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

Shen, Yufeng; Nicoletti, Paola; Floratos, Aris; Pirmohamed, Munir; Molokhia, Mariam; Geppetti, Pierangelo; Benemei, Silvia; Giomi, Barbara; Schena, Donatella; Vultaggio, Alessandra; Stern, Robert S.; Daly, Mark J.; John, Sally; Nelson, .; Pe’er, Itsik

doi:10.1038/tpj.2010.84

Cited by 32 publications

(25 citation statements)

References 43 publications

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“…We selected 10588 European ancestry controls from multiple available sources; Welcome Trust Case Control Consortium (WTCCC) (http://www.wtccc.org.uk), the population reference sample (POPRES) 18 , PGX40001 19 and Spanish Bladder cancer cohort (phs000346.v1) from dbGAP. 20 In order to increase the case/control ratio for Italian, Spanish and Swedish, we added samples from Hypergenes cohort (http://www.hypergenes.eu/dissemination.html#pub), the National Spanish DNA Bank (http://www.bancoadn.org/), Italian Penicillin Tolerant Controls (IPTC), and the Swedish Twin Registry (http://ki.se/en/research/the-swedish-twin-registry).…”

Section: Methodsmentioning

confidence: 99%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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BACKGROUND & AIMS We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.

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Section: Methodsmentioning

confidence: 99%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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“…Out of the cumulative 43 CBZ‐SCAR cases, three PGX40001 cases were previously genotyped with Illumina 1M Duo chip . DNA from the rest of British and broadly European cases was extracted from whole blood and stored in the Wolfson Centre for Personalized Medicine in Liverpool.…”

Section: Methodsmentioning

confidence: 99%

Shared Genetic Risk Factors Across Carbamazepine‐Induced Hypersensitivity Reactions

Nicoletti

Barrett

McEvoy

et al. 2019

Clin Pharma and Therapeutics

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Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug‐induced liver injury (CBZ‐DILI). In order to evaluate shared or phenotype‐specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta‐analysis of two genomewide association studies (GWAS) on a total of 43 well‐phenotyped Northern and Southern European CBZ‐SCAR cases and 10,701 population controls and a GWAS on 12 CBZ‐DILI cases and 8,438 ethnically matched population controls. HLA‐A*31:01 was identified as the strongest genetic predisposing factor for both CBZ‐SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ‐DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA‐A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens‐Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA‐B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ‐SCAR cases, which needs replication in additional cohorts and functional evaluation.

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“…A criterion that has received attention in the pharmacogenomics literature [1,2] is control of the family-wise error rate (FWER), which is the probability of one or more false discoveries (type I errors). The Bonferroni correction controls the FWER at a level of α by taking the individual p -value threshold as α/J .…”

Section: Methodsmentioning

confidence: 99%

“…We describe two recent examples of case-control pharmacogenomic studies, in order to outline the usual current approach to the decision problem. In a recent study [1], epilepsy patients were treated with lamotrigine or related drugs. The cases had either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis, both of which are potentially life threatening adverse drug reactions characterized by skin blistering.…”

Section: Introductionmentioning

confidence: 99%

Detecting signals in pharmacogenomic genome-wide association studies

et al. 2014

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In one common pharmacogenomic scenario, outcome measures are compared for treated and untreated subjects across genotype defined subgroups. The key question is whether treatment benefit (or harm) is particularly strong in certain subgroups, and therefore statistical analysis focuses on the interaction between treatment and genotype. However, genome-wide analysis in such scenarios requires careful statistical thought since, in addition to the usual problems of multiple testing, the marker-defined sample sizes, and therefore power, vary across the individual genotypes being evaluated. The variability in power means the usual practice of using a common p-value threshold across tests has difficulties. The reason is that the use of a fixed threshold, with variable power, implies that the costs of type I and type II errors are varying across tests in a manner which is implicit rather than dictated by the analyst. In this paper we discuss this problem and describe an easily implementable solution based on Bayes factors. We pay particular attention to the specification of priors, which is not a straightforward task. The methods are illustrated using data from a randomized controlled clinical trial in which homocysteine levels are compared in individuals receiving low and high doses of folate supplements and across marker subgroups. The method we describe is implemented in the R computing environment with code available from http://faculty.washington.edu/jonno/cv.html.

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

Cited by 32 publications

References 43 publications

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

Shared Genetic Risk Factors Across Carbamazepine‐Induced Hypersensitivity Reactions

Detecting signals in pharmacogenomic genome-wide association studies

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