title: 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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica - SERGAS, Santiago de Compostela, Spain.
authors.forename: William
authors.initials: W
authors.lastname: Zabala
authors.forename: Raquel
authors.initials: R
authors.lastname: Cruz
authors.forename: Manuel
authors.initials: M
authors.lastname: Barreiro-de Acosta
authors.forename: María
authors.initials: M
authors.lastname: Chaparro
authors.forename: Julián
authors.initials: J
authors.lastname: Panes
authors.forename: Ana
authors.initials: A
authors.lastname: Echarri
authors.forename: Maria
authors.initials: M
authors.lastname: Esteve
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.forename: Esther
authors.initials: E
authors.lastname: García-Planella
authors.forename: Eugeni
authors.initials: E
authors.lastname: Domenech
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Javier P
authors.initials: JP
authors.lastname: Gisbert
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
mesh_terms: D000483:Alleles; D001855:Bone Marrow Diseases / Q000139:chemically induced* / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D050822:Cytokine Receptor gp130 / Q000235:genetics; D038702:Follistatin-Related Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics*; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects*; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: C569961:FSTL5 protein, human; D038702:Follistatin-Related Proteins; C494199:IL6ST protein, human; D011687:Purines; D013438:Sulfhydryl Compounds; D050822:Cytokine Receptor gp130; D008780:Methyltransferases; C022745:thiopurine methyltransferase