See

discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/269714063

CYP2D6 genetic polymorphisms in Southern

Mexican Mayan Lacandones and Mestizos from
Chiapas
ARTICLE in PHARMACOGENOMICS NOVEMBER 2014
Impact Factor: 3.22 DOI: 10.2217/pgs.14.139 Source: PubMed

READS

69

9 AUTHORS, INCLUDING:
Eva Peas-Lled

Pedro Dorado

Universidad de Extremadura

Universidad de Extremadura

53 PUBLICATIONS 581 CITATIONS

77 PUBLICATIONS 1,116 CITATIONS

SEE PROFILE

SEE PROFILE

Teresa Corona

Petra Yescas

Universidad Nacional Autnoma de Mxico

Instituto Nacional de Neurologa y Neuroci

29 PUBLICATIONS 149 CITATIONS

46 PUBLICATIONS 483 CITATIONS

SEE PROFILE

SEE PROFILE

Available from: Marisol Lpez

Retrieved on: 09 November 2015

Research Article
For reprint orders, please contact: reprints@futuremedicine.com

Pharmacogenomics

CYP2D6 genetic polymorphisms in

Southern Mexican Mayan Lacandones and
Mestizos from Chiapas

Aim: In previous CYP2D6 genotyping studies in MexicanAmerindians a very low

frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid
metabolizers (UMs) status has only been analyzed in some groups from Northern
Mexico. Materials & methods: In the present study we evaluated the hypothesis of
low frequency of PMs in MexicanAmerindians in Southern Mexican populations
from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also
reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number
variations were analyzed in 154 ML and 100 MM healthy volunteers. Results: The PM
frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in
MMs. Conclusion: The present data support previous findings reporting a very low
frequency of CYP2D6 PMs in MexicanAmerindians. Furthermore, the predicted UM
phenotype in both MMs and MLs was lower than those reported for most Mexican
populations.
Original submitted 16 May 2014; Revision submitted 26 September 2014
Keywords: CYP2D6 Lacandones MexicanMestizo pharmacogenetics

Background
The Mexican Genome Diversity Project
(MGDP) showed genetic differences in
MexicanMestizos (MM) from distant geographical regions, which were due to different populations dynamics related to both
the intermixture proportions of different
ancestral components, but also to demographic conditions [1] . In particular, it is of
interest to the polymorphic cytochrome
(CYP) P450. Interethnic differences in CYP
polymorphisms might be partially responsible for the variations in drug disposition
between populations. CYP2D6 is involved
in the biotransformation of several clinically important drugs, such as beta-blockers, antidepressants and neuroleptics [2,3] .
The polymorphism of the enzyme results in
poor (PM), efficient or extensive (EM) and
ultrarapid (UM) metabolizers of CYP2D6
substrates [4] . The worldwide distribution
of PMs and UMs varies markedly [3,57] .

10.2217/PGS.14.139 2014 Future Medicine Ltd

Alleles CYP2D6*3, *4, *5 and *6 are nonfunctional, *10, *17 and *41 are associated
with decreased activity, whereas duplication (or multiplication) of CYP2D6*1, *2 or
*35 leads to the increased enzyme activity
observed in some UM individuals [8] .
CYP2D6 genotyping studies in MexicanAmerindians populations have reported
very low frequencies of PMs (Table1) . Moreover, so far, UMs have only been analyzed in
Northern Mexicans [911] . The geographical
region of the Mexican populations where
CYP2D6 allele frequencies has been investigated is shown in Figure1. A potential
limitation of these data are the genotyping
methods used, since the decreased activity
of *17 and *41 or the defective *5 alleles was
not always evaluated. Currently, the Mexican
population is composed of Mestizos (90%)
and a different ethno linguistic indigenous
population the Lacandones (MLs), who are
Mexican indigenous individuals that speak

