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

• Main Authors: Swart Marelize, Whitehorn Heather, Ren Yuan, Smith Peter, Ramesar Rajkumar S, Dandara Collet
• Format: Article
• Language: English
• Published: BMC 2012-11-01
• Series: BMC Medical Genetics
• Subjects: CAR; Efavirenz; HIV/AIDS; PXR; Pharmacogenetics; South Africa
• Online Access: http://www.biomedcentral.com/1471-2350/13/112

<p>Abstract</p> <p>Background</p> <p>This study investigated variation in <it>NR1I2</it> and <it>NR1I3</it> 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 <it>NR1I2</it> and <it>NR1I3</it>, coding for PXR and CAR, respectively, that are involved in regulating DMEs.</p> <p>Methods</p> <p>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 <it>NR1I2</it> and <it>NR1I3</it>. 32 of the 301 patients had their DNA binding domains (DBDs) in <it>NR1I2</it> and <it>NR1I3</it> sequenced.</p> <p>Results</p> <p>Significantly decreased efavirenz plasma concentrations were observed in patients carrying the <it>NR1I3 rs3003596C/C</it> and <it>T/C</it> 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 <it>NR1I2</it>. There were significant differences in the distribution of <it>NR1I2</it> and <it>NR1I3</it> SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups.</p> <p>Conclusion</p> <p>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.</p>