Association of thymidylate synthase polymorphisms with acute pancreatitis and/or peripheral neuropathy in HIV-infected patients on stavudine-based therapy

PLoS One. 2013;8(2):e57347. doi: 10.1371/journal.pone.0057347. Epub 2013 Feb 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Pancreatitis / complications*
  • Pancreatitis / genetics
  • Peripheral Nervous System Diseases / complications*
  • Peripheral Nervous System Diseases / genetics
  • Polymorphism, Genetic*
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Stavudine / therapeutic use*
  • Thymidylate Synthase / genetics*

Substances

  • Reverse Transcriptase Inhibitors
  • Stavudine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Thymidylate Synthase

Grants and funding

This work has been partially funded by Fondo de Investigaciones Sanitarias (FIS 02/1280, 05/1591, 07/0976, 08/00256), Fundación para la Prevención del SIDA en España (FIPSE 36610, 36572/06), and Red de Investigación en SIDA (RIS RD06/006/0022). Pere Domingo is supported by Programa de Intensificación de Investigadores del Instituto de Salud Carlos III (INT12/383).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.