title: Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.
abstract: Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.
authors.affiliation: Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Mônica Barcellos
authors.initials: MB
authors.lastname: Arruda
authors.affiliation: Deoxi Biotecnologia. Araçatuba, São Paulo, Brasil.
authors.forename: Francine
authors.initials: F
authors.lastname: Campagnari
authors.affiliation: Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Tailah Bernardo
authors.initials: TB
authors.lastname: de Almeida
authors.affiliation: Laboratório de Aids e Imunologia Molecular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Couto-Fernandez
authors.affiliation: Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Tanuri
authors.affiliation: Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
authors.forename: Cynthia Chester
authors.initials: CC
authors.lastname: Cardoso
mesh_terms: D000483:Alleles; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006679:HIV Seropositivity / Q000188:drug therapy / Q000235:genetics*; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D018894:Reverse Transcriptase Inhibitors; C000715087:ABCC2 protein, human; C450859:SLCO2B1 protein, human