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Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant
Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976328/ https://www.ncbi.nlm.nih.gov/pubmed/24334606 http://dx.doi.org/10.1093/hmg/ddt619 |
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author | Almeida, Rodrigo Ricaño-Ponce, Isis Kumar, Vinod Deelen, Patrick Szperl, Agata Trynka, Gosia Gutierrez-Achury, Javier Kanterakis, Alexandros Westra, Harm-Jan Franke, Lude Swertz, Morris A. Platteel, Mathieu Bilbao, Jose Ramon Barisani, Donatella Greco, Luigi Mearin, Luisa Wolters, Victorien M. Mulder, Chris Mazzilli, Maria Cristina Sood, Ajit Cukrowska, Bozena Núñez, Concepción Pratesi, Riccardo Withoff, Sebo Wijmenga, Cisca |
author_facet | Almeida, Rodrigo Ricaño-Ponce, Isis Kumar, Vinod Deelen, Patrick Szperl, Agata Trynka, Gosia Gutierrez-Achury, Javier Kanterakis, Alexandros Westra, Harm-Jan Franke, Lude Swertz, Morris A. Platteel, Mathieu Bilbao, Jose Ramon Barisani, Donatella Greco, Luigi Mearin, Luisa Wolters, Victorien M. Mulder, Chris Mazzilli, Maria Cristina Sood, Ajit Cukrowska, Bozena Núñez, Concepción Pratesi, Riccardo Withoff, Sebo Wijmenga, Cisca |
author_sort | Almeida, Rodrigo |
collection | PubMed |
description | Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P = 1.79 × 10(−49)), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P < 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P = 1.35 × 10(−44)). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P = 3.12 × 10(−49)), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD. |
format | Online Article Text |
id | pubmed-3976328 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39763282014-04-07 Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant Almeida, Rodrigo Ricaño-Ponce, Isis Kumar, Vinod Deelen, Patrick Szperl, Agata Trynka, Gosia Gutierrez-Achury, Javier Kanterakis, Alexandros Westra, Harm-Jan Franke, Lude Swertz, Morris A. Platteel, Mathieu Bilbao, Jose Ramon Barisani, Donatella Greco, Luigi Mearin, Luisa Wolters, Victorien M. Mulder, Chris Mazzilli, Maria Cristina Sood, Ajit Cukrowska, Bozena Núñez, Concepción Pratesi, Riccardo Withoff, Sebo Wijmenga, Cisca Hum Mol Genet Association Studies Articles Using the Immunochip for genotyping, we identified 39 non-human leukocyte antigen (non-HLA) loci associated to celiac disease (CeD), an immune-mediated disease with a worldwide frequency of ∼1%. The most significant non-HLA signal mapped to the intronic region of 70 kb in the LPP gene. Our aim was to fine map and identify possible functional variants in the LPP locus. We performed a meta-analysis in a cohort of 25 169 individuals from six different populations previously genotyped using Immunochip. Imputation using data from the Genome of the Netherlands and 1000 Genomes projects, followed by meta-analysis, confirmed the strong association signal on the LPP locus (rs2030519, P = 1.79 × 10(−49)), without any novel associations. The conditional analysis on this top SNP-indicated association to a single common haplotype. By performing haplotype analyses in each population separately, as well as in a combined group of the four populations that reach the significant threshold after correction (P < 0.008), we narrowed down the CeD-associated region from 70 to 2.8 kb (P = 1.35 × 10(−44)). By intersecting regulatory data from the ENCODE project, we found a functional SNP, rs4686484 (P = 3.12 × 10(−49)), that maps to several B-cell enhancer elements and a highly conserved region. This SNP was also predicted to change the binding motif of the transcription factors IRF4, IRF11, Nkx2.7 and Nkx2.9, suggesting its role in transcriptional regulation. We later found significantly low levels of LPP mRNA in CeD biopsies compared with controls, thus our results suggest that rs4686484 is the functional variant in this locus, while LPP expression is decreased in CeD. Oxford University Press 2014-05-01 2013-12-11 /pmc/articles/PMC3976328/ /pubmed/24334606 http://dx.doi.org/10.1093/hmg/ddt619 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Association Studies Articles Almeida, Rodrigo Ricaño-Ponce, Isis Kumar, Vinod Deelen, Patrick Szperl, Agata Trynka, Gosia Gutierrez-Achury, Javier Kanterakis, Alexandros Westra, Harm-Jan Franke, Lude Swertz, Morris A. Platteel, Mathieu Bilbao, Jose Ramon Barisani, Donatella Greco, Luigi Mearin, Luisa Wolters, Victorien M. Mulder, Chris Mazzilli, Maria Cristina Sood, Ajit Cukrowska, Bozena Núñez, Concepción Pratesi, Riccardo Withoff, Sebo Wijmenga, Cisca Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title | Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title_full | Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title_fullStr | Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title_full_unstemmed | Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title_short | Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant |
title_sort | fine mapping of the celiac disease-associated lpp locus reveals a potential functional variant |
topic | Association Studies Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976328/ https://www.ncbi.nlm.nih.gov/pubmed/24334606 http://dx.doi.org/10.1093/hmg/ddt619 |
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