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PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese

Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation...

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Autores principales: Sun, Bao, Cheng, Lin, Xiong, Yan, Hu, Lei, Luo, Zhiying, Zhou, Maosong, Li, Ji, Xie, Hongfu, He, Fazhong, Yuan, Xiaoqing, Chen, Xiaoping, Zhou, Hong-Hao, Liu, Zhaoqian, Chen, Xiang, Zhang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776094/
https://www.ncbi.nlm.nih.gov/pubmed/29387007
http://dx.doi.org/10.3389/fphar.2017.00923
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author Sun, Bao
Cheng, Lin
Xiong, Yan
Hu, Lei
Luo, Zhiying
Zhou, Maosong
Li, Ji
Xie, Hongfu
He, Fazhong
Yuan, Xiaoqing
Chen, Xiaoping
Zhou, Hong-Hao
Liu, Zhaoqian
Chen, Xiang
Zhang, Wei
author_facet Sun, Bao
Cheng, Lin
Xiong, Yan
Hu, Lei
Luo, Zhiying
Zhou, Maosong
Li, Ji
Xie, Hongfu
He, Fazhong
Yuan, Xiaoqing
Chen, Xiaoping
Zhou, Hong-Hao
Liu, Zhaoqian
Chen, Xiang
Zhang, Wei
author_sort Sun, Bao
collection PubMed
description Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune diseases. However, the potential role of aberrant DNA methylation in allopurinol-SCARs is largely unknown. Objective: To address the knowledge gap between allopurinol-SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from allopurinol-SCARs and allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with allopurinol-SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched allopurinol-tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (cytosine-guanine dinucleotide) sites in an independent cohort of 40 allopurinol-SCARs and 48 allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between allopurinol-SCARs and allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 × 10(−13)), and SCARs and controls (P = 5.93 × 10(−15)). Conclusions: Our data identified differentially methylated genes between allopurinol-SCARs and allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with allopurinol-SCARs (OR = 30.22, 95%CI = 4.73–192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of allopurinol-SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease-associated changes of epigenome precede disease onset, or result from the disease progression, needs further investigation. Comparing the methylation status before patients develop allopurinol-SCARs and after may help examine methylation levels from disease onset to disease progression.
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spelling pubmed-57760942018-01-31 PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese Sun, Bao Cheng, Lin Xiong, Yan Hu, Lei Luo, Zhiying Zhou, Maosong Li, Ji Xie, Hongfu He, Fazhong Yuan, Xiaoqing Chen, Xiaoping Zhou, Hong-Hao Liu, Zhaoqian Chen, Xiang Zhang, Wei Front Pharmacol Pharmacology Background: Allopurinol-induced severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are life-threatening autoimmune reactions. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune diseases. However, the potential role of aberrant DNA methylation in allopurinol-SCARs is largely unknown. Objective: To address the knowledge gap between allopurinol-SCARs and DNA methylation, we studied the DNA methylation profiles in peripheral blood cells from allopurinol-SCARs and allopurinol-tolerant subjects. Methods: A genome-scale DNA methylation profiling was conducted using the Illumina Infinium HumanMethylation450 (HM450) platform on 15 patients with allopurinol-SCARs (3 TEN, 2 SJS/TEN overlap and 10 SJS) and 20 age- and gender-matched allopurinol-tolerant controls at disease onset. Pyrosequencing was used to validate the candidate CpG (cytosine-guanine dinucleotide) sites in an independent cohort of 40 allopurinol-SCARs and 48 allopurinol-tolerants. Results: After bioinformatics analysis of methylation data obtained from HM450 BeadChip, we identified 41 differentially methylated CpG loci (P < 0.05) annotated to 26 genes showing altered DNA methylation between allopurinol-SCARs and allopurinol-tolerants. Among these genes, significant hypomethylation of PSORS1C1 (cg24926791) was further validated in a larger sample cohort, showing significant difference between DRESS and controls (P = 0.00127), ST (SJS and TEN) and controls (P = 3.75 × 10(−13)), and SCARs and controls (P = 5.93 × 10(−15)). Conclusions: Our data identified differentially methylated genes between allopurinol-SCARs and allopurinol-tolerant controls and showed that PSORS1C1 hypomethylation was associated with allopurinol-SCARs (OR = 30.22, 95%CI = 4.73–192.96) during disease onset, suggesting that aberrant DNA methylation may be a mechanism of allopurinol-SCARs. Limitations: Firstly, the data come from whole blood samples known to possess epigenetic heterogeneity, i. e., blood samples comprise a heterogeneous cell population with varying proportions of distinct cell-types with different DNA methylation patterns. Consequently, the interpretation of DNA methylation results should be performed with great caution due to the heterogeneous nature of the sample. Secondly, whether the identified disease-associated changes of epigenome precede disease onset, or result from the disease progression, needs further investigation. Comparing the methylation status before patients develop allopurinol-SCARs and after may help examine methylation levels from disease onset to disease progression. Frontiers Media S.A. 2018-01-17 /pmc/articles/PMC5776094/ /pubmed/29387007 http://dx.doi.org/10.3389/fphar.2017.00923 Text en Copyright © 2018 Sun, Cheng, Xiong, Hu, Luo, Zhou, Li, Xie, He, Yuan, Chen, Zhou, Liu, Chen and Zhang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sun, Bao
Cheng, Lin
Xiong, Yan
Hu, Lei
Luo, Zhiying
Zhou, Maosong
Li, Ji
Xie, Hongfu
He, Fazhong
Yuan, Xiaoqing
Chen, Xiaoping
Zhou, Hong-Hao
Liu, Zhaoqian
Chen, Xiang
Zhang, Wei
PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title_full PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title_fullStr PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title_full_unstemmed PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title_short PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han Chinese
title_sort psors1c1 hypomethylation is associated with allopurinol-induced severe cutaneous adverse reactions during disease onset period: a multicenter retrospective case-control clinical study in han chinese
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776094/
https://www.ncbi.nlm.nih.gov/pubmed/29387007
http://dx.doi.org/10.3389/fphar.2017.00923
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