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IntroductionThiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1Thiopurine S-methyltransferase (TPMT)variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing.MethodWe recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses.ResultsWe first confirmed an association of TIM with TPMTin an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15(5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15genotype (OR 21.7,p=2.0×10-8) and TPMTgenotype (OR 2.2,p=2.6×10-4for MUT/WT and OR 51.2,p=1.8×10-4for MUT/MUT) were independently associated with TIM.ConclusionThese are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPTgenotype and thiopurine dose. Although NUDT15variants are less common than TPMTvariants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15heterozygotes is 59%. A future clinical decision tool incorporating NUDT15and TPMTgenotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity.Reference. Gisbert JP & Gomollón F.doi10.1111/j.1572-0241.2008.01848.x (2008). Yang SK et al. doi10.1038/ng.3060 (2014)Disclosure of InterestNone Declared