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HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis

The Pharmacogenomics Journal volume 14, pages 281–288 (2014)Cite this article

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Abstract

HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0–340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2–125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6–192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4–20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4–11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.

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Acknowledgements

The study was supported by the National Science Council (99-3114-B-182A-001; 101-2320-B-010-072-MY3; NSC101-2321-B-010-027; NSC102-2314-B-010 -014 -MY3), Taiwan Ministry of Education (Aim for the Top University Plan, Genomic Research Center, National Yang-Ming University) and Chang Gung Memorial Hospital (CMRPG 290051G), Taiwan.

Author contributions

EG, D-PC and. S-IH: analysis and interpretation of data, organizing, analysis and drafting the manuscript; PS, MS: data analysis; P-YC, S-HT and Dr T-LW: HLA genotyping and acquisition of data; TB, RT, CF, AT, DC, AH and PW: enrolling patients, collecting the clinical data from the medical charts; W-HC, MM and J-CR: supervising, monitoring, directing this study, enrolling patients, consulting the diagnosis and definition of diseases, and writing the manuscript.

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Author notes

  1. E Genin, D-P Chen and S-I Hung: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm U946, Saint Louis Hospital, Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France

    E Genin

  2. Department of Laboratory Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    D-P Chen, P-Y Chang, S-H Tsai & T-L Wu

  3. Department of Medical Biotechnology and Laboratory Science, Chang Gung University College of Medicine, Taoyuan, Taiwan

    D-P Chen, P-Y Chang, S-H Tsai & T-L Wu

  4. Institute of Pharmacology, School of Medicine, Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan

    S-I Hung

  5. Institute of Medical Biometry and Medical Informatics, Freiburg University—Medical Center, Freiburg, Germany

    P Sekula & M Schumacher

  6. Research Unit, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain

    T Bellón

  7. Jean Dausset Laboratory, Saint Louis Hospital, Paris, France

    R Tamouza, C Fortier, A Toubert & D Charron

  8. Inserm UMRS 940, Saint Louis Hospital, Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France

    R Tamouza, C Fortier, A Toubert, D Charron, A Hovnanian & P Wolkenstein

  9. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospitals, Keelung, Linko, Chang Gung University College of Medicine, Taipei, Taiwan

    W-H Chung

  10. Department of Dermatology, Dokumentationszentrum schwerer Hautreaktionen (dZh), Freiburg University—Medical Center, Freiburg, Germany

    M Mockenhaupt

  11. Service Dermatologie, Hôpital Henri-Mondor, Université Paris-Est, Créteil, France

    J-C Roujeau

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  1. E Genin
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Genin, E., Chen, DP., Hung, SI. et al. HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis. Pharmacogenomics J 14, 281–288 (2014). https://doi.org/10.1038/tpj.2013.40

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