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GENE-38512; No. of pages: 6; 4C: Gene xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations Osvaldo D. Castelán-Martínez a, b, Carlos Hoyo-Vadillo b, Emmanuel Sandoval-García a, Lucila Sandoval-Ramírez c, Miriam González-Ibarra a, Gloria Solano-Solano d, Rita A. Gómez-Díaz e, Esteban J. Parra f, Miguel Cruz a, Adán Valladares-Salgado a,⁎ a Unidad de Investigación Médica en Bioquímica Centro Médico Nacional, “Siglo XXI” IMSS, Mexico Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados, IPN, Mexico c Centro de Investigación Biomédica de Occidente, CMNO, IMSS, Mexico d Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Mexico e Unidad de Investigación Médica en Epidemiología Clínica, Centro Médico Nacional, “Siglo XXI” IMSS, Mexico f Department of Anthropology, University of Toronto at Mississauga, ON, Canada b a r t i c l e i n f o Article history: Accepted 27 March 2013 Available online xxxx Keywords: American-Indigenous CYP2C9*2 CYP2C9*3 Mexican-Indigenous Mexican-Mestizo Pharmacogenomics a b s t r a c t Allele frequency differences of functional CYP2C9 polymorphisms are responsible for some of the variation in drug response observed in human populations. The most relevant CYP2C9 functional variants are CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). These polymorphisms show variation in allele frequencies among different population groups. The present study aimed to analyze these polymorphisms in 947 Mexican-Mestizo from Mexico City and 483 individuals from five indigenous Mexican populations: Nahua, Teenek, Tarahumara, Purepecha and Huichol. The CYP2C9*2 allele frequencies in the Mestizo, Nahua and Teenek populations were 0.051, 0.007 and 0.005, respectively. As for CYP2C9*3, the allelic frequencies in the Mestizo, Nahua and Teenek populations were 0.04, 0.005 and 0.005, respectively. The CYP2C9*2 and CYP2C9*3 alleles were not observed in the Tarahumara, Purepecha and Huichol populations. These findings are in agreement with previous studies reporting very low allele frequencies for these polymorphisms in American Indigenous populations. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Several studies have reported that some interethnic differences in drug response have their origin in the presence of functional polymorphisms with varying allele frequencies in genes related to the absorption, distribution, metabolism and excretion of drugs, as well as their therapeutic targets (Evans and McLeod, 2003; Ingelman-Sundberg, 2001; Zhou et al., 2008). It has been estimated that genetics account for 20–95% of variability in drug disposition and effects (Hitchen, 2006). Genetic polymorphisms of cytochrome P450 (CYP) enzymes are major determinants of inter-individual variability in therapeutic responses and adverse events (Rendic and Di Carlo, 1997). A recent study focused on the CYP superfamily has indicated that many of the genes in this Abbreviations: CEPH-HGDP, Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Project; CYP, cytochrome P-450; CYP2C9, cytochrome P-450 CYP2C9 gene; CYP2C9*1, allele 1 of the CYP2C9 gene; CYP2C9*2, allele 2 of the CYP2C9 gene; CYP2C9*3, allele 3 of the CYP2C9 gene; DNA, deoxyribonucleic acid; IMSS, Mexican Institute of Social Security; LA, Los Angeles, CA, USA.; PCR, polymerase chain reaction; VKORC1, vitamin K epoxidase gene; SNP, single nucleotide polymorphism. ⁎ Corresponding author at: Centro Médico Nacional, “Siglo XXI” IMSS, Av Cuauhtemoc 330 Col. Doctores, CP 06720 México DF, Mexico. Tel.: +52 55 5761 2358; fax: +52 55 5627 6914. E-mail address: [email protected] (A. Valladares-Salgado). superfamily show substantial genetic differentiation in human populations (Polimanti et al., 2012). Within the CYP superfamily, the CYP2C subfamily plays a key role on the metabolism of many drugs commonly prescribed world-wide. CYP2C9 is a CYP enzyme that accounts for approximately 20% of the total human CYP protein content in adult liver (Xie et al., 2002). CYP2C9 is responsible for the