Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Daisuke Sakurai, Jian Zhao, Yun Deng, Jennifer A. Kelly, Elizabeth E. Brown, John B. Harley, Sang Cheol Bae, Marta E. Alarcn-Riquelme, Jeffrey C. Edberg, Robert P. Kimberly, Rosalind Ramsey-Goldman, Michelle Petri, John D. Reveille, Luis M. Vilá, Graciela S. Alarcón, Kenneth M. Kaufman, Timothy J. Vyse, Chaim O. Jacob, Patrick M. Gaffney, Kathy Moser Sivils & 128 others Judith A. James, Diane L. Kamen, Gary S. Gilkeson, Timothy B. Niewold, Joan T. Merrill, R. Hal Scofield, Lindsey A. Criswell, Anne M. Stevens, Susan A. Boackle, Jae Hoon Kim, Jiyoung Choi, Bernardo A. Pons-Estel, Barry I. Freedman, Juan Manuel Anaya, Javier Martin, C. Yung Yu, Deh Ming Chang, Yeong Wook Song, Carl D. Langefeld, Weiling Chen, Jennifer M. Grossman, Rita M. Cantor, Bevra H. Hahn, Betty P. Tsao, Johan Frostegård, Lennart Truedsson, Enrique de Ramón, José M. Sabio, Javier Martin, Norberto Ortego-Centeno, José Luis CAllejas, María F. González-Escribano, 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, Hugo 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, Hugo 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, Cristina G. Battagliotti

Research output: Contribution to journalArticle

Abstract

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10-8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

Original languageEnglish (US)
Article numbere1003870
JournalPLoS Genetics
Volume9
Issue number10
DOIs
StatePublished - Oct 2013

Fingerprint

lupus erythematosus
elks
Systemic Lupus Erythematosus
Interleukin-10
allele
Up-Regulation
Alleles
alleles
ancestry
Single Nucleotide Polymorphism
interleukin-10
serum
inhibitor
blood
assay
mononuclear leukocytes
B-lymphocytes
protein
gene
ets-Domain Protein Elk-1

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Sakurai, D., Zhao, J., Deng, Y., Kelly, J. A., Brown, E. E., Harley, J. B., ... Battagliotti, C. G. (2013). Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression. PLoS Genetics, 9(10), [e1003870]. https://doi.org/10.1371/journal.pgen.1003870

Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression. / Sakurai, Daisuke; Zhao, Jian; Deng, Yun; Kelly, Jennifer A.; Brown, Elizabeth E.; Harley, John B.; Bae, Sang Cheol; Alarcn-Riquelme, Marta E.; Edberg, Jeffrey C.; Kimberly, Robert P.; Ramsey-Goldman, Rosalind; Petri, Michelle; Reveille, John D.; Vilá, Luis M.; Alarcón, Graciela S.; Kaufman, Kenneth M.; Vyse, Timothy J.; Jacob, Chaim O.; Gaffney, Patrick M.; Sivils, Kathy Moser; James, Judith A.; Kamen, Diane L.; Gilkeson, Gary S.; Niewold, Timothy B.; Merrill, Joan T.; Scofield, R. Hal; Criswell, Lindsey A.; Stevens, Anne M.; Boackle, Susan A.; Kim, Jae Hoon; Choi, Jiyoung; Pons-Estel, Bernardo A.; Freedman, Barry I.; Anaya, Juan Manuel; Martin, Javier; Yu, C. Yung; Chang, Deh Ming; Song, Yeong Wook; Langefeld, Carl D.; Chen, Weiling; Grossman, Jennifer M.; Cantor, Rita M.; Hahn, Bevra H.; Tsao, Betty P.; Frostegård, Johan; Truedsson, Lennart; de Ramón, Enrique; Sabio, José M.; Martin, Javier; Ortego-Centeno, Norberto; CAllejas, José Luis; González-Escribano, María F.; 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, Hugo 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; Scherbarth, Hugo 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; Battagliotti, Cristina G.

In: PLoS Genetics, Vol. 9, No. 10, e1003870, 10.2013.

