دورية أكاديمية
An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element.
العنوان: | An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element. |
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المؤلفون: | Alex Clop, Anna Bertoni, Sarah L Spain, Michael A Simpson, Venu Pullabhatla, Raul Tonda, Christian Hundhausen, Paola Di Meglio, Pieter De Jong, Adrian C Hayday, Frank O Nestle, Jonathan N Barker, Robert J A Bell, Francesca Capon, Richard C Trembath |
المصدر: | PLoS ONE, Vol 8, Iss 8, p e71690 (2013) |
بيانات النشر: | Public Library of Science (PLoS), 2013. |
سنة النشر: | 2013 |
المجموعة: | LCC:Medicine LCC:Science |
مصطلحات موضوعية: | Medicine, Science |
الوصف: | Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS) have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC) locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1932-6203 |
Relation: | http://europepmc.org/articles/PMC3747202?pdf=render; https://doaj.org/toc/1932-6203 |
DOI: | 10.1371/journal.pone.0071690 |
URL الوصول: | https://doaj.org/article/41f8eada9fa3444ea06ae7240d5786c7 |
رقم الأكسشن: | edsdoj.41f8eada9fa3444ea06ae7240d5786c7 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 19326203 |
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DOI: | 10.1371/journal.pone.0071690 |