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      Genetic Markers for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in the Asian Indian Population: Implications on Prevention

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          Abstract

          This review attempts to collate all the studies performed in India or comprising a population originating from India and to find out if there is an association between the HLA (human leucocyte antigen) type of individual and development of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) subsequent to medication use. The authors performed a PubMed search of all articles published in English from 2009 to 2019 for articles that studied HLA type in patients who developed SJS/TEN after intake of a specific drug in the Asian Indian population or in individuals of Asian Indian origin. The selection criteria were satisfied by a total of 11 studies that reported HLA associations with specific drugs, which induced SJS/TEN, mainly anti-epileptic drugs, and cold medicine/non-steroidal anti-inflammatory drugs. These studies involved a small number of patients, and hence, there is limited evidence to conclude if these associations can be extrapolated to a larger population of the same ethnicity. Similar multi-center studies need to be conducted with a larger sample size to confirm these associations. This would have implications in policy making and for understanding the potential of using genetic markers as a screening tool before prescribing a drug to a patient, which might make them susceptible to developing a potentially life-threatening disease such as SJS/TEN. This is possibly the only mode of primary prevention for this potentially fatal severe cutaneous adverse drug reaction.

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          Most cited references82

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          ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis.

          Epidermal necrolysis (EN)--either Stevens-Johnson syndrome (SJS) or toxic EN (TEN)--is a severe drug reaction. We constructed and evaluated a specific algorithm, algorithm of drug causality for EN (ALDEN), in order to improve the individual assessment of drug causality in EN. ALDEN causality scores were compared with those from the French pharmacovigilance method in 100 cases and the case-control results of the EuroSCAR study. Scores attributed by ALDEN segregated widely. ALDEN pointed to a "probable" or "very probable" causality in 69/100 cases as compared to 23/100 with the French method (P < 0.001). It scored "very unlikely" causality for 64% of medications vs. none with the French method. Results of ALDEN scores were strongly correlated with those of the EuroSCAR case-control analysis for drugs associated with EN (r = 0.90, P < 0.0001), with probable causality being reported in 218/329 exposures. ALDEN excluded causality in 321 drugs that the case-control analysis had described as "probably not associated" and in 22/233 drugs that had been described as inconclusive exposures. Being more sensitive than a general method, ALDEN, which correlates well with case-control analysis results, can be considered a reference tool in SJS/TEN.
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            Medical genetics: a marker for Stevens-Johnson syndrome.

            Stevens-Johnson syndrome and the related disease toxic epidermal necrolysis are life-threatening reactions of the skin to particular types of medication. Here we show that there is a strong association in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and Stevens-Johnson syndrome induced by carbamazepine, a drug commonly prescribed for the treatment of seizures. It should be possible to exploit this association in a highly reliable test to predict severe adverse reaction, as well as for investigation of the pathogenesis of Stevens-Johnson syndrome.
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              HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.

              Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                12 January 2021
                2020
                : 11
                : 607532
                Affiliations
                [1] 1The Cornea Institute, L.V. Prasad Eye Institute , Hyderabad, India
                [2] 2Brien Holden Eye Research Centre (BHERC), L.V. Prasad Eye Institute , Hyderabad, India
                [3] 3Manipal Academy of Higher Education , Manipal, India
                [4] 4Kallam Anji Reddy Molecular Genetics Laboratory, L.V. Prasad Eye Institute , Hyderabad, India
                [5] 5Center for Ocular Regeneration (CORE), L.V. Prasad Eye Institute , Hyderabad, India
                Author notes

                Edited by: Jasmine Luzum, University of Michigan, United States

                Reviewed by: Youssef M. Roman, Virginia Commonwealth University, United States; Wen-Hung Chung, Chang Gung Memorial Hospital, Taiwan

                *Correspondence: Swapna S. Shanbhag, swapnashanbhag@ 123456lvpei.org

                This article was submitted to Pharmacogenetics and Pharmacogenomics, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2020.607532
                7837290
                33510770
                6010a2a9-f1b3-488a-a1e9-8fe84c815b05
                Copyright © 2021 Shanbhag, Koduri, Kannabiran, Donthineni, Singh and Basu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 September 2020
                : 14 December 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 83, Pages: 9, Words: 7765
                Funding
                Funded by: Hyderabad Eye Research Foundation 10.13039/501100005809
                Categories
                Genetics
                Mini Review

                Genetics
                human leucocyte antigen,genetic markers,india,carbamazepine,anti-epileptics,toxic epidermal necrolysis,stevens-johnson syndrome,severe cutaneous adverse drug reaction

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