Research output: Contribution to journalArticle

Sakurai, D, Zhao, J, Deng, Y, Kelly, JA, Brown, EE, Harley, JB, Bae, SC, Alarcn-Riquelme, ME, Edberg, JC, Kimberly, RP, Ramsey-Goldman, R, Petri, M, Reveille, JD, Vilá, LM, Alarcón, GS, Kaufman, KM, Vyse, TJ, Jacob, CO, Gaffney, PM, Sivils, KM, James, JA, Kamen, DL, Gilkeson, GS, Niewold, TB, Merrill, JT, Scofield, RH, Criswell, LA, Stevens, AM, Boackle, SA, Kim, JH, Choi, J, Pons-Estel, BA, Freedman, BI, Anaya, JM, Martin, J, Yu, CY, Chang, DM, Song, YW, Langefeld, CD, Chen, W, Grossman, JM, Cantor, RM, Hahn, BH, Tsao, BP, Frostegård, J, Truedsson, L, de Ramón, E, Sabio, JM, Martin, J, Ortego-Centeno, N, CAllejas, JL, González-Escribano, MF, Sánchez-Román, J, D'Alfonso, S, Migliarese, S, Sebastiani, GD, Galeazzi, M, Witte, T, Lauwerys, BR, Endreffy, E, Kovács, L, Vasconcelos, C, da Silva, BM, Scherbarth, HR, Marino, PC, Motta, EL, Gamron, S, Drenkard, C, Menso, E, Allievi, A, Tate, GA, Presas, JL, Palatnik, SA, Abdala, M, Bearzotti, M, Alvarellos, A, Caeiro, F, Bertoli, A, Paira, S, Roverano, S, Graf, CE, Bertero, E, Caprarulo, C, Buchanan, G, Guillerón, C, Grimaudo, S, Manni, J, Catoggio, LJ, Soriano, ER, Santos, CD, Prigione, C, Ramos, FA, Navarro, SM, Berbotto, GA, Jorfen, M, Romero, EJ, Garcia, MA, Marcos, JC, Marcos, AI, Perandones, CE, Eimon, A, Parque, S, Battagliotti, CG, Acevedo, E, Cucho, M, de la Torre, IG, Ríos, MC, Moctezuma, JF, Ceceña, MM, Scherbarth, HR, Marino, PC, Motta, EL, Gamron, S, Drenkard, C, Menso, E, Allievi, A, Tate, GA, Presas, JL, Palatnik, SA, Abdala, M, Bearzotti, M, Alvarellos, A, Caeiro, F, Bertoli, A, Paira, S, Roverano, S, Graf, CE, Bertero, E, Caprarulo, C, Buchanan, G, Guillerón, C, Grimaudo, S, Manni, J, Catoggio, LJ, Soriano, ER, Santos, CD, Prigione, C, Ramos, FA, Navarro, SM, Berbotto, GA, Jorfen, M, Romero, EJ, Garcia, MA, Marcos, JC, Marcos, AI, Perandones, CE, Eimon, A & Battagliotti, CG 2013, 'Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression', PLoS Genetics, vol. 9, no. 10, e1003870. https://doi.org/10.1371/journal.pgen.1003870
Sakurai, Daisuke ; Zhao, Jian ; Deng, Yun ; Kelly, Jennifer A. ; Brown, Elizabeth E. ; Harley, John B. ; Bae, Sang Cheol ; Alarcn-Riquelme, Marta E. ; Edberg, Jeffrey C. ; Kimberly, Robert P. ; Ramsey-Goldman, Rosalind ; Petri, Michelle ; Reveille, John D. ; Vilá, Luis M. ; Alarcón, Graciela S. ; Kaufman, Kenneth M. ; Vyse, Timothy J. ; Jacob, Chaim O. ; Gaffney, Patrick M. ; Sivils, Kathy Moser ; James, Judith A. ; Kamen, Diane L. ; Gilkeson, Gary S. ; Niewold, Timothy B. ; Merrill, Joan T. ; Scofield, R. Hal ; Criswell, Lindsey A. ; Stevens, Anne M. ; Boackle, Susan A. ; Kim, Jae Hoon ; Choi, Jiyoung ; Pons-Estel, Bernardo A. ; Freedman, Barry I. ; Anaya, Juan Manuel ; Martin, Javier ; Yu, C. Yung ; Chang, Deh Ming ; Song, Yeong Wook ; Langefeld, Carl D. ; Chen, Weiling ; Grossman, Jennifer M. ; Cantor, Rita M. ; Hahn, Bevra H. ; Tsao, Betty P. ; Frostegård, Johan ; Truedsson, Lennart ; de Ramón, Enrique ; Sabio, José M. ; Martin, Javier ; Ortego-Centeno, Norberto ; CAllejas, José Luis ; González-Escribano, María F. ; 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, Hugo 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 ; Scherbarth, Hugo 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 ; Battagliotti, Cristina G. / Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression. In: PLoS Genetics. 2013 ; Vol. 9, No. 10.
@article{7776e10953b44d2ab5ff11de513a9c83,
title = "Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression",
abstract = "Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10-8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.",
