{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T19:51:52Z","timestamp":1760385112174,"version":"3.38.0"},"reference-count":49,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2011,4,1]],"date-time":"2011-04-01T00:00:00Z","timestamp":1301616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T-TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjusted<jats:italic>post hoc<\/jats:italic>comparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol\/10<jats:sup>6<\/jats:sup>cells (interquartile range [IQR] = 8.12 to 13.87 fmol\/10<jats:sup>6<\/jats:sup>cells) in patients with a high-expression TS genotype (2\/3G, 3C\/3G, and 3G\/3G), whereas in those with a low-expression TS genotype (2\/2, 2\/3C, and 3C\/3C), they were 21.40 fmol\/10<jats:sup>6<\/jats:sup>cells (IQR = 18.90 to 27.0 fmol\/10<jats:sup>6<\/jats:sup>cells) (<jats:italic>P<\/jats:italic>&lt; 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable;<jats:italic>P<\/jats:italic>= 0.0023). The low-expression TS genotype was associated with the development of HIV\/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0;<jats:italic>P<\/jats:italic>= 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS.<\/jats:p>","DOI":"10.1128\/aac.01589-10","type":"journal-article","created":{"date-parts":[[2011,2,1]],"date-time":"2011-02-01T03:38:51Z","timestamp":1296531531000},"page":"1428-1435","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy"],"prefix":"10.1128","volume":"55","author":[{"given":"Pere","family":"Domingo","sequence":"first","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Carmen","family":"Cabeza","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Pruvost","sequence":"additional","affiliation":[{"name":"CEA, iBiTecS, SPI, Laboratoire d'Etude du Me\u0301tabolisme des Me\u0301dicaments, Gif sur Yvette F-91191, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferran","family":"Torres","sequence":"additional","affiliation":[{"name":"Statistics &amp; Methodology Support Unit (USEM), IDIBAPS (Hospital Clinic), Laboratory of Biostatistics &amp; Epidemiology, Universitat Autonoma de Barcelona, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Salazar","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hospital de la Santa Creu i Sant Pau, U-705 CIBERER, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"del Mar Gutierrez","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Gracia","family":"Mateo","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angels","family":"Fontanet","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Auto\u0300noma de Barcelona, Barcelona, Spain, and Red de Investigacio\u0301n en SIDA (RIS), Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan C.","family":"Domingo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain, and CIBER Fisiopatologia Obesidad y Nutricio\u0301n, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesc","family":"Villarroya","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain, and CIBER Fisiopatologia Obesidad y Nutricio\u0301n, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesc","family":"Vidal","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, Department of Internal Medicine, Hospital Universitari Joan XXIII, IISPV, Universitat Rovira I Virgili, Tarragona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montserrat","family":"Baiget","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hospital de la Santa Creu i Sant Pau, U-705 CIBERER, Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/381678"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0953-6205(03)00022-0"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(00)00050-4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2004.03.015"},{"key":"e_1_3_2_6_2","first-page":"1005","volume":"11","year":"1995","unstructured":"Betticher, D. 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