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

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%CI [2.97, 9.69] p=2.55x10−8). 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 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. This article is protected by copyright. All rights reserved.