author = "Daisuke Sakurai and Jian Zhao and Yun Deng and Kelly, {Jennifer A.} and Brown, {Elizabeth E.} and Harley, {John B.} and Bae, {Sang Cheol} and Alarcn-Riquelme, {Marta E.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Rosalind Ramsey-Goldman and Michelle Petri and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Alarc{\'o}n, {Graciela S.} and Kaufman, {Kenneth M.} and Vyse, {Timothy J.} and Jacob, {Chaim O.} and Gaffney, {Patrick M.} and Sivils, {Kathy Moser} and James, {Judith A.} and Kamen, {Diane L.} and Gilkeson, {Gary S.} and Niewold, {Timothy B.} and Merrill, {Joan T.} and Scofield, {R. Hal} and Criswell, {Lindsey A.} and Stevens, {Anne M.} and Boackle, {Susan A.} and Kim, {Jae Hoon} and Jiyoung Choi and Pons-Estel, {Bernardo A.} and Freedman, {Barry I.} and Anaya, {Juan Manuel} and Javier Martin and Yu, {C. Yung} and Chang, {Deh Ming} and Song, {Yeong Wook} and Langefeld, {Carl D.} and Weiling Chen and Grossman, {Jennifer M.} and Cantor, {Rita M.} and Hahn, {Bevra H.} and Tsao, {Betty P.} and Johan Frosteg{\aa}rd and Lennart Truedsson and {de Ram{\'o}n}, Enrique and Sabio, {Jos{\'e} M.} and Javier Martin and Norberto Ortego-Centeno and CAllejas, {Jos{\'e} Luis} and Gonz{\'a}lez-Escribano, {Mar{\'i}a F.} and Julio S{\'a}nchez-Rom{\'a}n and Sandra D'Alfonso and Sergio Migliarese and Sebastiani, {Gian Domenico} and Mauro Galeazzi and Torsten Witte and Lauwerys, {Bernard R.} and Emoke Endreffy and L{\'a}szl{\'o} Kov{\'a}cs and Carlos Vasconcelos and {da Silva}, {Berta Martins} and Scherbarth, {Hugo R.} and Marino, {Pilar C.} and Motta, {Estela L.} and Susana Gamron and Cristina Drenkard and Emilia Menso and Alberto Allievi and Tate, {Guillermo A.} and Presas, {Jose L.} and Palatnik, {Simon A.} and Marcelo Abdala and Mariela Bearzotti and Alejandro Alvarellos and Francisco Caeiro and Ana Bertoli and Sergio Paira and Susana Roverano and Graf, {Cesar E.} and Estela Bertero and Cesar Caprarulo and Griselda Buchanan and Carolina Guiller{\'o}n and Sebastian Grimaudo and Jorge Manni and Catoggio, {Luis J.} and Soriano, {Enrique R.} and Santos, {Carlos D.} and Cristina Prigione and Ramos, {Fernando A.} and Navarro, {Sandra M.} and Berbotto, {Guillermo A.} and Marisa Jorfen and Romero, {Elisa J.} and Garcia, {Mercedes A.} and Marcos, {Juan C.} and Marcos, {Ana I.} and Perandones, {Carlos E.} and Alicia Eimon and Sanatorio Parque and Battagliotti, {Cristina G.} and Eduardo Acevedo and Mariano Cucho and {de la Torre}, {Ignacio Garc{\'i}a} and R{\'i}os, {Mario Cardiel} and Moctezuma, {Jos{\'e} Francisco} and Cece{\~n}a, {Marco Maradiaga} and Scherbarth, {Hugo R.} and Marino, {Pilar C.} and Motta, {Estela L.} and Susana Gamron and Cristina Drenkard and Emilia Menso and Alberto Allievi and Tate, {Guillermo A.} and Presas, {Jose L.} and Palatnik, {Simon A.} and Marcelo Abdala and Mariela Bearzotti and Alejandro Alvarellos and Francisco Caeiro and Ana Bertoli and Sergio Paira and Susana Roverano and Graf, {Cesar E.} and Estela Bertero and Cesar Caprarulo and Griselda Buchanan and Carolina Guiller{\'o}n and Sebastian Grimaudo and Jorge Manni and Catoggio, {Luis J.} and Soriano, {Enrique R.} and Santos, {Carlos D.} and Cristina Prigione and Ramos, {Fernando A.} and Navarro, {Sandra M.} and Berbotto, {Guillermo A.} and Marisa Jorfen and Romero, {Elisa J.} and Garcia, {Mercedes A.} and Marcos, {Juan C.} and Marcos, {Ana I.} and Perandones, {Carlos E.} and Alicia Eimon and Battagliotti, {Cristina G.}",
year = "2013",
month = "10",
doi = "10.1371/journal.pgen.1003870",
language = "English (US)",
volume = "9",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

