Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV-1 infected Thai adults

Authors

  • Chonlaphat Sukasem,

    Corresponding author
    1. Laboratory for Pharmacogenomics and Personalized Medicine
    2. Laboratory for Virology and Molecular Microbiology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
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  • Tim R. Cressey,

    1. Program for HIV Prevention and Treatment (IRD URI 174), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
    2. Harvard School of Public Health, Boston, MA, USA
    3. Institut de Recherché pour le Développement (IRD), UMI 174-PHPT, France
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  • Pattamawan Prapaithong,

    1. Laboratory for Pharmacogenomics and Personalized Medicine
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  • Yardpiroon Tawon,

    1. Program for HIV Prevention and Treatment (IRD URI 174), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
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  • Ekawat Pasomsub,

    1. Laboratory for Virology and Molecular Microbiology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
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  • Chutatip Srichunrusami,

    1. Laboratory for Virology and Molecular Microbiology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
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  • Thawinee Jantararoungtong,

    1. Laboratory for Pharmacogenomics and Personalized Medicine
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  • Marc Lallement,

    1. Program for HIV Prevention and Treatment (IRD URI 174), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
    2. Harvard School of Public Health, Boston, MA, USA
    3. Institut de Recherché pour le Développement (IRD), UMI 174-PHPT, France
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  • Wasun Chantratita

    1. Laboratory for Virology and Molecular Microbiology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
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Dr Chonlaphat Sukasem B.Pharm., PhD, Laboratory for Pharmacogenetics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Tel.: +66 2 2004 3301. Fax: +66 2200 4332. E-mail: racska@mahidol.ac.th

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Interindividual variability in efavirenz plasma concentrations is associated with CYP2B6 genetic polymorphisms.

• Twenty-nine different alleles of the CYP2B6 gene are listed. CYP2B6*6, *9, *16, *26, *27 and *28 carriers are reported to be associated with slower efavirenz oral clearance.

• The allelic variant 516G>T is associated with diminished activity of CYP2B6 and high efavirenz plasma concentrations are associated with an increase risk of neuropsychological toxicity.

WHAT THIS STUDY ADDS

• This study identified three SNPs in the CYP2B6 gene which could potentially act as additional independent predictors of efavirenz plasma concentrations beyond that provided by the CYP2B6 c.516G>T polymorphism.

• The GAC-CYP2B6 haplotype (G516T/A785G/C21563T) is associated with higher plasma efavirenz concentrations in HIV-infected Thai adults.

• The CYP2B6 g.18492 T>C polymorphism was significantly associated with lower efavirenz concentrations than those with the homozygous wild-type.

Aims

To investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV-1 infection.

Methods

Genotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real-time PCR-based allelic discrimination on blood samples from 52 HIV-infected adults who had received an efavirenz-based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography.

Results

The minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations.

Conclusions

Our data indicate that the GAC-CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV-infected Thai adults.

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