Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

PLoS One. 2013 Jun 26;8(6):e67035. doi: 10.1371/journal.pone.0067035. Print 2013.

Abstract

Purpose: To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS).

Methods: Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method.

Results: HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53-3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/10(6) cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): 'A+A'; OR for 'A+B' vs. ref.: 1.39 [0.69-2.80]; OR for 'B+A' vs. ref.: 2.16 [1.22-3.83]; OR for 'B+B' vs. ref.: 3.13, 95%CI: 1.54-6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56-4.14, P = 0.001), (c) use of EFV (1.10 [1.00-1.21], P = 0.008, per year of use).

Conclusion: HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Genotype
  • HIV Infections / complications
  • HIV Infections / drug therapy*
  • HLA-B40 Antigen / genetics*
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Lipodystrophy / chemically induced
  • Lipodystrophy / enzymology*
  • Lipodystrophy / genetics*
  • Lipodystrophy / pathology
  • Male
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / diagnosis
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Middle Aged
  • Polymorphism, Genetic*
  • Pyrimidines / metabolism*
  • Stavudine / adverse effects*
  • Stavudine / therapeutic use
  • Thymidylate Synthase / genetics
  • Thymidylate Synthase / metabolism

Substances

  • HLA-B40 Antigen
  • Pyrimidines
  • Stavudine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Thymidylate Synthase
  • pyrimidine

Grants and funding

This work has been partially funded by Fondo de Investigaciones Sanitarias (FIS PI08/00256, PI10/2635 and PI11/0376), Fundación para la Investigación y Prevención del SIDA en España (FIPSE 36610, 36572/06), Ministerio de Sanidad, Politica Social e Igualdad (EC11-293), Programa de Suport als Grups de Recerca AGAUR (2009 SGR 1061), and Red de Investigación en SIDA (RIS RD12/0017/0005, RD12/0017/0014). Pere Domingo and Francesc Vidal are supported by grants from the Programa de Intensificación de Investigadores, Instituto de Salud Carlos III (INT12/383, INT11/240 and INT12/282). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.