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

• Published in: PloS one Vol. 8; no. 2; p. e57347
• Main Authors: Domingo, Pere, Cabeza, Maria del Carmen, Torres, Ferran, Salazar, Juliana, Gutierrez, Maria del Mar, Mateo, Maria Gracia, Martínez, Esteban, Domingo, Joan Carles, Fernandez, Irene, Villarroya, Francesc, Ribera, Esteban, Vidal, Francesc, Baiget, Montserrat
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.02.2013; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Acute Disease; AIDS; Antiretroviral drugs; Assaigs clínics; Biology; CD4 antigen; Clinical trials; Gene polymorphism; Genotypes; HIV; HIV infections; HIV Infections - complications; HIV Infections - drug therapy; Human immunodeficiency virus; Humans; Infeccions per VIH; Lipodystrophy; Malalties del sistema nerviós; Medicine; Methylenetetrahydrofolate reductase; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Mutation; Nervous system diseases; Pancreatitis; Pancreatitis - complications; Pancreatitis - genetics; Patients; Peripheral Nervous System Diseases - complications; Peripheral Nervous System Diseases - genetics; Peripheral neuropathy; Polymorphism; Polymorphism, Genetic; Regression analysis; Reverse Transcriptase Inhibitors - therapeutic use; Stavudine; Stavudine - therapeutic use; Tetrahydrofolic acid; Thymidylate synthase; Thymidylate Synthase - genetics; Variance analysis; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0057347

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. 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. 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). Low expression TS plus a MTHFR genotype associated with increased activity is associated with the development of peripheral neuropathy in d4T-exposed patients.