Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals

Mônica Barcellos Arruda; Francine Campagnari; Tailah Bernardo de Almeida; José Carlos Couto-Fernandez; Amilcar Tanuri; Cynthia Chester Cardoso

doi:10.1371/journal.pone.0163170

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals

PLoS One. 2016 Sep 20;11(9):e0163170. doi: 10.1371/journal.pone.0163170. eCollection 2016.

Authors

Mônica Barcellos Arruda¹, Francine Campagnari², Tailah Bernardo de Almeida¹, José Carlos Couto-Fernandez³, Amilcar Tanuri¹, Cynthia Chester Cardoso¹

Affiliations

¹ Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
² Deoxi Biotecnologia. Araçatuba, São Paulo, Brasil.
³ Laboratório de Aids e Imunologia Molecular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil.

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.

MeSH terms

Alleles
Anti-HIV Agents / therapeutic use*
Case-Control Studies
Female
HIV Infections / drug therapy
HIV Infections / genetics*
HIV Seropositivity / drug therapy
HIV Seropositivity / genetics*
HIV-1
Haplotypes
Humans
Male
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins / genetics*
Organic Anion Transporters / genetics*
Pharmacogenetics
Polymorphism, Single Nucleotide*
Reverse Transcriptase Inhibitors / therapeutic use*

Substances

ABCC2 protein, human
Anti-HIV Agents
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
Organic Anion Transporters
Reverse Transcriptase Inhibitors
SLCO2B1 protein, human

Grants and funding

This work was supported by the “Brazilian Ministry of Science and Technology” [FINEP 01/2010 – contract number 03.12.0057.00]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Deoxi Biotecnologia provided support in the form of salaries for authors [FC], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.