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Clin Pharmacol Ther. 2018 May;103(5):843-853. doi: 10.1002/cpt.805. Epub 2017 Sep 28.

Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.

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Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Charité - Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.
Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine de l'Université de Toulouse, Toulouse, France.
Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Fundació Institut Català de Farmacologia, Barcelona, Spain.
Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain.
S Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga (IBIMA), H Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Madrid, Spain.
Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, Sant Cugat del Vallès, Spain.
NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London Department of Primary Care and Public Health Sciences, London, UK.
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Medical Products Agency, Uppsala, Sweden.
Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Immunology, Genetics and Pathology, Clinical Immunology, Uppsala University, Uppsala, Sweden.


Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome-wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine-induced agranulocytosis and 5,170 population controls. Sulfasalazine-induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA-B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10-8 ). We HLA-sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA-B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA-B*08:01 haplotype HLA-DQB1*02:01-DRB1*03:01-B*08:01-C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA-A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA-B*08:01 and HLA-A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA-B*08:01 or HLA-A*31:01.

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