Pharmacogenomics (2014) 15(15), 18591865

Marisol Lpez-Lpez1,
Eva Peas-Lled2, Pedro
Dorado2,3, Alberto Ortega1,
Teresa Corona4, Adriana
Ochoa5, Petra Yescas5, Elisa
Alonso5 & Adrin LLerena*,2
1
Department of Biological Systems,
Universidad Autnoma MetropolitanaXochimilco, Mexico City, Mexico
2
CICAB, Clinical Research Center,
Extremadura University Hospital &
Medical School, Badajoz, Spain
3
University of Extremadura, Plasencia,
Spain
4
Neurodegenerative Diseases Laboratory,
Instituto Nacional de Neurologa y
Neurociruga Manuel Velasco Surez,
Mexico City, Mexico
5
Department of Neurogenetics &
Molecular Biology, Instituto Nacional
de Neurologa y Neurociruga Manuel
Velasco Surez, Mexico City, Mexico
*Author for correspondence:
Tel.: +34 924 218 040
Fax: +34 924 219 881
allerena@ unex.es

part of

ISSN 1462-2416

1859

1860

Pharmacogenomics (2014) 15(15)

349

264

50

243

112

96

125

100

88

85

43

56

99

19

39

19

15

129

44

107

81

74

154

MexicanAmerican

MexicanMestizo

Tarahumaras

Purpechas

Tojolabales

Tzotziles

Tepehuanos

Tzeltales

Mexicaneros

Seris

Guarijos

Tepehuanos

Mayos

Huicholes

Coras

Tarahumaras

Mayan Lacandones

20.8

15.5

26.5

20.1

10.2

18.8

23.3

5.3

20.5

n.e

20.0

n.e.

n.e.

n.e.

n.e.

23.5

n.e.

25.5

10.7

19.3

n.e.

18.0

22.8

*2

0.3

n.e

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

4.1

n.e.

n.e.

n.e.

n.e.

*35

Normal alleles
(%)

1.2

0.9

1.4

0.2

0.3

*3

10.4

10.1

1.2

7.5

0.4

3.3

21.1

5,3

0.6

2.7

1.2

2.9

7.3

11

5.6

14.0

13.1

11.2

17.0

10.0

10.3

*4

4.1

1.2

0.5

0.4

1.3

n.e

0.5

n.e.

n.e.

n.e.

n.e.

2.0

n.e.

2.0

1.3

2.7

2.0

1.7

2.3

*5

Null alleles
(%)

3.4

n.e.

n.e.

0.4

n.e.

*6

0.6

0.7

n.e.

n.e.

n.e.

n.e.

n.e.

1.0

n.e.

2.6

2.3

12.4

1.0

2.8

7.4

*10

0.0

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

1.7

2.0

0.2

0.7

*17

1.3

4.1

1.2

3.4

0.4

n.e.

1.0

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

2.2

n.e.

n.e.

5.5

n.e.

*41

Reduced activity
alleles (%)

1.3

6.1

4.3

10.8

9.1

2.7

10

5.3

7.7

n.e.

1.5

n.e.

n.e.

n.e.

n.e.

1.5

n.e.

3.6

4.1

4.5

3.0

0.4

1.0

Multiple
normal
alleles
(%)

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

n.e.

0.2

n.e.

Multiple
null
alleles
(%)

n.e.: Not evaluated; PM: Poor metabolizers, individuals with zero CYP2D6 active genes; UM: Ultrarapid metabolizers, individuals with more than two CYP2D6 active genes.

Population

1.4

1.0

3.1

6.8

2.1

6.0

2.7

2.3

PM
(%)

Table 1. CYP2D6 allele frequencies in the studied populations and comparison with several previously reported Mexican populations.

2.6

10.8

8.7

20.6

18.2

5.4

20

10.5

15.4

n.e.

1.0

n.e.

n.e.

n.e.

n.e.

3.0

n.e.

