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

Mia Wadelius, Niclas Eriksson, Reinhold Kreutz, Emmanuelle Bondon-Guitton, Luisa Ibañez, Alfonso Carvajal, M. Isabel Lucena, Esther Sancho Ponce, Mariam Molokhia, Javier Martin, Tomas Axelsson, Hugo Kohnke, Qun Ying Yue, Patrik K.E. Magnusson, Mats Bengtsson, Pär Hallberg

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)


© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics 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.
Original languageEnglish
Pages (from-to)843-853
JournalClinical Pharmacology and Therapeutics
Issue number5
Publication statusPublished - 1 May 2018


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