New genetic associations in thiopurine-related bone marrow toxicity among inflammatory bowel disease patients

Abstract

Background: The toxicity related to thiopurine drug therapy for inflammatory bowel disease (IBD) varies widely among patients. Almost 15–30% of patients with IBD develop side effects during treatment, often bone marrow suppression. Several factors have been implicated in determining this toxicity, mainly individual genetic variation related to formation of active thiopurine metabolites. The aim was to identify genes involved in thiopurine-related myelosuppression. Materials & methods: A two-stage investigation of 19,217 coding SNPs (cSNPs) was performed in a Spanish (Inflammatory Bowel Disease Group of Galicia [EIGA]) cohort of 173 IBD patients, 15 with bone marrow suppression. The top 20 cSNPs identified in the first stage with p < 10-3 for allelic test association and SNPs that define the common TPMT alleles were replicated in a different Spanish (ENEIDA) cohort (87 patients, 29 with bone marrow suppression). Results: Several cSNPs showed a significant p-value in the allelic joint analysis (p-Cochran–Mantel–Haenszel test ≤2.55 × 10-3) despite no cSNP passing correction for multiple testing in the first cohort. Of note is rs3729961 in the gene IL6ST, a transducer signal chain shared by many cytokines including IL6 (p-value combined = 2.36 × 10-4, odds ratio [95% CI]: 3.41 [1.71–6.78]). In addition, we detected association with rs3749598 in the FSTL5 gene that appears to interact with metalloproteases at the extracellular matrix level (p-value combined = 4.89 × 10-4), odds ratio (95% CI): 3.67 (1.68–8.01). Conclusion: We have identified IL6ST and FSLT5 as new bone marrow suppression susceptibility candidate genes after thiopurine treatment in IBD patients. This is the first report of variants associated with thiopurine-related myelosuppression that was identified by a genome-wide association study. Its validation awaits functional analyses and replication in additional studies. Original submitted 14 September 2012; Revision submitted 13 February 2013