title: Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Maria Gracia
authors.initials: MG
authors.lastname: Mateo
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
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: 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: Francesc
authors.initials: F
authors.lastname: Vidal
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Oscar
authors.initials: O
authors.lastname: de la Calle-Martín
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D059947:HLA-B40 Antigen / Q000235:genetics*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008060:Lipodystrophy / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000175:diagnosis; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000378:metabolism*; D018119:Stavudine / Q000009:adverse effects* / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D059947:HLA-B40 Antigen; D011743:Pyrimidines; D018119:Stavudine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; C030986:pyrimidine