title: Body Mass Index and Smoking Affect Thioguanine Nucleotide Levels in Inflammatory Bowel Disease.
abstract: BACKGROUND
  Optimal levels of the thiopurine metabolite, 6-thioguanine nucleotides [6-TGN] correlate with remission of inflammatory bowel disease [IBD]. Apart from variations in the thiopurine methyl transferase [TPMT] gene, little is known about other predictors of 6-TGN levels. Obesity adversely affects response to infliximab and adalimumab and clinical course in IBD, but little is known about the interaction of thiopurines and obesity. We investigated the relationship between body mass index [BMI] and 6-TGN levels and sought to examine other predictors of 6-TGN levels.
  
  
  METHODS
  This retrospective cohort study included patients with concurrent measurements of 6-TGN and BMI. The association between 6-TGN and clinical variables including BMI was estimated using a multivariable linear regression model.
  
  
  RESULTS
  Of 132 observations, 77 [58%] had Crohn's disease and 55 [42%] ulcerative colitis. BMI, smoking, and TPMT levels were associated with 6-TGN levels in multivariable analysis. Every 5kg/m(2) increase in BMI was associated with an 8% decrease in 6-TGN (0.92; 95% confidence interval [CI] 0.87-0.98; p = 0.009). Smokers had higher 6-TGN levels in comparison with non-/ex-smokers [1.43; 95% CI 1.02-2.02; p = 0.041]. Patients with intermediate TPMT had higher 6-TGN compared to those with normal levels [2.13; 95% CI 1.62-2.80; p < 0.001]. Obese patients were more likely to have sub-therapeutic 6-TGN levels and a higher methyl mercaptopurine nucleotide [MMPN/TGN] ratio despite a similar dose of thiopurines.
  
  
  CONCLUSIONS
  Active smoking and intermediate TPMT values were associated with higher 6-TGN levels but increasing BMI resulted in lower 6-TGN and higher MMPN levels. This may explain the worse outcome that has been reported previously in obese IBD subjects.
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Shi Sum
authors.initials: SS
authors.lastname: Poon
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, Waterhouse Building, Liverpool, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Asher
authors.affiliation: Cancer Research UK Liverpool Cancer Trials Unit, Waterhouse Building, Liverpool, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kneebone
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Collins
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Probert
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK.
authors.forename: Martyn
authors.initials: M
authors.lastname: Dibb
authors.affiliation: Department of Gastroenterology, Royal Liverpool University Hospital, Liverpool, UK sreedhar.subramanian@rlbuht.nhs.uk.
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Subramanian
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D003093:Colitis, Ulcerative / Q000097:blood / Q000150:complications / Q000188:drug therapy; D003424:Crohn Disease / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D016014:Linear Models; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000175:diagnosis; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects*; D013873:Thionucleotides / Q000097:blood*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D001379:Azathioprine
keywords: Crohn’s disease; Inflammatory bowel disease; body mass index; smoking; thioguanine nucleotides; thiopurines; ulcerative colitis