metabolism of approximately 16% of clinically used drugs cleared by oxidative pathways (Williams et al., 2004). Several of these drugs have narrow therapeutic indices, such as the anticoagulant warfarin and the anticonvulsant phenytoin (Lee et al., 2002; Ross et al., 2010). Other therapeutically important drugs metabolized by CYP2C9 include the anti-diabetic drugs tolbutamide, glipizide and glibenclamide, the diuretic torsemide, cardiovascular drugs like losartan and rosuvastatine, and several nonsteroidal anti-inflammatory drugs, including flurbiprofen, ibuprofen and diclofenac (Miners and Birkett, 1998; Zanger et al., 2008). The human CYP2C9 gene has been mapped to chromosome 10q24 (Nelson et al., 1996; Zanger et al., 2008). The most common allele, considered as the wild type, is denoted CYP2C9*1. Many polymorphisms within the CYP2C9 gene have been reported, with at least eight known as nonfunctional alleles found in different ethnics groups (De Lozier et al., 2005). These codify enzymes with either decreased activity or with a truncated inactive protein. Among these functional variants, CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910) have been extensively studied. 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.03.128 Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128 1.0 – – – – – 73 0 0 0 0 0 – – – – – – 48 0 0 0 0 0 52 0 0 0 0 0 0.97 0.02 0.01 0.01 0 0.00 0.91–0.99 0.0011–0.075 0.00–0.061 – – – 0.97 0.02 0.01 0 0 0 95 2 1 0 0 0 0.98 0.014 0.009 0.01 – 0.001 0.94–0.99 0.003–0.04 0.003–0.036 – – – 0.976 0.014 0.009 0 0 0 a Expected frequency calculated by Hardy–Weinberg law. 207 3 2 0 0 0 0.83 0.089 0.068 0.002 0.0064 0.0013 0.81–0.85 0.07–0.106 0.053–0.085 0.001–0.012 0.003–0.015 0.00–0.008 0.83 0.087 0.068 0.004 0.007 0.002 788 82 64 4 7 2 CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 95% CI 1.0 – – – – – – – – – – – 1.0 – – – – – Observed frequency N Observed frequency N 95% CI Observed frequency N 95% CI Observed frequency N N Expected frequencya Nahua n = 212 Mexico City-Mestizo n = 947 CYP2C9 genotype Table 1 CYP2C9 genotype frequencies among Mexico City Mestizo and five Native Mexican populations. 2.1. Subjects and study protocol Four hundred eighty-three unrelated healthy Mexicans from five indigenous groups (Nahua, Teenek, Tarahumara, Purepecha and Huichol), living in different states of Mexico, were included in the present study. The Tarahumara, Purepecha and Huichol population have been previously described elsewhere (Garcia-Ortiz et al., 2004; Nuño-Arana et al., 2005; Villalobos-Arámbula et al., 2000). The 212 Nahua individuals came from 6 municipalities: Agua Blanca, Metepec, Tenango de Doria, Tutotepec, Acaxochitlán and San Bartolo, which are located in central Mexico in the area between the Tulancingo valley and the Huasteca Hidalguense region. The 98 Teenek individuals were from the Huasteca Potosina region within the Panuco River basin, east of the state of San Luis Potosi. The 48 Purepecha individuals were from the municipalities of Erongericuaro, Cutzamala de Pinzón, Uruapan, Mapízaro, Patzcuaro and Cueneo in Michoacan. The 52 Tarahumara participants from the northern region of Chihuahua came from 6 different municipalities: Bocoyna, Guachochi, Urique, Guazapares, Temosachi, and Uruachi. Finally, the 73 Huichol individuals came from Nayarit in the following municipalities: Mezquitic, Nayar, Jesús María, Guasave, La Yesca, Tepic and Rosa Morada. To be considered as Mexican indigenous, subjects' families must have lived for at least three generations in the same community, and speak their native indigenous language. In addition, we analyzed 947 unrelated Mestizo individuals who were recruited at the blood bank of the Mexican Institute of Social Security (IMSS) located in the southern area of Mexico City. To be considered as Mexican Mestizo, their families must have lived in Mexico for at least three generations. Written consent was obtained from all participants, if participants do not speak Spanish a translator explained the purpose