3.6

4.5

6.2

2.0

1.1

2.0

UM
(%)

This
study

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[11]

[16]

[9,10]

[16]

[16]

[16]

[16]

This
study

[16]

[14]

[9,10]

[15]

[14]

[13]

[12]

Ref.

Research Article Lpez-Lpez, Peas-Lled, Dorado et al.

future science group

CYP2D6 genetic polymorphism in Mexican populations from Chiapas

Seris

Guarijos

Research Article

USA

Tarahumaras
Tepehuanos

Coras
Mayan
Lacandons
Mayos
Tzotziles
Mexicaneros,
Huicholes

Purpechas

Tojolabales

Tzeltales
T ltales
Tze

Figure 1. Map of Mexico showing Mexican Amerindians populations with reported allele frequencies of CYP2D6.

Lacandon, a language from the Mayan linguistic family. They inhabit the state of Chiapas, in particular the
Lacandon rain forest in the frontier between Mexico
and Guatemala.
The main aim of this study was to determine the
frequency of the PM and UM status evaluated from a
genetic analysis of CYP2D6 in two populations living
in Chiapas in order to evaluate previous data reporting
a very low frequency of PMs among MexicanAmerindians, and also to analyze the frequency of UMs in
these Southern Mexican populations.
Materials & methods
Subjects

The CYP2D6 genotype was analyzed in 100 MMs

from Chiapas and 154 MLs unrelated healthy volunteers. It was considered as MM only in those who for
two generations, including their own, had been born in
Mexico, leaving in Chiapas and have Spanish-derived
last names. ML subjects were recruited with the help
of community translators. To ensure their Lacandon
origin they were interviewed regarding their ancestral
status for at least two previous generations. All gave
oral or written informed consent prior authorization from the community leader. The study was per-

future science group

formed according to the Helsinki Declaration and it

was approved by the Local Ethical Committees of the
institutions involved.
Genotyping procedure

For the genotyping, genomic DNA was obtained from

peripheral blood leukocytes by standard procedures.
To detect the presence of allelic variants harboring a
CYP2D6*5 gene deletion or gene duplication, long
range XL-PCR was performed as described in detail
elsewhere [17] . Subjects positive for a duplication were
further characterized for gene copy number. To discriminate between CYP2D6*1xN, *2xN and *4xN
alleles, a 10 kb long XL-PCR fragment was generated from duplication-positive subjects and tested
for respective SNPs by an established PCR-RFLP
approach [17] . Genotype analysis for the CYP2D6*2,
*3, *4, *5, *6, *10, *17, *35 and *41 allelic variants
was carried out on genomic DNA using commercially
available TaqMan assay. The CYP2D6 genotype was
determined based on the presence of key SNPs associated with the alleles of interest (-1584C>G, 31G>A,
100C>T, 1023C>T, 1707T>del, 1846G>A, 2549A>del
and 2988G>A) as previously described [8] . CYP2D6*2
alleles were defined by the presence of -1584C>G and

www.futuremedicine.com

1861

Research Article Lpez-Lpez, Peas-Lled, Dorado et al.

