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Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy

Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family membe...

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Autores principales: Sun, Yonghu, Irwanto, Astrid, Toyo-oka, Licht, Hong, Myunghee, Liu, Hong, Andiappan, Anand Kumar, Choi, Hyunchul, Hitomi, Yuki, Yu, Gongqi, Yu, Yongxiang, Bao, Fangfang, Wang, Chuan, Fu, Xian, Yue, Zhenhua, Wang, Honglei, Zhang, Huimin, Kawashima, Minae, Kojima, Kaname, Nagasaki, Masao, Nakamura, Minoru, Yang, Suk-Kyun, Ye, Byong Duk, Denise, Yosua, Rotzschke, Olaf, Song, Kyuyoung, Tokunaga, Katsushi, Zhang, Furen, Liu, Jianjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979016/
https://www.ncbi.nlm.nih.gov/pubmed/27507062
http://dx.doi.org/10.1038/srep31429
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author Sun, Yonghu
Irwanto, Astrid
Toyo-oka, Licht
Hong, Myunghee
Liu, Hong
Andiappan, Anand Kumar
Choi, Hyunchul
Hitomi, Yuki
Yu, Gongqi
Yu, Yongxiang
Bao, Fangfang
Wang, Chuan
Fu, Xian
Yue, Zhenhua
Wang, Honglei
Zhang, Huimin
Kawashima, Minae
Kojima, Kaname
Nagasaki, Masao
Nakamura, Minoru
Yang, Suk-Kyun
Ye, Byong Duk
Denise, Yosua
Rotzschke, Olaf
Song, Kyuyoung
Tokunaga, Katsushi
Zhang, Furen
Liu, Jianjun
author_facet Sun, Yonghu
Irwanto, Astrid
Toyo-oka, Licht
Hong, Myunghee
Liu, Hong
Andiappan, Anand Kumar
Choi, Hyunchul
Hitomi, Yuki
Yu, Gongqi
Yu, Yongxiang
Bao, Fangfang
Wang, Chuan
Fu, Xian
Yue, Zhenhua
Wang, Honglei
Zhang, Huimin
Kawashima, Minae
Kojima, Kaname
Nagasaki, Masao
Nakamura, Minoru
Yang, Suk-Kyun
Ye, Byong Duk
Denise, Yosua
Rotzschke, Olaf
Song, Kyuyoung
Tokunaga, Katsushi
Zhang, Furen
Liu, Jianjun
author_sort Sun, Yonghu
collection PubMed
description Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.
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spelling pubmed-49790162016-08-19 Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy Sun, Yonghu Irwanto, Astrid Toyo-oka, Licht Hong, Myunghee Liu, Hong Andiappan, Anand Kumar Choi, Hyunchul Hitomi, Yuki Yu, Gongqi Yu, Yongxiang Bao, Fangfang Wang, Chuan Fu, Xian Yue, Zhenhua Wang, Honglei Zhang, Huimin Kawashima, Minae Kojima, Kaname Nagasaki, Masao Nakamura, Minoru Yang, Suk-Kyun Ye, Byong Duk Denise, Yosua Rotzschke, Olaf Song, Kyuyoung Tokunaga, Katsushi Zhang, Furen Liu, Jianjun Sci Rep Article Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC. Nature Publishing Group 2016-08-10 /pmc/articles/PMC4979016/ /pubmed/27507062 http://dx.doi.org/10.1038/srep31429 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Sun, Yonghu
Irwanto, Astrid
Toyo-oka, Licht
Hong, Myunghee
Liu, Hong
Andiappan, Anand Kumar
Choi, Hyunchul
Hitomi, Yuki
Yu, Gongqi
Yu, Yongxiang
Bao, Fangfang
Wang, Chuan
Fu, Xian
Yue, Zhenhua
Wang, Honglei
Zhang, Huimin
Kawashima, Minae
Kojima, Kaname
Nagasaki, Masao
Nakamura, Minoru
Yang, Suk-Kyun
Ye, Byong Duk
Denise, Yosua
Rotzschke, Olaf
Song, Kyuyoung
Tokunaga, Katsushi
Zhang, Furen
Liu, Jianjun
Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title_full Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title_fullStr Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title_full_unstemmed Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title_short Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn’s disease and leprosy
title_sort fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of tnfsf15 in primary biliary cholangitis, crohn’s disease and leprosy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979016/
https://www.ncbi.nlm.nih.gov/pubmed/27507062
http://dx.doi.org/10.1038/srep31429
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