of the study and signed the consent form. Observed frequency Expected frequencya 2. Material and methods N Teenek n = 98 95% CI Expected frequencya Tarahumara n = 52 Purepecha n = 48 95% CI Huichol n = 73 95% CI The CYP2C9*2 allele encodes a moderately defective protein whereas the CYP2C9*3 allele has lower affinity and markedly lower intrinsic clearance for numerous drugs both in vitro and in vivo (Lee et al., 2002). The CYP2C9*2 allele is primarily restricted to European, Middle Eastern and Central/South Asian populations, and is absent or found at very low frequencies in other geographic regions (Africa, East Asia, Oceania and the Americas). The CYP2C9*3 allele has a broader geographic distribution, but the highest allele frequencies are also found in European and Central/South Asian populations (Ross et al., 2010). The majority of the Mexican population is comprised of Mestizos, the result of an admixture process between the original Mexican indigenous groups and Europeans who arrived to Mexico early in the 16th century, and, to a smaller extent, Africans brought to the country as slaves. Some studies have indicated that admixture proportions show regional variation, with an increased European background in the north and a relatively larger indigenous contribution in the south (Bonilla et al., 2005; R.M. Cerda-Flores et al., 2002; R. Cerda-Flores et al., 2002b; Lisker et al., 1986; Silva-Zolezzi et al., 2009). In addition to the Mestizo population, Mexico currently has 62 indigenous groups representing 9.54% of the total population (Navarrete-Linares, 2008). Variation in allele frequencies has been described for the CYP2C9*2 and CYP2C9*3 polymorphisms in Mexico. These alleles are absent or have very low frequencies in the limited number of Mexican indigenous groups that have been studied and Mexican Mestizo samples are characterized by intermediate frequencies between European and indigenous groups (Aguilar et al., 2008; Dorado et al., 2011; Llerena et al., 2004; Ross et al., 2010). The aim of this study was to characterize the frequency of the CYP2C9*2 and CYP2C9*3 variants in five Mexican indigenous populations; Nahua, Teenek, Tarahumara, Purepecha and Huichol, and a Mestizo population from Mexico City, in order to increase the information available for these polymorphisms of pharmacogenomic relevance in the Mexican population. – – – – – – O.D. Castelán-Martínez et al. / Gene xxx (2013) xxx–xxx Observed frequency 2 Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128 O.D. Castelán-Martínez et al. / Gene xxx (2013) xxx–xxx 3 Table 2 CYP2C9 allele frequencies in Native Mexicans and Mexican Mestizo population. Ethnic group N CYP2C9*1 Frequency Nahua Teenek Tarahumara Purepecha Huichol Mexico City Mestizo a 424 196 104 96 146 1894 0.989 0.990a 1.0a 1.0a 1.0a 0.910 CYP2C9*2 95% CI Frequency a 0.975–0.997 0.961–0.999 – – – 0.896–0.922 0.007 0.005a 0a 0a 0a 0.051 CYP2C9*3 95% CI 0.002–0.024 0.000–0.031 – – – 0.041–0.061 Frequency a 0.004 0.005a 0a 0a 0a 0.039 (95% CI) 0.000–0.018 0.000–0.031 – – – 0.031–0.048 N represents the number of alleles. a P b 0.05 compared with Mexican Mestizos from Mexico City using Fisher's exact test. The percentages of women in Mexico City Mestizos, Nahua, Teenek, Tarahumara, Purepecha and Huichol groups were 67.5%, 80%, 66%, 61.5%, 71.4% and 32%, respectively. The average ages in Mexico City Mestizos, Nahua, Teenek, Tarahumara, Purepecha and Huichol groups were 58, 53, 35, 31, 37 and 28 years, respectively. The protocol was approved by the Institutional Review Board of the National Ethical Committee of the IMSS and is in compliance with the Ethical principles for medical research involving human subjects of the Helsinki Declaration. 