PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites
Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phen...
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| Veröffentlicht in: | PloS one 2012-12, Vol.7 (12), p.e52873-e52873 |
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| creator | Glas, Jürgen Seiderer, Julia Czamara, Darina Pasciuto, Giulia Diegelmann, Julia Wetzke, Martin Olszak, Torsten Wolf, Christiane Müller-Myhsok, Bertram Balschun, Tobias Achkar, Jean-Paul Kamboh, M Ilyas Franke, Andre Duerr, Richard H Brand, Stephan |
| description | Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.
A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility. |
| doi_str_mv | 10.1371/journal.pone.0052873 |
| format | Article |
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A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0052873</identifier><identifier>PMID: 23300802</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Asthma ; Binding Sites ; Biology ; Child ; Chromosome 5 ; Chromosomes ; Chromosomes, Human, Pair 5 - genetics ; Crohn Disease - genetics ; Crohn's disease ; Crohns disease ; Dentistry ; DNA-Binding Proteins - metabolism ; Epistasis ; Epistasis, Genetic ; Female ; Gastroenterology ; Gene Expression ; Gene Frequency ; Genes ; Genetic Predisposition to Disease ; Genetics ; Genomes ; Genomics ; Hepatology ; Hospitals ; Humans ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Intestine ; Male ; Medicine ; Middle Aged ; Molecular biology ; NF-kappa B - metabolism ; NF-κB protein ; Pathogenesis ; Patients ; Polymorphism, Single Nucleotide ; Population ; Psychiatry ; Public health ; Receptors, Prostaglandin E, EP4 Subtype - genetics ; Receptors, Prostaglandin E, EP4 Subtype - metabolism ; Regulatory Factor X Transcription Factors ; Replication ; Rodents ; Sequence Analysis, DNA ; Single-nucleotide polymorphism ; Studies ; Susceptibility ; Transcription factors ; Transcription Factors - metabolism ; Ulcerative colitis ; X-Box Binding Protein 1 ; Young Adult</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e52873-e52873</ispartof><rights>2012 Glas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Glas et al 2012 Glas et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-cacc719d60ed6d2b688618a397d04a6b28adb218918bd2613c5126f0868073a43</citedby><cites>FETCH-LOGICAL-c526t-cacc719d60ed6d2b688618a397d04a6b28adb218918bd2613c5126f0868073a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531335/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531335/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2097,2916,23848,27906,27907,53773,53775,79350,79351</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23300802$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yao, Yong-Gang</contributor><creatorcontrib>Glas, Jürgen</creatorcontrib><creatorcontrib>Seiderer, Julia</creatorcontrib><creatorcontrib>Czamara, Darina</creatorcontrib><creatorcontrib>Pasciuto, Giulia</creatorcontrib><creatorcontrib>Diegelmann, Julia</creatorcontrib><creatorcontrib>Wetzke, Martin</creatorcontrib><creatorcontrib>Olszak, Torsten</creatorcontrib><creatorcontrib>Wolf, Christiane</creatorcontrib><creatorcontrib>Müller-Myhsok, Bertram</creatorcontrib><creatorcontrib>Balschun, Tobias</creatorcontrib><creatorcontrib>Achkar, Jean-Paul</creatorcontrib><creatorcontrib>Kamboh, M Ilyas</creatorcontrib><creatorcontrib>Franke, Andre</creatorcontrib><creatorcontrib>Duerr, Richard H</creatorcontrib><creatorcontrib>Brand, Stephan</creatorcontrib><title>PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.
A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Asthma</subject><subject>Binding Sites</subject><subject>Biology</subject><subject>Child</subject><subject>Chromosome 5</subject><subject>Chromosomes</subject><subject>Chromosomes, Human, Pair 5 - genetics</subject><subject>Crohn Disease - genetics</subject><subject>Crohn's disease</subject><subject>Crohns disease</subject><subject>Dentistry</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Epistasis</subject><subject>Epistasis, Genetic</subject><subject>Female</subject><subject>Gastroenterology</subject><subject>Gene Expression</subject><subject>Gene Frequency</subject><subject>Genes</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Hepatology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Inflammatory bowel disease</subject><subject>Inflammatory bowel diseases</subject><subject>Intestine</subject><subject>Male</subject><subject>Medicine</subject><subject>Middle Aged</subject><subject>Molecular biology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Population</subject><subject>Psychiatry</subject><subject>Public health</subject><subject>Receptors, Prostaglandin E, EP4 Subtype - genetics</subject><subject>Receptors, Prostaglandin E, EP4 Subtype - metabolism</subject><subject>Regulatory Factor X Transcription Factors</subject><subject>Replication</subject><subject>Rodents</subject><subject>Sequence Analysis, DNA</subject><subject>Single-nucleotide polymorphism</subject><subject>Studies</subject><subject>Susceptibility</subject><subject>Transcription factors</subject><subject>Transcription Factors - metabolism</subject><subject>Ulcerative colitis</subject><subject>X-Box Binding Protein 1</subject><subject>Young 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one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Glas, Jürgen</au><au>Seiderer, Julia</au><au>Czamara, Darina</au><au>Pasciuto, Giulia</au><au>Diegelmann, Julia</au><au>Wetzke, Martin</au><au>Olszak, Torsten</au><au>Wolf, Christiane</au><au>Müller-Myhsok, Bertram</au><au>Balschun, Tobias</au><au>Achkar, Jean-Paul</au><au>Kamboh, M Ilyas</au><au>Franke, Andre</au><au>Duerr, Richard H</au><au>Brand, Stephan</au><au>Yao, Yong-Gang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-27</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e52873</spage><epage>e52873</epage><pages>e52873-e52873</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes.
A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD.
We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23300802</pmid><doi>10.1371/journal.pone.0052873</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-12, Vol.7 (12), p.e52873-e52873 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1327225395 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adolescent Adult Aged Aged, 80 and over Asthma Binding Sites Biology Child Chromosome 5 Chromosomes Chromosomes, Human, Pair 5 - genetics Crohn Disease - genetics Crohn's disease Crohns disease Dentistry DNA-Binding Proteins - metabolism Epistasis Epistasis, Genetic Female Gastroenterology Gene Expression Gene Frequency Genes Genetic Predisposition to Disease Genetics Genomes Genomics Hepatology Hospitals Humans Inflammatory bowel disease Inflammatory bowel diseases Intestine Male Medicine Middle Aged Molecular biology NF-kappa B - metabolism NF-κB protein Pathogenesis Patients Polymorphism, Single Nucleotide Population Psychiatry Public health Receptors, Prostaglandin E, EP4 Subtype - genetics Receptors, Prostaglandin E, EP4 Subtype - metabolism Regulatory Factor X Transcription Factors Replication Rodents Sequence Analysis, DNA Single-nucleotide polymorphism Studies Susceptibility Transcription factors Transcription Factors - metabolism Ulcerative colitis X-Box Binding Protein 1 Young Adult |
| title | PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites |
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