Sulfasalazine-induced agranulocytosis is associated with the human leukocyte antigen locus
Wadelius, Mia (Uppsala University. Clinical Pharmacology and Science for Life Laboratory)
Eriksson, Niclas (Uppsala University. Center and Department of Medical Sciences)
Kreutz, Reinhold (Universitätsmedizin Berlin. Institut für Klinische Pharmakologie und Toxikologie)
Bondon-Guitton, Emmanuelle (Université de Toulouse. Faculté de Médecine. Centre Hospitalier Universitaire)
Ibáñez, Luisa (Fundació Institut Català de Farmacologia)
Carvajal, Alfonso (Universidad de Valladolid. Centro de Estudios sobre la Seguridad de los Medicamentos)
Lucena, M. Isabel (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Sancho Ponce, Esther (Hospital General de Catalunya)
Molokhia, Mariam (King's College London)
Martin Martinez, Javier (Instituto de Parasitología y Biomedicina "López-Neyra")
Axelsson, Tomas (Uppsala University. Molecular Medicine and Science for Life Laboratory)
Kohnke, Hugo (Uppsala University. Clinical Pharmacology and Science for Life Laboratory)
Yue, Qun-Ying (Medical Products Agency. Sweden)
Magnusson, Patrik K. E. (Karolinska Institutet (Estocolm, Suècia). Department of Medical Epidemiology and Biostatistics)
Bengtsson, Mats (Uppsala University. Department of Immunology, Genetics and Pathology)
Hallberg, Pär (Uppsala University. Clinical Pharmacology and Science for Life Laboratory)
Universitat Autònoma de Barcelona

Data:	2018
Resum:	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.
Ajuts:	Instituto de Salud Carlos III FIS10-02632 Instituto de Salud Carlos III FIS12-00378
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Clinical Pharmacology and Therapeutics, Vol. 103, núm. 5 (May 2018) , p. 843-853, ISSN 1532-6535

DOI: 10.1002/cpt.805
PMID: 28762467

Published Version 11 p, 416.9 KB

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