2.2. Genotyping Genomic DNA was extracted from a peripheral blood sample using a QIAamp (Qiagen, Germany) kit, and DNA concentration was determined using a VICTOR3 1420 spectrophotometer (Perkin-Elmer, Germany). The SNP analyses were made using real-time PCR (RT-PCR) using TaqMan allelic discrimination assay C_25625805_10 for CYP2C9*2 and C_27104892_10 for CYP2C9*3 (7900HT Applied Biosystems, Foster City, CA, USA), following standard protocols. The plate was run at 95 °C for 10 min, 92 °C for 15 s and then 60 °C for 1 min for 40 cycles. To verify genotyping quality, 714 samples were genotyped as blind duplicated, and the concordance rate between the samples and duplicates was 100%. 2.3. Statistical analysis Deviations of the CYP2C9 genotype frequencies from Hardy– Weinberg proportions were evaluated using the tests available at http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl, (Strom and Wienker, 2009). Allele frequency differences between populations were examined using Fisher's exact tests. A p-value b 0.05 was regarded as statistically significant in all cases. The confidence intervals of the allele frequencies were estimated with GraphPad QuickCalcs (GraphPad Software, Inc., San Diego, CA). 3. Results The CYP2C9 genotype frequencies for the six Mexican populations studied are shown in Table 1. No significant deviations from Hardy– Weinberg proportions were observed in populations where variants are present. No CYP2C9*2 or CYP2C9*3 alleles were present in the Tarahumara, Purepecha and Huichol samples. The allele frequencies of CYP2C9*2 in the Mexico City Mestizo, Nahua and Teenek samples were 0.051, 0.007 and 0.005, respectively (Table 2). As for the CYP2C9*3 allele, the frequencies observed in the Mexico City Mestizo, Nahua and Teenek were 0.039, 0.004 and 0.005, respectively (Table 2). Four CYP2C9*2/*2 and two CYP2C9*3/*3 homozygous individuals were observed in the Mexican Mestizo from Mexico City. This is the first study to find homozygous states for these variants in the Mexican population. Additionally, seven Mestizo individuals were heterozygotes carrying both the CYP2C9*2 and CYP2C9 *3 alleles (Table 1). Table 2 shows the results of the Fisher's exact tests for all possible pairwise comparisons. There were significant differences between the frequencies observed in the Mexico City sample and the five Mexican indigenous groups. In contrast, no significant differences were observed between any of the five indigenous groups, in which alleles CYP2C9*2 or CYP2C9*3 are absent or found in extremely low frequencies (Table 3). 4. Discussion This study examined the allele frequencies of two polymorphisms known to have important clinical implications, CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910), in five indigenous groups and a Mestizo sample from Mexico City. Several studies have indicated that the functional CYP2C9*2 and CYP2C9*3 variants are absent or present in extremely low frequencies in indigenous American populations (Dorado et al., 2011; Gaedigk et al., 2001; Ross et al., 2010; Sosa-Macías et al., 2013). Our results are in overall agreement with previous reports: the CYP2C9*2 and CYP2C9*3 alleles were not present in three of the five indigenous populations included in our analysis (Tarahumara, Purepecha and Huichol) and the frequency of both alleles is lower than 1% in the other two indigenous groups (Nahua and Teenek). The samples for the Tarahumara and Purepecha groups are relatively small (around 50), but even in these samples we would expect to identify variants with frequencies higher than 1%. In contrast, the frequencies of the CYP2C9*2 and CYP2C9*3 alleles in the Mexico City Mestizo sample were substantially Table 3 Results of exact tests for the comparisons of allele frequencies in Native Mexican and Mexican Mestizo populations. Nahua Teenek Tarahumara Purepecha Huichol Mexico City Mestizo Mexican Americans Monterrey Mexican Mestizo Teenek Tarahumara Purepecha Huichol Mexico City Mestizo Mexican Americans Monterrey Mexican Mestizo Durango Mexican Mestizo 1.000 0.2561 0.5455 0.5899 1.000 NA 0.3355 0.5093 NA NA 0.0001 0.0001 0.0002 0.0002 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0037 0.0001 0.0001 0.0001 0.0001 0.0001 0.0730 0.7052 0.0001 0.0006 0.0010 0.0020 0.0001 0.8970 0.0470 0.1475 NA: not applicable. Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128 4 O.D. Castelán-Martínez et al. / Gene xxx (2013) xxx–xxx higher (5% and 3.9% respectively), and significantly different from the frequencies observed in the indigenous samples (Table 2). Fig. 1 depicts the frequencies for the CYP2C9*2 and CYP2C9*3 alleles in indigenous and Mestizo populations from throughout the Americas (Aguilar et al., 2008; Bravo-Villalta et al., 2005; Dorado et al., 2011; Duconge et al., 2009; Gaedigk et al., 2001; Isaza et al., 2010; Llerena et al., 2004; Ross et al., 2010; Sosa-Macías et al., 2013; Vianna-Jorge et al., 2004), in addition to selected European populations (Llerena et al., 2004; The International HapMap Consortium, 2013a,b). The frequencies of the CYP2C9*2 and CYP2C9*3 alleles in indigenous groups are lower than those observed in the Mestizo samples. Some variation in allele frequencies is evident both in the indigenous and Mestizo groups, probably reflecting differences in European genetic contributions. Supporting this view is the fact that in the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Project (CEPH-HGDP) Maya and Pima samples, which have shown evidence of European admixture in studies based on dense SNP panels (Bryc et al., 2010), the frequencies of the CYP2C9 functional variants are higher than in other indigenous populations. Similarly, the higher frequencies of the CYP2C9 functional variants in the Mexican American sample from LA, and the Mexican Fig. 1. Allelic frequencies of CYP2C9*2 and CYP2C9*3 in different American Mestizo, American Indigenous and selected European populations. Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128 O.D. Castelán-Martínez et al. / Gene xxx (2013) xxx–xxx Mestizo sample from Monterrey, with respect to the Mexico City Mestizo sample, are also in agreement with the higher levels of European admixture reported for these populations (Martinez-Fierro et al., 2009; Martinez-Marignac et al., 2007; Parra et al., 2011). The genetic variation of the CYP2C9 gene affects drug dosage, and it is clinically relevant. The well-known effect of CYP2C9 variants on warfarin-dosing is an excellent example. Warfarin is the most broadly used anticoagulant worldwide and it has a narrow therapeutic index (Caraco et al., 2008; Higashi et al., 2002). Incorrect dosing is responsible for a high rate of adverse effects and warfarin is the leading cause of hospitalization in the emergency room due to adverse events in the elderly (Budnitz et al., 2011). Importantly, there is a substantial inter-individual variability in the required warfarin dose (International Warfarin Pharmacogenetics Consortium, 2009; Takahashi et al., 2006) and a large proportion of this variability is explained by polymorphisms in the VKORC1 and CYP2C9 genes (Carlquist et al., 2006; Takeuchi et al., 2009; Wadelius et al., 2005). Many studies have demonstrated the usefulness of the inclusion of CYP2C9 genotypes in warfarin-dosing algorithms (Anderson et al., 2012; Gong et al., 2011; Marin-Leblanc et al., 2012; Pavani et al., 2012). Adding genetic information to conventional dosing algorithms based on clinical variables has been shown to improve the estimates of the appropriate initial dose of warfarin (International Warfarin Pharmacogenetics Consortium, 2009). One of the ultimate goals of pharmacogenomics is to reduce adverse drug effects using genetic information. In summary, this is one of the largest surveys of the distribution of CYP2C9*2 and CYP2C9*3 variants in Mexican populations, and the first to explore these polymorphisms in Mexican indigenous groups such as Nahua, Teenek, Tarahumara, Purepecha and Huichol. Our study considerably expands the information about these functional variants in American indigenous populations and confirms previous evidence indicating that CYP2C9*2 and CYP2C9*3 are absent or present in very low frequencies in these populations. Conflict of interest The authors declare no conflict of interest. Acknowledgments We thank the scientific staff at the medical biochemistry research unit at the Mexican Institute of Social Security (IMSS) for all the help received during this project. This work was supported by Fundacion IMSS, A.C. Osvaldo Daniel Castelan-Martinez is grateful for the financial support of CONACYT with Scholarship number 17143 and IMSS for Scholarship number 99094418. References Aguilar, B., Rojas, J.C., Collados, M.T., 2008. Prevalence of CYP2C9 variants in the Mexican population. Arch. Med. Res. 39, 463. Anderson, J.L., et al., 2012. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 125, 1997–2005. Bonilla, C., Gutierrez, G., Parra, E., Kline, C., Shriver, M., 2005. Admixture analysis of a rural population of the state of Guerrero, Mexico. Am. J. Phys. Anthropol. 128, 861–869. Bravo-Villalta, H.V., Yamamoto, K., Nakamura, K., Bayá, A., Okada, Y., Horiuchi, R., 2005. Genetic polymorphism of CYP2C9 and CYP2C19 in a Bolivian population: an investigative and comparative study. Eur. J. Clin. Pharmacol. 61, 179–184. Bryc, K., et al., 2010. Colloquium paper: genome-wide patterns of population structure and admixture among Hispanic/Latino populations. Proc Natl Acad Sci USA 107 (Suppl. 2), 8954–8961. Budnitz, D.S., Lovegrove, M.C., Shehab, N., Richards, C.L., 2011. Emergency hospitalizations for adverse drug events in older Americans. N. Engl. J. Med. 365, 2002–2012. Caraco, Y., Blotnick, S., Muszkat, M., 2008. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin. Pharmacol. Ther. 83, 460–470. Carlquist, J.F., et al., 2006. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J. Thromb. Thrombolysis 22, 191–197. 5 Cerda-Flores, R.M., et al., 2002a. Genetic admixture in three Mexican Mestizo population based on D1S180 and HLA-DQA1 loci. Am. J. Hum. Biol. 14, 257–263. Cerda-Flores, R., Budowle, B., Jin, L., Barton, S., Deka, R., Chakraborty, R., 2002b. Maximum likelihood estimates northeastern Mexico using 13 short tandem repeat loci. Am. J. Hum. Biol. 14, 429–439. De Lozier, T., Lee, S., Coulter, S., Goh, B., Goldstein, J., 2005. Functional characterization of novel allelic variants of CYP2C9 recently discovered in Southeast Asians. J. Pharmacol. Exp. Ther. 315, 1085–1090. Dorado, P., et al., 2011. CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards. Pharmacogenomics J. 11, 108–112. Duconge, J., et al., 2009. Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics. Ethn. Dis. 19, 390–395. Evans, W.E., McLeod, H.L., 2003. Pharmacogenomics-drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549. Gaedigk, A., Casley, W.L., Tyndale, R.F., Sellers, E.M., Jurima-Romet, M., Leeder, J.S., 2001. Cytochrome P4502C9 (CYP2C9) allele frequencies in Canadian Native Indian and Inuit populations. Can. J. Physiol. Pharmacol. 79, 841–847. Garcia-Ortiz, J.E., et al., 2004. A novel HLA-A allele: A*0257. Tissue Antigens 63, 85–87. Gong, I.Y., et al., 2011. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 118, 3163–3171. Higashi, M.K., et al., 2002. Association between CYP2C9 genetic variants and anticoagulationrelated outcomes during warfarin therapy. JAMA 287, 1690–1698. Hitchen, L., 2006. Adverse drug reactions results in 250,000 UK admissions a year. BMJ 332, 1109. Ingelman-Sundberg, M., 2001. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J. Intern. Med. 250, 186–200. International Warfarin Pharmacogenetics Consortium, et al., 2009. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360, 753–764. Isaza, C., et al., 2010. Genetic and bioenvironmental factors associated with warfarin response in Colombian patients. Biomedica 30, 410–420. Lee, C., Goldstein, J., Pieper, J., 2002. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12, 251–263. Llerena, A., Dorado, P., O'Kirwan, F., Jepson, R., Licinio, J., Wong, M.L., 2004. Lower frecuency of CYP2C9*2 in Mexican Americans compared to Spaniards. Pharmacogenomics 4, 403–406. Lisker, R., et al., 1986. Gene frequencies and admixture estimates in a Mexico City population. Am J Phys Antrophol. 71, 203–207. Marin-Leblanc, M., et al., 2012. Validation of warfarin pharmacogenetic algorithms in clinical practice. Pharmacogenomics 13, 21–29. Martinez-Fierro, M.L., et al., 2009. Ancestry informative markers and admixture proportions in northeastern Mexico. J. Hum. Genet. 