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Genome-wide association study of serious blistering skin rash caused by drugs

The Pharmacogenomics Journal volume 12, pages 96–104 (2012)Cite this article

Abstract

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.

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Acknowledgements

We thank Arthur L Holden (Serious Adverse Events Consortium) Brian Spear (Abbott), Joe Walker (Daiichi-Sankyo), Lon Cardon (GlaxoSmithKline), Vincent Mooser (GlaxoSmithKline), Nadine Cohen (Johnson & Johnson), Joanne Meyer (Novartis) Klaus Lindpaintner (Roche), Robert Dix (Sanofi-Aventis), Leonardo Sahelijo (Takeda), Michael Dunn (Wellcome Trust), and Michael E Burczynski (Wyeth) for their support. We also thank Bernd Jagla for his early contribution to the project. We also thank Julian Arbuckle and Clive Bowman for their contribution in recruiting the SJS–TEN cohort from study PGX40001, and all the clinicians who recruited cases and controls to the study, and all the patients who contributed DNA for the study. This work was funded by the International Serious Adverse Events Consortium.

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Author notes

  1. Y Shen and P Nicoletti: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA

    Y Shen, P Nicoletti, A Floratos & I Pe'er

  2. Department of Computer Science, Columbia University, New York, NY, USA

    Y Shen & I Pe'er

  3. Department of Clinical Pharmacology, University of Florence, Florence, Italy

    P Nicoletti, P Geppetti, S Benemei & B Giomi

  4. Department of Pharmacology, MRC Centre for Drug Safety Sciences, The University of Liverpool, Liverpool, UK

    M Pirmohamed

  5. London School of Hygiene and Tropical Medicine, University of London, London, UK

    M Molokhia

  6. Department of Dermatology, University of Verona, Verona, Italy

    D Schena

  7. Department of Internal Medicine, Immunoallergology Section, Careggi Teaching Hospital, University of Florence, Florence, Italy

    A Vultaggio

  8. Department of Dermatology Beth Israel, Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    R Stern

  9. Program in Medical and Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA

    M J Daly

  10. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    M J Daly

  11. Pfizer, New London, CT, USA

    S John

  12. GlaxoSmithKline, Research Triangle Park, NC, USA

    M R Nelson

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Shen, Y., Nicoletti, P., Floratos, A. et al. Genome-wide association study of serious blistering skin rash caused by drugs. Pharmacogenomics J 12, 96–104 (2012). https://doi.org/10.1038/tpj.2010.84

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