P670. Identification of new genetic variants related to thiopurine-induced myelotoxicity in inflammatory bowel disease (IBD) patients with normal thiopurine s-methyltransferase (TPMT): a genome-wide association study
M. Chaparro1, A. González-Neira2, M. Román3, G. Pita2, T. Cabaleiro4, D. Herrero2, B. Herraez2, R. Alonso2, C. Taxonera5, P. López-Serrano6, P. Martínez Montiel7, I. Vera8, F. Bermejo9, A. López-San Román10, F. Abad-Santos4, J.P. Gisbert1, 1Hospital Universitario de la Princesa-IP, Gastroenterology and CIBEREHD, Madrid, Spain, 2Spanish National Cancer Research Centre, Madrid, Spain, 3Hospital Universitario de la Princesa-IP, Clinical Pharmacology and CIBEREHD, Madrid, Spain, 4Hospital Universitario de La Princesa, Clinical Pharmacology Service, Madrid, Spain, 5Hospital Universitario Clínico San Carlos, Gastroenterology, Madrid, Spain, 6Hospital de Alcorcón, Gastroenterology, Madrid, Spain, 7Hospital Universitario Doce de Octubre, Gastroenterology, Madrid, Spain, 8Hospital Universitario Puerta de Hierro, Gastroenterology, Madrid, Spain, 9Hospital Universitario de Fuenlabrada, Gastroenterology, Madrid, Spain, 10Hospital Universitario Ramón y Cajal, Gastroenterology, Madrid, Spain
Patients with low TPMT activity are at increased risk of developing thiopurine-induced myelotoxicity. However, only a minority of patients with myelotoxicity are carriers of a mutant TPMT allele.
Aim: To identify genetic variants associated with thiopurine-induced myelotoxicity in IBD patients with TPMT wild-type alleles and normal activity of this enzyme.
93 IBD patients with normal TPMT activity and wild-type genotype treated with thiopurines were included. Case group: patients with thiopurine-induced myelotoxicity and without other thiopurine-induced adverse effect. Control group: patients without thiopurine-induced side effects consecutively included. TPMT activity over 13.7 UI/mL was considered normal. DNA was extracted from peripheral blood nucleated cells. TPMT genotype was determined by sequencing (TPMT*2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, *9, *10, *15, *16, *19 and *22 alleles). Myelotoxicity was defined as <3,000/ml leucocytes, <1,500/ml neutrophils, or <100,000/ml platelets. Genomic DNA was analysed using Illumina OmniExpress Exome BeadChip genotyping array. This array interrogates a total of 951,117 SNPs (660K common and 200k rare coding variants). Genotype calls were generated using Illumina GenomeStudio. After standard QC control, associations between SNPs and myelotoxicity were assessed using logistic regression analysis.
93 patients were included (37 cases and 56 controls). The distribution of gender, type of IBD, mean age, mean TPMT activity and mean dose of mercaptopurine (1.3 vs. 1.4 mg/kg) were similar between cases and controls. The percentage of patients with mercaptopurine was higher among cases (32.4 vs. 12.5%, p = 0.02), while mean azathioprine dose was slightly higher among controls (2.2 vs. 2.5 mg/kg, p = 0.03). A total of four SNPs showed significant association: SNP1: p = 6.5×10−5, OR = 10.4 (2.5–21); SNP2: p = 6.6×10−5, OR = 6.2 (2.4–12); SNP3: p = 8.5×10−5, OR = 0.1 (0.07–0.5); and SNP4: p = 8.8×10−5, OR = 0.2 (0.1–0.4). The SNP1 is located close to a gene that encodes a relevant enzyme of the thiopurine metabolic pathway.
An exome-wide association study identified four new SNPs that could explain thiopurine-induced toxicity not related to TPMT deficiency. The SNP with the strongest association could regulate the expression of an enzyme of the thiopurine metabolic pathway. Although further validation is required, these variants could be promising genetic predictors of thiopurine-induced myelotoxicity.
- Posted in: Poster presentations: Genetics (2013)