Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

Sergey V. Kozyrev; Susanna Lewén; Prasad M.V.Linga Reddy; Bernardo Pons-Estel; Torsten Witte; Peter Junker; Helle Laustrup; Carmen Gutiérrez; Ana Suárez; Maria Francisca González-Escribano; Javier Martín; Marta E. Alarcón-Riquelme; 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; K. Armadi-Simab; Wolfgang L. Gross; Erika Gromnica-IhIe; Hans Hartmut Peter; Karin Manger; Sebastian Schnarr; Henning Zeidler; Reinhold E. Schmidt; Norberto Ortego; Enrique De Ramón; Juan Jiménez-Alonso; Julio Sánchez-Román; Miguel Ángel López-Nevot

doi:10.1002/art.22497

Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

Sergey V. Kozyrev, Susanna Lewén, Prasad M.V.Linga Reddy, Bernardo Pons-Estel, Torsten Witte, Peter Junker, Helle Laustrup, Carmen Gutiérrez, Ana Suárez, Maria Francisca González-Escribano, Javier Martín, Marta E. Alarcón-Riquelme^*, Hugo R. Scherbarth, Pilar C. Marino, Estela L. Motta, Susana Gamron, Cristina Drenkard, Emilia Menso, Alberto Allievi, Guillermo A. TateJose 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, K. Armadi-Simab, Wolfgang L. Gross, Erika Gromnica-IhIe, Hans Hartmut Peter, Karin Manger, Sebastian Schnarr, Henning Zeidler, Reinhold E. Schmidt, Norberto Ortego, Enrique De Ramón, Juan Jiménez-Alonso, Julio Sánchez-Román, Miguel Ángel López-Nevot

^*Corresponding author for this work

Clinic of Rheumatology

80 Citations (Scopus)

Abstract

Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 ^-11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.

Original language	English
Journal	Arthritis and Rheumatism
Volume	56
Issue number	4
Pages (from-to)	1234-1241
Number of pages	8
ISSN	0004-3591
DOIs	https://doi.org/10.1002/art.22497
Publication status	Published - 04.2007

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Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1002/art.22497

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Kozyrev, S. V., Lewén, S., Reddy, P. M. V. L., Pons-Estel, B., Witte, T., Junker, P., Laustrup, H., Gutiérrez, C., Suárez, A., González-Escribano, M. F., Martín, J., Alarcón-Riquelme, M. E., Scherbarth, H. R., Marino, P. C., Motta, E. L., Gamron, S., Drenkard, C., Menso, E., Allievi, A., ... López-Nevot, M. Á. (2007). Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis and Rheumatism, 56(4), 1234-1241. https://doi.org/10.1002/art.22497

@article{704bd8e14ae64bd08ea46ac4ed9bbc12,

title = "Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus",

abstract = "Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.",

author = "Kozyrev, {Sergey V.} and Susanna Lew{\'e}n and Reddy, {Prasad M.V.Linga} and Bernardo Pons-Estel and Torsten Witte and Peter Junker and Helle Laustrup and Carmen Guti{\'e}rrez and Ana Su{\'a}rez and Gonz{\'a}lez-Escribano, {Maria Francisca} and Javier Mart{\'i}n and Alarc{\'o}n-Riquelme, {Marta E.} 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 K. Armadi-Simab and Gross, {Wolfgang L.} and Erika Gromnica-IhIe and Peter, {Hans Hartmut} and Karin Manger and Sebastian Schnarr and Henning Zeidler and Schmidt, {Reinhold E.} and Norberto Ortego and {De Ram{\'o}n}, Enrique and Juan Jim{\'e}nez-Alonso and Julio S{\'a}nchez-Rom{\'a}n and L{\'o}pez-Nevot, {Miguel {\'A}ngel}",

year = "2007",

month = apr,

doi = "10.1002/art.22497",

language = "English",

volume = "56",

pages = "1234--1241",

journal = "Arthritis and Rheumatism",

issn = "0004-3591",

number = "4",

}

Kozyrev, SV, Lewén, S, Reddy, PMVL, Pons-Estel, B, Witte, T, Junker, P, Laustrup, H, Gutiérrez, C, Suárez, A, González-Escribano, MF, Martín, J, Alarcón-Riquelme, ME, 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, Armadi-Simab, K, Gross, WL, Gromnica-IhIe, E, Peter, HH, Manger, K, Schnarr, S, Zeidler, H, Schmidt, RE, Ortego, N, De Ramón, E, Jiménez-Alonso, J, Sánchez-Román, J & López-Nevot, MÁ 2007, 'Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus', Arthritis and Rheumatism, vol. 56, no. 4, pp. 1234-1241. https://doi.org/10.1002/art.22497

Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. / Kozyrev, Sergey V.; Lewén, Susanna; Reddy, Prasad M.V.Linga et al.
In: Arthritis and Rheumatism, Vol. 56, No. 4, 04.2007, p. 1234-1241.

Research output: Journal Articles › Journal articles › Research › peer-review

TY - JOUR

T1 - Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

AU - Kozyrev, Sergey V.

AU - Lewén, Susanna

AU - Reddy, Prasad M.V.Linga

AU - Pons-Estel, Bernardo

AU - Witte, Torsten

AU - Junker, Peter

AU - Laustrup, Helle

AU - Gutiérrez, Carmen

AU - Suárez, Ana

AU - González-Escribano, Maria Francisca

AU - Martín, Javier

AU - Alarcón-Riquelme, Marta E.

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 - Armadi-Simab, K.

AU - Gross, Wolfgang L.

AU - Gromnica-IhIe, Erika

AU - Peter, Hans Hartmut

AU - Manger, Karin

AU - Schnarr, Sebastian

AU - Zeidler, Henning

AU - Schmidt, Reinhold E.

AU - Ortego, Norberto

AU - De Ramón, Enrique

AU - Jiménez-Alonso, Juan

AU - Sánchez-Román, Julio

AU - López-Nevot, Miguel Ángel

PY - 2007/4

Y1 - 2007/4

N2 - Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.

AB - Objective. To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. Methods. Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. Results. Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5′-untranslated regions (5′-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5′-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-α. The SNP most strongly associated with SLE was SNP no. rs2070197 (P = 5.2 × 10 -11), which is a proxy of the risk haplotype, but does not appear to be functional. Conclusion. None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.

UR - http://www.scopus.com/inward/record.url?scp=34247254495&partnerID=8YFLogxK

U2 - 10.1002/art.22497

DO - 10.1002/art.22497

M3 - Journal articles

C2 - 17393452

AN - SCOPUS:34247254495

SN - 0004-3591

VL - 56

SP - 1234

EP - 1241

JO - Arthritis and Rheumatism

JF - Arthritis and Rheumatism

IS - 4

ER -

Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

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