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  • 1.
    Nicoletti, Paola
    et al.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Sema4, Stamford, CT USA.
    Barrett, Sarah
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    McEvoy, Laurence
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Daly, Ann K.
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Aithal, Guruprasad
    Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Unit, NIHR, Nottingham, England;Univ Nottingham, Nottingham, England.
    Isabel Lucena, M.
    Univ Malaga, UGC Digest, Clin Pharmacol Serv, Inst Invest Biomed Malaga IBIMA,Hosp Univ Virgen, Malaga, Spain;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain.
    Andrade, Raul J.
    Univ Malaga, UGC Digest, Clin Pharmacol Serv, Inst Invest Biomed Malaga IBIMA,Hosp Univ Virgen, Malaga, Spain;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stephens, Camilla
    Univ Malaga, UGC Digest, Clin Pharmacol Serv, Inst Invest Biomed Malaga IBIMA,Hosp Univ Virgen, Malaga, Spain;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain.
    Bjornsson, Einar S.
    Landspitali Univ Hosp, Dept Internal Med, Reykjavik, Iceland.
    Friedmann, Peter
    Univ Southampton, Sch Med, Dermatol Unit, Southampton, Hants, England.
    Kainu, Kati
    Univ Helsinki, Cent Hosp, Clin Res Unit Pulm Dis, Helsinki, Finland.
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Clin Res Unit Pulm Dis, Helsinki, Finland.
    Marson, Anthony
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Molokhia, Mariam
    Kings Coll London, Sch Populat Sci & Hlth Serv Res, London, England.
    Phillips, Elizabeth
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Pichler, Werner
    ADR AC GmbH, Bern, Switzerland.
    Romano, Antonino
    Complesso Integrato Columbus, Allergy Unit, Rome, Italy.
    Shear, Neil
    Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada.
    Sills, Graeme
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Tanno, Luciana K.
    Hosp Sirio Libanes, Sao Paulo, Brazil.
    Swale, Ashley
    Columbia Univ, Dept Syst Biol, New York, NY USA.
    Floratos, Aris
    Columbia Univ, Dept Syst Biol, New York, NY USA.
    Shen, Yufeng
    Columbia Univ, Dept Syst Biol, New York, NY USA.
    Nelson, Matthew R.
    GSK, Target Sci, King Of Prussia, PA USA.
    Watkins, Paul B.
    Univ N Carolina, Eshelman Sch Pharm, Inst Drug Safety Sci, Chapel Hill, NC 27515 USA.
    Daly, Mark J.
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02115 USA.
    Morris, Andrew P.
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Alfirevic, Ana
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Pirmohamed, Munir
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions2019In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 106, no 5, p. 1028-1036Article in journal (Refereed)
    Abstract [en]

    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 x 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 x 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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