Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

Elena Sánchez; Rogelio J. Palomino-Morales; Norberto Ortego-Centeno; Juan Jiménez-Alonso; Miguel A. González-Gay; Miguel A. López-Nevot; Julio Sánchez-Román; Enrique de Ramón; M. Francisca González-Escribano; Bernardo A. Pons-Estel; Sandra D'Alfonso; Gian Domenico Sebastiani; Marta E. Alarcón-Riquelme; Javier Martín; 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; Nadia Barizzone; Mauro Galeazzi; Maria Giovanna Danieli; Sergio Migliaresi; Enrica Bozzolo

doi:10.1093/hmg/ddp301

Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

Elena Sánchez, Rogelio J. Palomino-Morales, Norberto Ortego-Centeno, Juan Jiménez-Alonso, Miguel A. González-Gay, Miguel A. López-Nevot, Julio Sánchez-Román, Enrique de Ramón, M. Francisca González-Escribano, Bernardo A. Pons-Estel, Sandra D'Alfonso, Gian Domenico Sebastiani, Marta E. Alarcón-Riquelme, Javier Martín, Hugo R. Scherbarth, Pilar C. Marino, Estela L. Motta, Susana Gamron, Cristina Drenkard, Emilia MensoAlberto 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, Nadia Barizzone, Mauro Galeazzi, Maria Giovanna Danieli, Sergio Migliaresi, Enrica Bozzolo

Dipartimento di Scienze della Salute

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

Abstract

Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR 5 1.37, 95% CI 1.21-1.54, combined P 5 3.8E-07, Pc 5 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.

Lingua originale	Inglese
pagine (da-a)	3739-3748
Numero di pagine	10
Rivista	Human Molecular Genetics
Volume	18
Numero di pubblicazione	19
DOI	https://doi.org/10.1093/hmg/ddp301
Stato di pubblicazione	Pubblicato - 1 ott 2009

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10.1093/hmg/ddp301

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Sánchez, E., Palomino-Morales, R. J., Ortego-Centeno, N., Jiménez-Alonso, J., González-Gay, M. A., López-Nevot, M. A., Sánchez-Román, J., de Ramón, E., González-Escribano, M. F., Pons-Estel, B. A., D'Alfonso, S., Sebastiani, G. D., Alarcón-Riquelme, M. E., Martín, J., Scherbarth, H. R., Marino, P. C., Motta, E. L., Gamron, S., Drenkard, C., ... Bozzolo, E. (2009). Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus. Human Molecular Genetics, 18(19), 3739-3748. https://doi.org/10.1093/hmg/ddp301

@article{98556a46a99840c993f9d66fe0c07ce1,

title = "Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus",

abstract = "Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR 5 1.37, 95% CI 1.21-1.54, combined P 5 3.8E-07, Pc 5 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.",

author = "Elena S{\'a}nchez and Palomino-Morales, {Rogelio J.} and Norberto Ortego-Centeno and Juan Jim{\'e}nez-Alonso and Gonz{\'a}lez-Gay, {Miguel A.} and L{\'o}pez-Nevot, {Miguel A.} and Julio S{\'a}nchez-Rom{\'a}n and {de Ram{\'o}n}, Enrique and Gonz{\'a}lez-Escribano, {M. Francisca} and Pons-Estel, {Bernardo A.} and Sandra D'Alfonso and Sebastiani, {Gian Domenico} and Alarc{\'o}n-Riquelme, {Marta E.} and Javier Mart{\'i}n 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.} and Nadia Barizzone and Mauro Galeazzi and Danieli, {Maria Giovanna} and Sergio Migliaresi and Enrica Bozzolo",

year = "2009",

month = oct,

day = "1",

doi = "10.1093/hmg/ddp301",

language = "English",

volume = "18",

pages = "3739--3748",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

}

Sánchez, E, Palomino-Morales, RJ, Ortego-Centeno, N, Jiménez-Alonso, J, González-Gay, MA, López-Nevot, MA, Sánchez-Román, J, de Ramón, E, González-Escribano, MF, Pons-Estel, BA, D'Alfonso, S, Sebastiani, GD, Alarcón-Riquelme, ME, Martín, J, 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, Barizzone, N, Galeazzi, M, Danieli, MG, Migliaresi, S & Bozzolo, E 2009, 'Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus', Human Molecular Genetics, vol. 18, n. 19, pagg. 3739-3748. https://doi.org/10.1093/hmg/ddp301

TY - JOUR

T1 - Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

AU - Sánchez, Elena

AU - Palomino-Morales, Rogelio J.

AU - Ortego-Centeno, Norberto

AU - Jiménez-Alonso, Juan

AU - González-Gay, Miguel A.

AU - López-Nevot, Miguel A.

AU - Sánchez-Román, Julio

AU - de Ramón, Enrique

AU - González-Escribano, M. Francisca

AU - Pons-Estel, Bernardo A.

AU - D'Alfonso, Sandra

AU - Sebastiani, Gian Domenico

AU - Alarcón-Riquelme, Marta E.

AU - Martín, Javier

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.

AU - Barizzone, Nadia

AU - Galeazzi, Mauro

AU - Danieli, Maria Giovanna

AU - Migliaresi, Sergio

AU - Bozzolo, Enrica

PY - 2009/10/1

Y1 - 2009/10/1

N2 - Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR 5 1.37, 95% CI 1.21-1.54, combined P 5 3.8E-07, Pc 5 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.

AB - Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in chronic inflammation and autoimmune disorders. In this study, we aimed to determine the potential role of the IL18 gene in SLE. To define the genetic association of the IL18 and SLE, we have genotyped nine SNPs in an independent set of Spanish cases and controls. The IL18 polymorphisms were genotyped by PCR, using a predeveloped TaqMan allele discrimination assay. Two SNPs were still significant after fine mapping of the IL18 gene. The SNP (rs360719) surviving correction for multiple tests was genotyped in two replication cohorts from Italy and Argentina. After the analysis, a significance with rs360719 C-allele remained across the sets and after the meta-analysis (Pooled OR 5 1.37, 95% CI 1.21-1.54, combined P 5 3.8E-07, Pc 5 1.16E-06). Quantitative real-time PCR was performed to assess IL18 mRNA expression in PBMC from subjects with different IL18 rs360719 genotypes. We tested the effect of the IL18 rs360719 polymorphism on the transcription of IL18 by electrophoretic mobility shift assay and western blot. We found a significant increase in the relative expression of IL18 mRNA in individuals carrying the rs360719 C-risk allele; in addition we show that the polymorphism creates a binding site for the transcriptional factor OCT-1. These findings suggest that the novel IL18 rs360719 variant may play an important role in determining the susceptibility to SLE and it could be a key factor in the expression of the IL18 gene.

UR - http://www.scopus.com/inward/record.url?scp=70350755715&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp301

DO - 10.1093/hmg/ddp301

M3 - Article

SN - 0964-6906

VL - 18

SP - 3739

EP - 3748

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 19

ER -

Identification of a new putative functional IL18 gene variant through an association study in systemic lupus erythematosus

Abstract

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