STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk

A. K. Abelson, A. M. Delgado-Vega, S. V. Kozyrev, E. Sánchez, R. Velázquez-Cruz, N. Eriksson, J. Wojcik, M. V P Linga Reddy, G. Lima, S. D'Alfonso, S. Migliaresi, V. Baca, L. Orozco, T. Witte, N. Ortego-Centeno, H. Abderrahim, B. A. Pons-Estel, C. Gutiérrez, A. Suárez, M. F. González-Escribano & 11 others J. Martin, M. E. Alarcón-Riquelme, José L. Callejas-Rubio, Juan Jiménez-Alonso, Mario Sabio, Julio Sánchez-Román, Francisco J. García-Hernández, Enrique De-Ramon, Mayte Camps, Rosa García-Portales, Miguel A. López-Nevot

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 59-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

Original languageEnglish
Pages (from-to)1746-1753
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume68
Issue number11
DOIs
Publication statusPublished - 1 Nov 2009
Externally publishedYes

Fingerprint

Gene expression
Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
Genes
Tissue
Gene Expression
Transcription
Regression analysis
Exons
Complementary DNA
Testing
Haplotypes
Regression Analysis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Abelson, A. K., Delgado-Vega, A. M., Kozyrev, S. V., Sánchez, E., Velázquez-Cruz, R., Eriksson, N., ... López-Nevot, M. A. (2009). STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Annals of the Rheumatic Diseases, 68(11), 1746-1753. https://doi.org/10.1136/ard.2008.097642

STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. / Abelson, A. K.; Delgado-Vega, A. M.; Kozyrev, S. V.; Sánchez, E.; Velázquez-Cruz, R.; Eriksson, N.; Wojcik, J.; Linga Reddy, M. V P; Lima, G.; D'Alfonso, S.; Migliaresi, S.; Baca, V.; Orozco, L.; Witte, T.; Ortego-Centeno, N.; Abderrahim, H.; Pons-Estel, B. A.; Gutiérrez, C.; Suárez, A.; González-Escribano, M. F.; Martin, J.; Alarcón-Riquelme, M. E.; Callejas-Rubio, José L.; Jiménez-Alonso, Juan; Sabio, Mario; Sánchez-Román, Julio; García-Hernández, Francisco J.; De-Ramon, Enrique; Camps, Mayte; García-Portales, Rosa; López-Nevot, Miguel A.

In: Annals of the Rheumatic Diseases, Vol. 68, No. 11, 01.11.2009, p. 1746-1753.

Research output: Contribution to journalArticle

Abelson, AK, Delgado-Vega, AM, Kozyrev, SV, Sánchez, E, Velázquez-Cruz, R, Eriksson, N, Wojcik, J, Linga Reddy, MVP, Lima, G, D'Alfonso, S, Migliaresi, S, Baca, V, Orozco, L, Witte, T, Ortego-Centeno, N, Abderrahim, H, Pons-Estel, BA, Gutiérrez, C, Suárez, A, González-Escribano, MF, Martin, J, Alarcón-Riquelme, ME, Callejas-Rubio, JL, Jiménez-Alonso, J, Sabio, M, Sánchez-Román, J, García-Hernández, FJ, De-Ramon, E, Camps, M, García-Portales, R & López-Nevot, MA 2009, 'STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk', Annals of the Rheumatic Diseases, vol. 68, no. 11, pp. 1746-1753. https://doi.org/10.1136/ard.2008.097642
Abelson, A. K. ; Delgado-Vega, A. M. ; Kozyrev, S. V. ; Sánchez, E. ; Velázquez-Cruz, R. ; Eriksson, N. ; Wojcik, J. ; Linga Reddy, M. V P ; Lima, G. ; D'Alfonso, S. ; Migliaresi, S. ; Baca, V. ; Orozco, L. ; Witte, T. ; Ortego-Centeno, N. ; Abderrahim, H. ; Pons-Estel, B. A. ; Gutiérrez, C. ; Suárez, A. ; González-Escribano, M. F. ; Martin, J. ; Alarcón-Riquelme, M. E. ; Callejas-Rubio, José L. ; Jiménez-Alonso, Juan ; Sabio, Mario ; Sánchez-Román, Julio ; García-Hernández, Francisco J. ; De-Ramon, Enrique ; Camps, Mayte ; García-Portales, Rosa ; López-Nevot, Miguel A. / STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. In: Annals of the Rheumatic Diseases. 2009 ; Vol. 68, No. 11. pp. 1746-1753.
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title = "STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk",
abstract = "Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 59-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.",
author = "Abelson, {A. K.} and Delgado-Vega, {A. M.} and Kozyrev, {S. V.} and E. S{\'a}nchez and R. Vel{\'a}zquez-Cruz and N. Eriksson and J. Wojcik and {Linga Reddy}, {M. V P} and G. Lima and S. D'Alfonso and S. Migliaresi and V. Baca and L. Orozco and T. Witte and N. Ortego-Centeno and H. Abderrahim and Pons-Estel, {B. A.} and C. Guti{\'e}rrez and A. Su{\'a}rez and Gonz{\'a}lez-Escribano, {M. F.} and J. Martin and Alarc{\'o}n-Riquelme, {M. E.} and Callejas-Rubio, {Jos{\'e} L.} and Juan Jim{\'e}nez-Alonso and Mario Sabio and Julio S{\'a}nchez-Rom{\'a}n and Garc{\'i}a-Hern{\'a}ndez, {Francisco J.} and Enrique De-Ramon and Mayte Camps and Rosa Garc{\'i}a-Portales and L{\'o}pez-Nevot, {Miguel A.}",
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T1 - STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk

AU - Abelson, A. K.

AU - Delgado-Vega, A. M.

AU - Kozyrev, S. V.

AU - Sánchez, E.

AU - Velázquez-Cruz, R.

AU - Eriksson, N.

AU - Wojcik, J.

AU - Linga Reddy, M. V P

AU - Lima, G.

AU - D'Alfonso, S.

AU - Migliaresi, S.

AU - Baca, V.

AU - Orozco, L.

AU - Witte, T.

AU - Ortego-Centeno, N.

AU - Abderrahim, H.

AU - Pons-Estel, B. A.

AU - Gutiérrez, C.

AU - Suárez, A.

AU - González-Escribano, M. F.

AU - Martin, J.

AU - Alarcón-Riquelme, M. E.

AU - Callejas-Rubio, José L.

AU - Jiménez-Alonso, Juan

AU - Sabio, Mario

AU - Sánchez-Román, Julio

AU - García-Hernández, Francisco J.

AU - De-Ramon, Enrique

AU - Camps, Mayte

AU - García-Portales, Rosa

AU - López-Nevot, Miguel A.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 59-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

AB - Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 59-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

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DO - 10.1136/ard.2008.097642

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