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

Pere Domingo, Maria Gracia Mateo, Alain Pruvost, Ferran Torres, Juliana Salazar, Marial Mar de Gutierrez, M. Cabeza Carmen, Joan Carles Domingo, Irene Fernandez, Francesc Villarroya, Francesc Vidal, Montserrat Baiget, Oscar de la Calle-Martín

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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. © 2013 Domingo et al.
Original languageEnglish
Article numbere67035
JournalPLoS ONE
Volume8
Issue number6
DOIs
Publication statusPublished - 26 Jun 2013

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