Location 59UTR dbSNP rs1523130 Intron 1 rs2472677 Exon 2 rs12727613 Exon 2 rs12721607 Exon 4 - Exon 4 rs12721608 Exon 4 rs12721611 Exon 5 rs12721600 Exon 6 rs12721612 Intron 6 rs2276707 Exon 8 rs59152710 -25913 C.T -6994 C.T 79 C.T 106 G.A 4306 C.G 4321 G.A 4447 T.C 4499 C.T 4773 G.A 8055 C.T 8528 G.A CC CT TT CC CT TT CC CT TT GG GA AA CC CG GG GG GA AA TT TC CC CC CT TT GG GA AA CC CT TT GG GA AA 0.325 0.35 0.325 0.368 0.352 0.282 0.957 0.043 0 0.974 0.026 0 0.974 0.026 0 0.974 0.026 0 0.983 0.017 0 0.983 0.017 0 0.992 0.08 0 0.769 0.214 0.017 0.992 0.08 0 CLINICS 2011;66(6):1041-1044 Table 2 - Genotypic frequency of polymorphisms in the PXR gene in Brazilians. *Position in AF364606 Frequency Italics: new variant, *Position in relation to translation start site of PXR (NR1I2): GenBank Accession AF364606. This study was carried out in order to determine the frequency of variants of the PXR gene in a sample of the Brazilian population. We found 11 polymorphisms in the PXR gene, including the 4306 C.G substitution in exon 4 that has not been previously described. This variant is not predicted to alter the splice site in exon 4 of the PXR gene and is unlikely to alter protein function. The Brazilian population is highly heterogeneous, result- ing from centuries of interbreeding among peoples from three continents: European colonizers (mostly Portuguese), African slaves, and native Indians.21 Although Brazilians contain approximately 28% of African alleles, we found that the variant C79T (rs12727613), which occurs in 20% of alleles Africans, occurred at a much lower than expected frequency in our sample (2.1%). On the other hand, the –25913 C.T (rs1523130) polymorphism that is present in 28% of African alleles was present at a significantly higher frequency in our population (50%, p = 0.003). We also found that the - 6994T.C (rs2472677), which is present in 38% of African alleles, was significantly more frequent in the Brazilian alleles (46%, p = 0.03). Finally, the –25913 C.T and – 6994T.C polymorphisms were not as frequent in the Brazilian alleles as in Caucasian alleles (p , 0.05). Our results are distinctly clustered. This could represent the unique admixture of the regional subpopulation from the southeast region of Brazil, which has similar ancestral 1043 Genetic polymorphisms of PXR in Brazilians Moreira RPP et al. contributions from African (34%), European (31%), and Native American (33%) alleles, in contrast to the higher proportion of African lineages observed in the northeast region.21-23 Our study emphasizes the population-dependent fre- quency of PXR polymorphisms. The polymorphism fre- quencies found in our sample differ greatly from those previously described in Caucasians and Africans. Our results suggest that variants in the PXR gene should be considered in pharmacogenetic studies involving Brazilians from the southeast region, since the miscegenation varies from region to region. ACKNOWLEDGEMENTS The authors gratefully acknowledge Mr. Ricardo de Paula for language editing. This research was supported by grants from FAPESP # 05/04726-0 and 09/54238-2, RPP Moreira by FAPESP # 08/50959-4 and 09/54394-4, and Bachega TASS, Jorge AA, and Mendonca BB by CNPq #305117/ 2009-2, #301477/2009-4, and #301339/2008-9, respectively. REFERENCES 1. Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci. 1999;20:342-9, doi: 10.1016/S0165- 6147(99)01363-2. 2. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L, et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000;10:373-88, doi: 10.1097/00008571-200007000-00001. 3. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487-91, doi: 10. 1126/science.286.5439.487. 4. Lamba J, Lamba V, Strom S, Venkataramanan R, Schuetz E. Novel single nucleotide polymorphisms in the promoter and intron 1 of human pregnane X receptor/NR1I2 and their association with CYP3A4 expression. Drug Metab Dispos. 2008;36:169-81, doi: 10.1124/dmd.107. 016600. 5. Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst. 1998;90:1225-9, doi: 10.1093/jnci/90.16.1225. 6. Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, et al. Population distribution and effects on drug metabolism of a genetic variant in the 59 promoter region of CYP3A4. Clin Pharmacol Ther. 1999;66:288-94, doi: 10.1016/S0009-9236(99)70037-8. 7. Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedel E, Hustert E, et al. Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics. 2001;11:447-58, doi: 10.1097/ 00008571-200107000-00008. 8. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow- Backman M, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A. 1998;95:12208-13, doi: 10.1073/pnas.95.21.12208. 9. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998;92:73-82, doi: 10.1016/S0092- 8674(00)80900-9. 10. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998;102:1016-23, doi: 10.1172/JCI3703. 11. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med. 2001;7:584- 90, doi: 10.1038/87912. 12. Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, et al. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001;11:555-72, doi: 10.1097/00008571-200110000- 00003. 13. Svard J, Spiers JP, Mulcahy F, Hennessy M. Nuclear Receptor-Mediated Induction of CYP450 by Antiretrovirals: Functional Consequences of NR1I2 (PXR) Polymorphisms and Differential Prevalence in Whites and Sub-Saharan Africans. J Acquir Immune Defic Syndr. 14. Wang XD, Deng XY, Chen J, Li JL, Chen X, Zhao LZ, et al. Single nucleotide polymorphisms of the pregnane x receptor gene in Han