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

Abstract

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 .