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Several nuclear receptors are being increasingly recognized for their role as master xenosensors. Among them, CAR-RXRα heterodimer, as encoded by NR1I3and NR2B1,responds to the presence of drug compounds and regulates the transcription of a wide array of genes involved in their disposition. To investigate the frequency distribution and linkage disequilibrium patterns of NR1I3and NR2B1genetic variations, these genes were screened in 168 healthy local Asian subjects, namely Chinese, Malays, and Indians (n= 56 subjects each). A total of 38 and 88 SNPs were identified in NR1I3and NR2B1,respectively. Among them, there were 13 and 43 novel SNPs present at low allelic frequencies (<10%) in NR1I3and NR2B1,respectively. Notably, the genetic variations in the NR1I3and NR2B1genes were mainly confined to the introns whilst the exons were highly conserved across the ethnic populations. Indians harboured distinct frequency distributions from Chinese and Malays in both genes. Based on the linkage disequilibrium patterns of both genes, a number of tag-SNPs were selected for each population (n= 8-13 for NR1I3; n= 12-18 for NR2B1). In-silicoprediction analyses revealed a number of possible functional SNPs. Our data would be valuable for future pharmacogenetic studies on the drug substrates of CAR-RXRa target genes.

HNF4α(encoded by gene NR2A1) is a dominant transcriptional regulator of various drug disposition genes. It forms a circuitry of molecular cross-talk with other nuclear receptors such as PXR and CAR to synergistically initiate transcription. This study reports on the frequency, linkage disequilibrium pattern and tag-SNP selection of NR2A1polymorphisms in three local Asian populations, namely Chinese, Malays and Indians (n=56 subjects each). A total of 69 polymorphisms were identified in the genomic region of NR2A1, of which thirty-three were novel polymorphisms with low allelic frequencies (<0.02). The exonic region of NR2A1was highly conserved with only 4 novel and 1 reported SNPs identified at low allelic frequencies of less than 0.02. Based on the criteria of MAF≥0.05 and R2≥0.80, there were 19, 20 and 22 tag-SNPs selected to represent the genetic polymorphisms of NR2A1in Chinese, Malays and Indians, respectively. In-silicopredictions suggested that some of these polymorphic variants may exert functional effects through affecting the binding sites of transcription and splicing factors. Our study provides valuable information on the genetic variability of NR2A1which would be useful for pharmacogenetics studies in the local Asian populations.

Warfarin exhibits wide interpatient variability in dosing requirements. Recent studies have shown a novel polymorphism (rs2108622, V433M) in the CYP4F2gene to be associated with variability in warfarin requirements in Caucasians. The purpose of this study was to evaluate the impact of rs2108622 on warfarin dose requirements in the Asian population. The mean warfarin dose was found to be significantly lower in patients carrying homozygous wild-type allele CC when compared with patients carrying variant alleles CT and TT (CC vsCT+TT: 3.0 mg/day vs3.75 mg/day, p= 0.033). In patients harboring VKORC1diplotypes associated with low warfarin requirements, a linear regression model which included age, weight, CYP2C9 and CYP4F2variants accounted for 38% of the variability in warfarin dose. Approximately 11% of the dose variation was explained by CYP4F2rs2108622 (p= 0.004). The influence of rs2108622 in patients harboring VKORC1diplotypes associated with high warfarin requirements was not significant. This study suggests that CYP4F2rs2108622 may significantly affect warfarin dose requirements in carriers of VKORC1low-dose-associated diplotypes.

Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1diplotypes, CYP2C9and CYP2C19variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9and CYP2C19polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9and CYP2C19pharmacogenetics. The major VKORC1diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H*b(10%). Warfarin dose requirements were significantly lower in patients with VKORC1H1-H1 and H1-H*adiplotypes compared to patients harboring the H1-H7 and H1-H*bdiplotypes (P<0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1mRNA compared with liver tissues carrying the H1-H7 and H1-H*bdiplotypes (P=0.006). The percent variability explained by VKORC1diplotype status was 59.1% while the CYP2C9genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1diplotype status, CYP2C9genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.