Open Access Research article

PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients

Marelize Swart1, Heather Whitehorn1, Yuan Ren2, Peter Smith2, Rajkumar S Ramesar1 and Collet Dandara1*

Author Affiliations

1 Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa

2 Department of Clinical Pharmacology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa

For all author emails, please log on.

BMC Medical Genetics 2012, 13:112  doi:10.1186/1471-2350-13-112

Published: 22 November 2012

Abstract

Background

This study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/AIDS patients. Variability in plasma drug levels has largely led research on identifying causative variants in drug metabolising enzyme (DME) genes, with little focus on the nuclear receptor genes NR1I2 and NR1I3, coding for PXR and CAR, respectively, that are involved in regulating DMEs.

Methods

464 Bantu-speaking South Africans comprising of HIV/AIDS patients on efavirenz-based treatment (n=301) and 163 healthy subjects were genotyped for 6 SNPs in NR1I2 and NR1I3. 32 of the 301 patients had their DNA binding domains (DBDs) in NR1I2 and NR1I3 sequenced.

Results

Significantly decreased efavirenz plasma concentrations were observed in patients carrying the NR1I3 rs3003596C/C and T/C genotypes (P=0.015 and P=0.010, respectively). Sequencing resulted in the discovery of a further 13 SNPs, 3 of which are novel variants in the DBD of NR1I2. There were significant differences in the distribution of NR1I2 and NR1I3 SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups.

Conclusion

For the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.

Keywords:
CAR; Efavirenz; HIV/AIDS; PXR; Pharmacogenetics; South Africa