title: Association of thymidylate synthase polymorphisms with acute pancreatitis and/or peripheral neuropathy in HIV-infected patients on stavudine-based therapy.
abstract: BACKGROUND
  Low expression thymidylate synthase (TS) polymorphism has been associated with increased stavudine triphosphate intracellular (d4T-TP) levels and the lipodystrophy syndrome. The use of d4T has been associated with acute pancreatitis and peripheral neuropathy. However, no relationship has ever been proved between TS polymorphisms and pancreatitis and/or peripheral neuropathy.
  
  
  METHODS
  We performed a case-control study to assess the relationship of TS and methylene-tetrahydrofolate reductase (MTHFR) gene polymorphisms with acute pancreatitis and/or peripheral neuropathy in patients exposed to d4T. Student's t test, Pearson's correlations, one-way ANOVA with Bonferroni correction and stepwise logistic regression analyses were done.
  
  
  RESULTS
  Forty-three cases and 129 controls were studied. Eight patients (18.6%) had acute pancreatitis, and 35 (81.4%) had peripheral neuropathy. Prior AIDS was more frequent in cases than in controls (OR = 2.36; 95%CI 1.10-5.07, P = 0.0247). L7ow expression TS and MTHFR genotype associated with increased activity were more frequent in patients with acute pancreatitis and/or peripheral neuropathy than in controls (72.1% vs. 46.5%, OR = 2.97; 95%CI: 1.33-6.90, P = 0.0062, and 79.1% vs. 56.6%, OR = 2.90, 95%CI: 1.23-7.41, P = 0.0142, respectively). Independent positive or negative predictors for the development of d4T-associated pancreatitis and/or peripheral neuropathy were: combined TS and MTHFR genotypes (reference: A+A; P = 0.002; ORA+B = 0.34 [95%CI: 0.08 to 1.44], ORB+A = 3.38 [95%CI: 1.33 to 8.57], ORB+B = 1.13 [95%CI: 0.34 to 3.71]), nadir CD4 cell count >200 cells/mm(3) (OR = 0.38; 95%CI: 0.17-0.86, P = 0.021), and HALS (OR = 0.39 95%CI: 0.18-0.85, P = 0.018).
  
  
  CONCLUSIONS
  Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients.
authors.affiliation: Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. pdomingo@santpau.cat
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Maria del Carmen
authors.initials: Mdel C
authors.lastname: Cabeza
authors.forename: Ferran
authors.initials: F
authors.lastname: Torres
authors.forename: Juliana
authors.initials: J
authors.lastname: Salazar
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: Gutierrez
authors.forename: Maria Gracia
authors.initials: MG
authors.lastname: Mateo
authors.forename: Esteban
authors.initials: E
authors.lastname: Martínez
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Domingo
authors.forename: Irene
authors.initials: I
authors.lastname: Fernandez
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.forename: Esteban
authors.initials: E
authors.lastname: Ribera
authors.forename: Francesc
authors.initials: F
authors.lastname: Vidal
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
mesh_terms: D000208:Acute Disease; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D010195:Pancreatitis / Q000150:complications* / Q000235:genetics; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000235:genetics; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018119:Stavudine / Q000627:therapeutic use*; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase