Genetic Associations With 6MMP Preferential Metabolizers by Elevated 6MMP:6TGN Ratios Reveal Novel Pathways Involved in Purine Metabolism: Presidential Poster: 1929

Introduction: The thiopurine drugs, 6-mercaptopurine (6MP) and azathioprine (AZA), are the mainstay of immunomodulator treatment in inflammatory bowel disease (IBD). Thiopurine methyltransferase (TPMT) genotype and enzymatic activity play a role in determining 6-tioguanine (6TGN) and 6-methylmercaptopurine (6MMP) metabolite levels, which are associated with bone marrow suppression and hepatotoxicity, respectively. A portion of patients with normal TPMT demonstrate preferential metabolism towards 6-MMP and can be identified when the 6-MMP is noted to be >5700 pmol/8x108 RBC with a low 6TGN. Examination of the 6MMP:6TGN ratio in these patients when the 6MMP level is < 5700 can help identify patients at risk for preferential metabolism and help identify novel pathways in thiopurine metabolism. The aim of this study is to identify genetic factors associated with susceptibility to 6-MMP preferential metabolism. Methods: After quality control, there were 420 IBD subjects treated at Cedars-Sinai IBD Center with 6-MP or AZA from 1999-2012 in whom immunochip and thiopurine metabolite data were available. Known preferential metabolizers were defined as having 6MMP levels >5700 pmol/8x108 RBC. To identify an at-risk 6MMP:6TGN ratio, the highest 6-MMP level of these patients that was 19.00, regardless of absolute 6-MMP level, was identified as a suspected preferential metabolizer. Linear regression was performed on 133,530 post-QC Immunochip SNPs after correcting for population structure. Results: There were 189 suspected preferential metabolizers with a 6MMP:6TGN ratio>19.00 and 231 normal metabolizers. Three loci achieved a nominal level of significance: a SNP tagging LRIG1/KBTBD8 (rs1580143) showed strongest association (p=5.00E-05); rs3934809 tagging. ARL8A/GPR37L1/ LGR6/PTPN7 (p=2.06E-05); and rs58926232 (p=3.56E-05) that tags the known IBD locus at PRDM1/ATG5. The strongest associated SNP involved the gene LRIG1, which encodes proteins involved in granulocyte differentiation, neovascularization, metastasis, and TGFbeta signaling. Conclusion: The SNPs described may provide useful genetic markers for early identification of patients at greatest risk for preferential 6MMP metabolism. Pre-emptive use of allopurinol or split-dosing of thiopurines may reduce thiopurine toxicity in patients with these genetic markers.