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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Frontiers Media S.A.
2018-01-01
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Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00923/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bao Sun Bao Sun Lin Cheng Lin Cheng Yan Xiong Yan Xiong Lei Hu Zhiying Luo Zhiying Luo Maosong Zhou Ji Li Hongfu Xie Fazhong He Fazhong He Xiaoqing Yuan Xiaoqing Yuan Xiaoping Chen Xiaoping Chen Hong-Hao Zhou Hong-Hao Zhou Zhaoqian Liu Zhaoqian Liu Xiang Chen Xiang Chen Wei Zhang Wei Zhang |
spellingShingle |
Bao Sun Bao Sun Lin Cheng Lin Cheng Yan Xiong Yan Xiong Lei Hu Zhiying Luo Zhiying Luo Maosong Zhou Ji Li Hongfu Xie Fazhong He Fazhong He Xiaoqing Yuan Xiaoqing Yuan Xiaoping Chen Xiaoping Chen Hong-Hao Zhou Hong-Hao Zhou Zhaoqian Liu Zhaoqian Liu Xiang Chen Xiang Chen Wei Zhang Wei Zhang 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 Frontiers in Pharmacology allopurinol-SCARs DNA methylation HM450 methylated genes PSORS1C1 |
author_facet |
Bao Sun Bao Sun Lin Cheng Lin Cheng Yan Xiong Yan Xiong Lei Hu Zhiying Luo Zhiying Luo Maosong Zhou Ji Li Hongfu Xie Fazhong He Fazhong He Xiaoqing Yuan Xiaoqing Yuan Xiaoping Chen Xiaoping Chen Hong-Hao Zhou Hong-Hao Zhou Zhaoqian Liu Zhaoqian Liu Xiang Chen Xiang Chen Wei Zhang Wei Zhang |
author_sort |
Bao Sun |
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_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_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_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 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-01-01 |
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. |
topic |
allopurinol-SCARs DNA methylation HM450 methylated genes PSORS1C1 |
url |
http://journal.frontiersin.org/article/10.3389/fphar.2017.00923/full |
work_keys_str_mv |
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doaj-89df8056c5164b56a1616fc61122d29c2020-11-25T00:32:16ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-01-01810.3389/fphar.2017.00923284475PSORS1C1 Hypomethylation Is Associated with Allopurinol-Induced Severe Cutaneous Adverse Reactions during Disease Onset Period: A Multicenter Retrospective Case-Control Clinical Study in Han ChineseBao Sun0Bao Sun1Lin Cheng2Lin Cheng3Yan Xiong4Yan Xiong5Lei Hu6Zhiying Luo7Zhiying Luo8Maosong Zhou9Ji Li10Hongfu Xie11Fazhong He12Fazhong He13Xiaoqing Yuan14Xiaoqing Yuan15Xiaoping Chen16Xiaoping Chen17Hong-Hao Zhou18Hong-Hao Zhou19Zhaoqian Liu20Zhaoqian Liu21Xiang Chen22Xiang Chen23Wei Zhang24Wei Zhang25Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, ChinaShenzhen Eyeis Visual Science Research Institute, Shenzhen, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Pharmacy, Peking University People's Hospital, Beijing, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, ChinaHunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, ChinaBackground: 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.http://journal.frontiersin.org/article/10.3389/fphar.2017.00923/fullallopurinol-SCARsDNA methylationHM450methylated genesPSORS1C1 |