DNA methylation of ITGB2 contributes to allopurinol hypersensitivity

Liu Y 1 , Wang CW 2 , Chen CB 3 , Yu KH 4 , Wu YJ 5 , Choon SE 6 Show all authors , Chang WC 7 , Yang F 8 , Luo XQ 8 , Chung WH 9 , Zhao M 10 , Lu QJ 11

Affiliations 

  • 1 Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
  • 2 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan China; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan China; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, China; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
  • 3 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan China; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan China; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, China; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan China; College of Medicine, Chang Gung University, Taoyuan, Taiwan China
  • 4 College of Medicine, Chang Gung University, Taoyuan, Taiwan China; Division of Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan China
  • 5 College of Medicine, Chang Gung University, Taoyuan, Taiwan China; Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung and Linkou, Taiwan China
  • 6 Hospital Sultanah Aminah, Clinical School Johor Bahru, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Malaysia
  • 7 Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada
  • 8 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
  • 9 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan China; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan China; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, China; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan China; College of Medicine, Chang Gung University, Taoyuan, Taiwan China; Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan China; Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China; School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan China. Electronic address: wenhungchung@yahoo.com
  • 10 Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: zhaoming307@csu.edu.cn
  • 11 Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China; Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, China. Electronic address: qianlu5860@pumcderm.cams.cn
Clin Immunol, 2023 Mar;248:109250.
PMID: 36738816 DOI: 10.1016/j.clim.2023.109250

Abstract

BACKGROUNDS: HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR.

OBJECTIVE: To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing.

STUDY DESIGN: The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021.

RESULTS: The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083).

CONCLUSIONS: Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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