54, 504–509. Martinez-Marignac, V.L., et al., 2007. Admixture in Mexico City: implications for admixture mapping of type 2 diabetes genetic risk factors. Hum. Genet. 120, 807–819. Miners, J., Birkett, D., 1998. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol. 45, 525–538. Nelson, D., et al., 1996. P450 superfamily: update on new sequences, gene mapping, accession number and nomenclature. Pharmacogenetics 6, 1–42. Navarrete-Linares, F., 2008. Los pueblos indígenas de México. Comisión Nacional para el Desarrollo de los Pueblos Indígenas, Mexico City, Mexico (http://cdi.gob.mx/ index.php?id=276&option=com_content&task=view). Nuño-Arana, I., et al., 2005. High prevalence of 5G allele in Amerindian tribes and Mestizos from Mexico at 4G/5G PAI-I gene promoter polymorphism. Thromb. Haemost. 93, 1005–1007. Parra, E.J., et al., 2011. Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican–American sample from Starr County, Texas. Diabetologia 54, 2038–2046. Pavani, A., et al., 2012. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenomics J. 2012 (12), 306–311. Polimanti, R., Piacentini, S., Manfellotto, D., Fuciarelli, M., 2012. Human genetic variation of CYP450 superfamily: analysis of functional diversity in worldwide populations. Pharmacogenomics 13, 1951–1960. Rendic, S., Di Carlo, F., 1997. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab. Rev. 29, 413–580. Ross, K.A., Bigham, A.W., Edwards, M., Gozdzik, A., Suarez-Kurtz, G., Parra, E.J., 2010. World allele frequency distribution of four polymorphisms associated with warfarin dose requirements. J. Hum. Genet. 55, 582–589. Sosa-Macías, M., et al., 2013. Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico. Pharmacogenomics J. http://dx.doi.org/10.1038/tpj.2012.52 PubMed PMID:23358499. Silva-Zolezzi, I., et al., 2009. Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. Proc Natl Acad Sci USA 106, 8611–8616. Strom, T.M., Wienker, T.F., 2009. Test for deviation from Hardy–Weinberg equilibrium and tests for association. (http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/hwa1.pl). Takahashi, H., et al., 2006. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African–Americans. Pharmacogenet. Genomics 16, 101–110. Takeuchi, F., et al., 2009. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet. 5, e1000433. Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128 6 O.D. Castelán-Martínez et al. / Gene xxx (2013) xxx–xxx The International HapMap Consortium, 2013a. The International HapMap Project. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1799853. The International HapMap Consortium, 2013b. The International HapMap Project. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1057910. Vianna-Jorge, R., Perini, J.A., Rondinelli, E., Suarez-Kurtz, G., 2004. CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians. Clin. Pharmacol. Ther. 76, 18–26. Villalobos-Arámbula, A.R., et al., 2000. Beta (A) globin gene haplotypes in Mexican Huichols: genetic relatedness to other populations. Am. J. Hum. Biol. 12, 201–206. Wadelius, M., et al., 2005. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 5, 262–270. Williams, J.A., et al., 2004. Drug–drug interactions for UDP-glucoronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab. Dispos. 32, 1201–1208. Xie, H., Prasad, H., Kim, R., Stein, C., 2002. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv. Drug Deliv. Rev. 54, 1257–1270. Zanger, U., Turpeinen, M., Klein, K., Schwab, M., 2008. Functional pharmacogenetics/ genomics of human cytochromes P450 involved in drug biotransformation. Anal. Bioanal. Chem. 392, 1093–1108. Zhou, S.F., et al., 2008. Clinical pharmacogenetics and potential application in personalized medicine. Curr. Drug Metab. 9, 738–784. Please cite this article as: Castelán-Martínez, O.D., et al., Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations, Gene (2013), http://dx.doi.org/10.1016/j.gene.2013.03.128