John B.} and Langefeld, {Carl D.} and Gaffney, {Patrick M.} and Brown, {Elizabeth E.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Daniela Ulgiati and Tsao, {Betty P.} and Boackle, {Susan A.}",
year = "2014",
month = "9",
day = "1",
doi = "10.1136/annrheumdis-2014-205584",
language = "English (US)",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",

}

Zhao, J, Giles, BM, Taylor, RL, Yette, GA, Lough, KM, Ng, HL, Abraham, LJ, Wu, H, Kelly, JA, Glenn, SB, Adler, AJ, Williams, AH, Comeau, ME, Ziegler, JT, Marion, M, Alarcón-Riquelme, ME, Alarcón, GS, Anaya, JM, Bae, SC, Kim, D, Lee, HS, Criswell, LA, Freedman, BI, Gilkeson, GS, Guthridge, JM, Jacob, CO, James, JA, Kamen, DL, Merrill, JT, Sivils, KM, Niewold, TB, Petri, MA, Ramsey-Goldman, R, Reveille, JD, Scofield, RH, Stevens, AM, Vilá, LM, Vyse, TJ, Kaufman, KM, Harley, JB, Langefeld, CD, Gaffney, PM, Brown, EE, Edberg, JC, Kimberly, RP, Ulgiati, D, Tsao, BP & Boackle, SA 2014, 'Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2014-205584

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.

En: Annals of the Rheumatic Diseases, 01.09.2014.

Resultado de la investigación: Contribución a RevistaArtículo

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.

PY - 2014/9/1

Y1 - 2014/9/1

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. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.

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. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.

U2 - 10.1136/annrheumdis-2014-205584

DO - 10.1136/annrheumdis-2014-205584

M3 - Article

C2 - 25180293

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -