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Genome-Wide Association Study of Serious Blistering Skin Rash Caused by Drugs

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Genome-Wide Association Study of Serious Blistering Skin Rash Caused by Drugs The Pharmacogenomics Journal (2012) 12, 96–104 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Genome-wide association study of serious blistering skin rash caused by drugs Y Shen1,2,13, P Nicoletti1,3,13, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are 1 4 rare but severe, potentially life threatening adverse drug reactions character- A Floratos , M Pirmohamed , ized by skin blistering. Previous studies have identified drug-specific and 5 3 M Molokhia , P Geppetti , population-specific genetic risk factors with large effects. In this study, we S Benemei3, B Giomi3, report the first genome-wide association study (GWAS) of SJS/TEN induced D Schena6, A Vultaggio7, by a variety of drugs. Our aim was to identify common genetic risk factors R Stern8, MJ Daly9,10, S John11, with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 12 1,2 96 retrospective cases and 198 controls with a panel of over one million MR Nelson and I Pe’er , single-nucleotide polymorphisms (SNPs). We further improved power with the International Serious Adverse about 4000 additional controls from publicly available datasets. No genome- Events Consortium (SAEC) wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a 1Center for Computational Biology and role in predisposing to drug-induced SJS/TEN. Our GWAS did not find Bioinformatics, Columbia University, New York, common, highly penetrant genetic risk factors responsible for SJS/TEN events 2 NY, USA; Department of Computer Science, in the cases selected. Columbia University, New York, NY, USA; 3Department of Clinical Pharmacology, University The Pharmacogenomics Journal (2012) 12, 96–104; doi:10.1038/tpj.2010.84; of Florence, Florence, Italy; 4MRC Centre for Drug published online 11 January 2011 Safety Sciences, Department of Pharmacology, The 5 University of Liverpool, Liverpool, UK; London Keywords: pharmacogenetics; GWAS; serious skin rash; Stevens–Johnson syndrome; SNP; School of Hygiene and Tropical Medicine, drug adverse reactions University of London, London, UK; 6Department of Dermatology, University of Verona, Verona, Italy; 7Department of Internal Medicine, Immunoallergology Section, Careggi Teaching Hospital, University of Florence, Florence, Italy; 8Department of Dermatology Beth Israel, Introduction Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; 9Program in Medical Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the and Population Genetics, Broad Institute of extreme clinical manifestations of mucocutaneous eruptions. SJS/TEN are the Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA; 10Center for rarest varieties of severe cutaneous adverse reactions, mostly induced by a variety 1–2 Human Genetic Research, Massachusetts General of medications through a dose-independent immune response. SJS/TEN are Hospital,Boston,MA,USA;11Pfizer, New London, characterized by mortality rates between 1 and 30%, depending on the extent of 12 CT, USA and GlaxoSmithKline, Research Triangle blistering, and up to 35% of serious sequelae in survivors.2 Park, NC, USA Over the past few decades, a series of studies addressed the epidemiology of 3 Correspondence: SJS/TEN in terms of variability according to ethnicity and causative drugs. Each 4 Dr I Pe’er, Department of Computer Science, year, SJS/TEN affects eight Asian, and only one to two ethnically European Columbia University, 1214 Amsterdam Avenue, individuals per million persons. Antibacterial sulfonamides (for example, co- Mail code 0401, New York, NY 10027, USA. trimoxazole), allopurinol and antiepileptic drugs (phenytoin, carbamazepine and E-mail: [email protected] and Dr MR Nelson, 5 GlaxoSmithKline, 5 Moore Drive, MAI.A1227, lamotrigine) are consistently the most frequent SJS/TEN-inducing drugs. Drug Research Triangle Park, NC 27709, USA. specific relative risk differs significantly among ethnic groups. For instance, E-mail: [email protected] carbamazepine accounts for 25–33% of SJS cases in east Asians, but only 5–6% in Europeans.6 13 These authors contributed equally to this work. Heritable predisposition to SJS/TEN was recognized by several case–control candidate gene studies, but this is likely to be drug and often ethnicity specific. Received 14 January 2010; revised 7 October 6–8 2010; accepted 27 October 2010; Indeed, in a broader east Asian population Human leucocyte antigen (HLA)- published online 11 January 2011 B*1502 is a predictive marker for carbamazepine-related severe cutaneous adverse Genetic risk factors with large effects on SJS/TEN risk Y Shen et al 97 reaction with a positive predictive value of 7%. SJS/TEN detachment during the course of the disease. A diagnosis of caused by phenytoin also shows a weaker association with SJS was considered if blistering did not exceed 10%, whereas HLA-B*1502.9 This allele is rare in Europeans, which could TEN cases had 430% of the body surface area