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Gene xxx (2013) xxx–xxx
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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