Abstract
BackgroundThis 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.Methods464 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.ResultsSignificantly 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.ConclusionFor the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.
Highlights
This study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/ AIDS patients
The efavirenz plasma concentration in the South African HIV/AIDS patients showed a large degree of variation (36-fold), ranging between 0.59 and 22 μg/mL, suggesting extensive inter-individual variability in efavirenz drug metabolism and disposition
Genotype frequencies Genotype frequencies were compared between the healthy subjects and HIV/AIDS patients for the six SNPs, three each in NR1I2 and NR1I3, genotyped using SNaPshot or PCR-RFLP
Summary
This study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/ AIDS patients. NR1I2 gene, which encodes PXR, consists of 10 exons and is located on chromosome 3q13-21 [5]. The NR1I2 DNA binding domain (DBD) is encoded by exons 3 and 4 whereas exons 5–10 code for the ligand binding domain (LBD). Several SNPs have been reported in NR1I2 and some are associated with changes in PXR function. NR1I2 63396C>T (rs2472677), which is located in a putative transcription factor binding site, has been associated with increased NR1I2 expression in the presence of the 63396T variant, which leads to increased CYP3A4 expression leading to decreased atazanavir (ATV) plasma concentrations [6,7,8]. Three SNPs in exon 2 have been reported, namely NR1I2 52G>A (E18K; rs59371185), 79C>T (P27S; rs12721613) and 106G>A (G36R; rs12721607). Another SNP, NR1I2 7635A>G (rs6785049), is present in intron 5 and the 7635G allele has been associated with increased expression of CYP3A4 in the presence of rifampicin [9]
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