blistered, with be the reason why similar HLA risk factors have not been SJS–TEN overlap cases occupying an intermediate position.3 identified.10 In contrast, ethnicity does not seem to Etiology assessment was performed on all cases, and only influence the incidence of allopurinol severe cutaneous cases with drug as the most likely cause were included in the adverse reaction,11 in which HLA-B*5801 has been shown to study. Exclusion criteria were (a) concomitant human be strongly associated in both European12 and Asian immunodeficiency virus infection, and (b) concomitant populations.13 Finally, a candidate gene study in Japanese immunosuppressant drugs. Ethical approval was provided patients with SJS/TEN to a number of drugs showed an by the University of Florence Ethics committee. association with HLA-A*0260.14 Although there have been a number of studies investigating the role that candidate Control selection genes may have in drug-induced SJS/TEN, no highly The controls from PGX40001 were collected at the same site reproducible genetic predictors other than HLA-B*1502 as the cases, matched on the basis of ethnicity and gender. and HLA-B*5801 have emerged. The controls in LAM30004 were matched on drug treatment Here, we report the first genome-wide association study as well as age and ethnicity. No specific control matching (GWAS) of SJS/TEN. In this retrospective study, we used was carried out for the Italian cases. We obtained the standard phenotypic criteria to identify SJS/TEN cases that genotypes of 88 HapMap3 TSI17 subjects as the controls for were due to a number of drugs. Our aim was to discover the Italian cases. We also included 659 POPRES (population highly penetrant and common genetic factors that increase reference sample) controls genotyped by Serious Adverse the risk of developing SJS/TEN, which may not necessarily Events Consortium as the basis for separating sub-popula- be drug specific. tions within Europeans using principal components analysis (PCA; see below). In addition, about 4837 WTCCC2 subjects Materials and methods were analyzed and 4108 of these were chosen to match the northwestern Europeans (nw-EU) cases. Subjects PGX40001 collection. Cases were defined by Pirmohamed Genotyping et al.15 Briefly, cases were retrospectively enrolled and All subjects from PGX40001 and LAM30004 and POPRES screened by expert review based on SJS/TEN inclusion and controls and Italian collection were genotyped at Expression exclusion criteria. The controls were collected at the site of Analysis (Research Triangle Park, NC, USA). PGX40001 and case matching for age, gender and ethnicity. Six of the cases LAM30004 and were genotype together using Illumina 1M were defined as SJS–TEN spectrum, that is, they were within chip, whereas the Italian cases by Illumina 1M-duo chip. the spectrum of the blistering skin reactions (SJS, overlap The POPRES subjects were genotyped by Illumina 1M or 1M- syndrome, TEN), but incomplete clinical data meant that we Duo for another Serious Adverse Events Consortium study18 were unable to categorize accurately. In total, 71 cases and The chips contain about 1.07 and 1.2 million markers 135 controls were genotyped using Illumina 1M in our study of single-nucleotide polymorphisms (SNPs) and copy num- (Illumina, http://www.illumina.com). ber variant (CNV) probes, respectively. The genotypes of HapMap TSI were downloaded from http://hapmap.org LAM30004 collection. Cases were defined by Kazeem et al.16 public release no. 27. The genotypes of WTCCC2 subjects All cases and controls were epilepsy patients treated with were downloaded from The European Genome–phenome lamotrigine and recruited retrospectively. Cases were Archive (http://www.ebi.ac.uk/ega/)—1958 British Birth patients who developed SJS/TEN or hypersensitivity Cohort and United Kingdom Blood Service Group (only reactions (although only SJS/TEN cases are included in Illumina 1M data). this study), whereas controls were patients exposed to lamotrigine without developing SJS/TEN. In addition to Genotype quality control matching for the drug of interest, the controls were also For each set of genotype data, we applied a series of quality chosen on the basis of other factors, such as age, ethnicity control steps. Specifically, any marker that did not pass any and concurrent valproic acid usage. SJS/TEN was defined by of the following criteria was discarded: dermatologists using standard phenotypic criteria. In total, 1. Call rate 495%; 6 cases and 63 controls were included in this study. 2. Minor allele frequency 41%; 3. A P-value for Hardy–Weinberg equilibrium 410À7 in Italian cases. Between November 2007 and March 2008, 19 controls (if applicable). retrospective Caucasian cases of SJS because of the number of drugs were collected from Dermatology Department at the After applying these criteria, 837 175 SNPs were left in the University of Florence and Dermatology Department at PGX40001 and LAM30004 subjects. The Italian collection University of Verona. Cases were defined on the basis of was merged with HapMap TSI subjects.
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