Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens–Johnson syndrome with severe ocular complications

Ueta, Mayumi; Sawai, Hiromi; Shingaki, Ryusei; Kawai, Yusuke; Sotozono, Chie; Kojima, Kazuyuki; Yoon, Kyung Chul; Kim, Mee Kum; Seo, Kyoung Yul; Joo, Choun Ki; Nagasaki, Masao; Kinoshita, Shigeru; Tokunaga, Katsushi

doi:10.1038/jhg.2016.160

Cited by 21 publications

(22 citation statements)

References 22 publications

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“…In Japanese individuals, the HLA‐A*3101 allele has been suggested to be a risk factor for carbamazepine‐induced severe CADR . Furthermore, a recent genome‐wide association study has identified genetic predictors for cold medicine‐related SJS with severe ocular complications in a Japanese population . Ethosuximide, an antiepileptic, is mainly used to control absence seizures .…”

Section: Discussionmentioning

confidence: 99%

“…7 Furthermore, a recent genome-wide association study has identified genetic predictors for cold medicinerelated SJS with severe ocular complications in a Japanese population. 8 Ethosuximide, an antiepileptic, is mainly used to control absence seizures. 9 Unlike other anticonvulsants, only one case has been reported as ethosuximide-induced SJS.…”

Section: Discussionmentioning

confidence: 99%

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Ethosuximide‐induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high‐dose corticosteroid therapy

Tachibana

Hamada

Tsuchiya

et al. 2018

The Journal of Dermatology

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We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens-Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ethosuximide‐induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high‐dose corticosteroid therapy

Tachibana

Hamada

Tsuchiya

et al. 2018

The Journal of Dermatology

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“…43 HLA-A*02:06 with Rec114 rs16957893 CG also exerted more than additive effects in CM-SJS/TEN with SOC (OR ¼ 110 [95% CI, 6.36-1905], P ¼ 4.45 3 10 À8 ). 6 This interaction was independent of the interaction between HLA-A*02:06 and TLR3 rs3775296 T/T because Japanese CM-SJS/TEN with SOC patients with both HLA-A*02:06 and Rec114 rs16957893 CG did not harbor TLR3 rs3775296 T/T. 6 In the Japanese, combined genotyping for the associated variants thus far identified (i.e., HLA-A*02:06, Rec114 rs16957893 CG, TLR3 rs3775296 T/T, and PTGER3 rs1327464 GA or AA) may help to predict the risk for CM-SJS/TEN with SOC.…”

Section: Interaction Between the Hla Genotype And Susceptibility Genesmentioning

confidence: 99%

“…Our ophthalmologic diagnosis of SJS/TEN was based on a confirmed history of acuteonset high fever, serious mucocutaneous illness with skin eruptions, and involvement of at least two mucosal sites including the ocular. [2][3][4][5][6][7][8] SJS/TEN patients with severe ocular complications (SOC) in the acute stage often suffer severe ocular sequelae such as vision loss and very severe dry eye that prevent their having a normal life. 9 We defined acute-stage SOC as a condition with severe conjunctivitis with pseudomembrane and epithelial defects on the ocular surface (cornea and/or conjunctiva), 10 and chronicstage as a condition with ocular sequelae such as severe dry eye, trichiasis, symblepharon, and conjunctival invasion into the cornea.…”

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confidence: 99%

Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Ueta

2018

Invest. Ophthalmol. Vis. Sci.

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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We found that cold medicines, including multi-ingredient cold medications and nonsteroidal antiinflammatory drugs, were the main causative drugs especially in patients with SJS/TEN with SOC. Cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC was strongly associated with HLA-A*02:06 in the Japanese populations, and significantly associated with HLA-B*44:03 in the Japanese and in Indian and Brazilian populations. Single nucleotide polymorphism association analysis showed that the Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKZF1 gene were significantly associated with CM-SJS/TEN with SOC and that they could regulate mucocutaneous inflammation including that of the ocular surface. As we found several HLA-SNP sets with a high odds ratio, we postulated that they may help to predict the possible development of SJS/TEN with SOC. From our findings we suggest that besides microbial infection and cold medicines, a combination of multiple gene polymorphisms and their interactions contribute strongly to the onset of CM-SJS/TEN with SOC.

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“…This new array will foster genetic and epidemiological research with the aim to improve health across diverse African populations. Recently, other arrays have become available, specific for Hispanic, African-American or Japanese [22] populations. In addition, further development of GWAS arrays together with increased availability of reference datasets generated by next generation sequencing from diverse populations, may improve HLA imputation methods.…”

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confidence: 99%

Patient Ethnicity and the Risk of Immune-Mediated Adverse Drug Reactions

Alfirevic

2017

Pharmacogenomics

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Immune-mediated adverse drug reactions (ADRs) lead to hospitalization in approximately 9% of US patients who visit Emergency Departments for adverse drug events [1]. However, most severe immune ADRs are rare, but can be life-threatening. They are categorized as type B or 'off target' reactions that cannot be predicted from the known pharmacological action of the drug that caused it. Immune-mediated ADRs, comprising <20% of all ADRs, could be further classified according to Gell and Coombs into immediate (antibody dependent) and delayed (T-cell mediated) reactions. Clinical phenotypes vary considerably; immediate reactions include urticaria, angioedema, bronchospasm and pruritus usually occurring within 1 h after drug administration; delayed reactions occurring within 6 weeks after drug administration often present with skin symptoms ranging from mild maculopapular exanthema to sometimes severe blistering skin reactions with systemic symptoms such as StevensJohnson syndrome, toxic epidermal necrolysis or acute generalized exanthematous pustulosis. Nomenclature for severe drug-induced cutaneous adverse reactions with systemic symptoms is variable and includes the following terms: drug hypersensitivity syndrome, hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms. Organ-specific toxicities such as drug-induced myotoxicity, liver injury, agranulocytosis, kidney or pancreas injury can also include immunological etiology as demonstrated by clinical phenotype characteristics and significant associations with genes with immune function within the MHC on chromosome 6, primarily HLA genes [2][3][4][5][6][7].Pathophysiological mechanisms of immune ADRs are not fully understood, however, there are three recognized models that explain T-cell-mediated hypersensitivity [8]. They include: hapten/prohapten model (drug example -sulfamethoxazole), where a small drug or its reactive metabolite induces an immune response by covalently binding to an endogenous protein to become immunogenic and is then presented on an MHC molecule to a T-cell receptor; the pharmacological interactions (p-i) model proposes that a drug can bind directly to the T-cell receptor or MHC molecule and stimulate T cells directly, independent of antigen processing (drug examplecarbamazepine); and the altered repertoire model, where a drug binds noncovalently in a concentration-dependent manner to the peptide binding groove of the HLA molecule and changes the chemistry of the HLA molecule that displays altered self-peptides which are recognized by T cells (drug example -abacavir).Genetic factors have been implicated in immune-mediated ADRs. Particularly prominent are genetic associations with the HLA alleles. HLA allelic frequencies vary greatly in diverse worldwide populations (Allelefrequency.net database) [9] and there are many population-specific associations described. One of the examples often cited in literature is an association between HLA-B*15:02 and carbamazepine-induced SJS/TEN in individuals of east Asian ancestry, but n...

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Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens–Johnson syndrome with severe ocular complications

Cited by 21 publications

References 22 publications

Ethosuximide‐induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high‐dose corticosteroid therapy

Ethosuximide‐induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high‐dose corticosteroid therapy

Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Patient Ethnicity and the Risk of Immune-Mediated Adverse Drug Reactions

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