Association of SLCO1B1 *15 Allele with Methotrexate-Induced Nausea in Pediatric Inflammatory Bowel Disease

Abstract

By Rishi Mehta, Medical Sciences

Advisor: Laura Ramsey

Abstract: SLCO1B1 is the only gene to contain single nucleotide polymorphisms (SNPs) associated with Methotrexate (an immunomodulator) clearance. A patient's clearance of MTX is negatively correlated to his/her drug exposure. MTX intolerance is defined as gastrointestinal and behavioral symptoms occurring before or after MTX administration that may lead to treatment discontinuation. We hypothesize that variants in SLCO1B1 that are associated with increased exposure to MTX will be associated with MTX side effects. We retrospectively analyzed the electronic medical records of 278 patients <19 years of age who were prescribed MTX for Inflammatory Bowel Disease (IBD; Crohn's Disease, ulcerative colitis, or IBD-unclassified) with DNA in the biobank and successfully genotyped for 3 SNPs in SLCO1B1 (rs4149056, rs2306283, and rs11045819). MTX intolerance and nausea were abstracted from the clinician notes. There was a significant association of the SLCO1B1 diplotype and frequency of nausea (p = 0.012) after adjusting for dose of MTX and preemptive prescription of anti-nausea medication. Among carriers of the reduced function *15 allele that is associated with higher exposure of MTX, there was an increased incidence of nausea (p = 0.023). There was an association between the *15 allele and nausea in patients receiving MTX orally (p=0.022) rather than subcutaneously (p=0.35). SLCO1B1 *15 alleles that are associated with decreased exposure to MTX may be associated with MTX-induced nausea. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in pediatric IBD patients. Patients carrying the *15 allele may require a lower MTX dose than non-carriers to avoid MTX-induced