AU - Sakurai, Daisuke

AU - Zhao, Jian

AU - Deng, Yun

AU - Kelly, Jennifer A.

AU - Brown, Elizabeth E.

AU - Harley, John B.

AU - Bae, Sang Cheol

AU - Alarcn-Riquelme, Marta E.

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

AU - Ramsey-Goldman, Rosalind

AU - Petri, Michelle

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Alarcón, Graciela S.

AU - Kaufman, Kenneth M.

AU - Vyse, Timothy J.

AU - Jacob, Chaim O.

AU - Gaffney, Patrick M.

AU - Sivils, Kathy Moser

AU - James, Judith A.

AU - Kamen, Diane L.

AU - Gilkeson, Gary S.

AU - Niewold, Timothy B.

AU - Merrill, Joan T.

AU - Scofield, R. Hal

AU - Criswell, Lindsey A.

AU - Stevens, Anne M.

AU - Boackle, Susan A.

AU - Kim, Jae Hoon

AU - Choi, Jiyoung

AU - Pons-Estel, Bernardo A.

AU - Freedman, Barry I.

AU - Anaya, Juan Manuel

AU - Martin, Javier

AU - Yu, C. Yung

AU - Chang, Deh Ming

AU - Song, Yeong Wook

AU - Langefeld, Carl D.

AU - Chen, Weiling

AU - Grossman, Jennifer M.

AU - Cantor, Rita M.

AU - Hahn, Bevra H.

AU - Tsao, Betty P.

AU - Frostegård, Johan

AU - Truedsson, Lennart

AU - de Ramón, Enrique

AU - Sabio, José M.

AU - Martin, Javier

AU - Ortego-Centeno, Norberto

AU - CAllejas, José Luis

AU - González-Escribano, María F.

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, Hugo 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

AU - Scherbarth, Hugo 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 - Battagliotti, Cristina G.

PY - 2013/10

Y1 - 2013/10

N2 - Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10-8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

AB - Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10-8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

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U2 - 10.1371/journal.pgen.1003870

DO - 10.1371/journal.pgen.1003870

M3 - Article

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 10

M1 - e1003870

ER -