The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I...
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| Format: | Online |
| Language: | English |
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Public Library of Science
2013
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553151/ |
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pubmed-35531512013-01-31 The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis Carmona, F. David Martin, Jose-Ezequiel Beretta, Lorenzo Simeón, Carmen P. Carreira, Patricia E. Callejas, José Luis Fernández-Castro, Mónica Sáez-Comet, Luis Beltrán, Emma Camps, María Teresa Egurbide, María Victoria Airó, Paolo Scorza, Raffaella Lunardi, Claudio Hunzelmann, Nicolas Riemekasten, Gabriela Witte, Torsten Kreuter, Alexander Distler, Jörg H. W. Madhok, Rajan Shiels, Paul van Laar, Jacob M. Fonseca, Carmen Denton, Christopher Herrick, Ariane Worthington, Jane Schuerwegh, Annemie J. Vonk, Madelon C. Voskuyl, Alexandre E. Radstake, Timothy R. D. J. Martín, Javier Research Article Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10−8, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10−7, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10−20, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10−22, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific. Public Library of Science 2013-01-23 /pmc/articles/PMC3553151/ /pubmed/23372721 http://dx.doi.org/10.1371/journal.pone.0054419 Text en © 2013 Carmona et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Carmona, F. David Martin, Jose-Ezequiel Beretta, Lorenzo Simeón, Carmen P. Carreira, Patricia E. Callejas, José Luis Fernández-Castro, Mónica Sáez-Comet, Luis Beltrán, Emma Camps, María Teresa Egurbide, María Victoria Airó, Paolo Scorza, Raffaella Lunardi, Claudio Hunzelmann, Nicolas Riemekasten, Gabriela Witte, Torsten Kreuter, Alexander Distler, Jörg H. W. Madhok, Rajan Shiels, Paul van Laar, Jacob M. Fonseca, Carmen Denton, Christopher Herrick, Ariane Worthington, Jane Schuerwegh, Annemie J. Vonk, Madelon C. Voskuyl, Alexandre E. Radstake, Timothy R. D. J. Martín, Javier |
| spellingShingle |
Carmona, F. David Martin, Jose-Ezequiel Beretta, Lorenzo Simeón, Carmen P. Carreira, Patricia E. Callejas, José Luis Fernández-Castro, Mónica Sáez-Comet, Luis Beltrán, Emma Camps, María Teresa Egurbide, María Victoria Airó, Paolo Scorza, Raffaella Lunardi, Claudio Hunzelmann, Nicolas Riemekasten, Gabriela Witte, Torsten Kreuter, Alexander Distler, Jörg H. W. Madhok, Rajan Shiels, Paul van Laar, Jacob M. Fonseca, Carmen Denton, Christopher Herrick, Ariane Worthington, Jane Schuerwegh, Annemie J. Vonk, Madelon C. Voskuyl, Alexandre E. Radstake, Timothy R. D. J. Martín, Javier The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| author_facet |
Carmona, F. David Martin, Jose-Ezequiel Beretta, Lorenzo Simeón, Carmen P. Carreira, Patricia E. Callejas, José Luis Fernández-Castro, Mónica Sáez-Comet, Luis Beltrán, Emma Camps, María Teresa Egurbide, María Victoria Airó, Paolo Scorza, Raffaella Lunardi, Claudio Hunzelmann, Nicolas Riemekasten, Gabriela Witte, Torsten Kreuter, Alexander Distler, Jörg H. W. Madhok, Rajan Shiels, Paul van Laar, Jacob M. Fonseca, Carmen Denton, Christopher Herrick, Ariane Worthington, Jane Schuerwegh, Annemie J. Vonk, Madelon C. Voskuyl, Alexandre E. Radstake, Timothy R. D. J. Martín, Javier |
| author_sort |
Carmona, F. David |
| title |
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| title_short |
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| title_full |
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| title_fullStr |
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| title_full_unstemmed |
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis |
| title_sort |
systemic lupus erythematosus irf5 risk haplotype is associated with systemic sclerosis |
| description |
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10−8, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10−7, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10−20, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10−22, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific. |
| publisher |
Public Library of Science |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553151/ |
| _version_ |
1611949119525355520 |