CYP2D6*35 alleles by -1584C>G and 31G>A; none of
the subjects appeared to carry CYP2D6*2 alleles that
lacked the -1584C>G polymorphism.
PCR-RealTime genotyping was carried out using
Taqman and CYP2D6 CopyNumber assays
(Hs00010001_cn, Applied Biosystems, CA, USA)
according to the manufacturers instructions, including
specific primers and probes for these polymorphisms
and the Universal PCR Master Mix, No AmpErase
UNG, which contains AmpliTaq Gold DNA polymerase, dNTP, buffers and passive internal reference
based on ROXTM. The amplification conditions consisted of 10 min pre-incubation at 95C to activate the
Taq DNA polymerase, followed by 40 cycles of denaturation at 95C for 15 s, and then primer annealing
and extension for 1 min at 60C. All assays were carried out in 96 well plates, with each plate including
negative (without DNA) and positive (heterozygous
and/or homozygous) controls. The genotypes used for
the positive controls were from previous studies of our
group. Plates were read on an ABI 7300 instrument
(Applied Biosystems, CA, USA). Hs00010001_cn
specifically targets CYP2D6 exon 9 sequences and
will not amplify CYP2D7 or CYP2D8 pseudogenes,
or CYP2D6 alleles having CYP2D7 sequences in
exon 9 (e.g. CYP2D6*36 ). The CYP2D6*1 allele was
assumed when all CYP2D6 alleles tested were absent
since we did not perform DNA sequencing.
The relationship between CYP2D6 genotype and the
predicted metabolizer status was evaluated using the
activity score [7,18] . The value assigned to the reference
allele CYP2D6 *1, *2 and *35 was 1, to CYP2D6*3, *4,
*4N, *5, and *6 was 0, to CYP2D6*10, *17, *29, and
*41 was 0.5, and to multiplications of active CYP2D6
(*1N or *2N) was n (number of copies). The subjects
with zero and with more than two CYP2D6 active genes
were classified as PMs and UMs, respectively, while the
rest were EMs.
Statistical analysis

The differences in CYP2D6 allele frequencies were

compared by using the 2 test and/or Fishers exact
test. p-values less than 0.05 were regarded as statistically significant. Statistical analysis was performed
using STATISTICA 4.3 (StatSoft Inc., OK, USA) and
GraphPad Prism 5.0 (GraphPad Software, Inc., CA,
USA) programs.
Results
The frequencies of the CYP2D6 genotypes found in the
MM and ML subjects studied are shown in Table2. The
percentages of CYP2D6 alleles with normal, decreased,
null or increased activity, as well as the predictive PM
and UM metabolic phenotype in the Mexican popula-

1862

Pharmacogenomics (2014) 15(15)

tions from the present and previous studies to date are

shown in Table1. The percentage of individuals with
zero CYP2D6 active genes (PM predicted phenotype)
was 1.0% in MMs, while it was 0% in MLs. The frequency of UM were 2.6% and 3% for MLs and MMs,
respectively.
Discussion
To the best of our knowledge, this is the first study of
CYP2D6 polymorphisms in Mexican Mayan Amerindian Lacandones (MLs) and in a Mexican Mestizo
(MMs) population from Southern Mexico. The absence
of PMs in the present population of MLs was similar to
those found in most previous Mexican-Amerindian populations [911,19] . There is only an exception in a group of
Tarahumaras that also reported a very low frequency of
1.4% [11] . The low PM frequency found in MMs from
Chiapas (1.0%) contrasts with higher percentages of PMs
in other MM populations previously studied (Table1).
The UM frequency in both populations studied here
is lower than previous reports in European Caucasians [5]
and other Mexican populations (Table2). CYP2D6 multiplications, as well as copy number variations, were analyzed in both populations. Previously, these analyses in
Mexican populations have been reported only for MMs
from Central and Northern Mexico [10,15] , and Amerindians from Northern Mexico [10,11] . This is the first
analysis of UMs among Southern-Mexican populations,
specifically of Mayan groups. A possible explanation for
the variability in UMs frequencies could be the genetic
heterogeneity among Mexican Amerindian groups [20] .
However, another possibility is the genotyping methodology employed in the different studies since the majority of previous reports did not discriminate multiplication of nonfunctional CYP2D6 alleles, and UMs were
considered solely on multiplication status.
The percentages of alleles with diminished activity
(*10, *17 and *41) in MMs and MLs were similar to those
reported in other Mexican Mestizos and Amerindian
Tepehuanos [9,10] populations, respectively (Table1). The
*3 and *6 alleles (with null activity) in the MM and ML
populations studied were absent. The low presence of
these alleles is similar to that observed in other MexicanMestizos [16] , in Tepehuanos [9,10] and in Tzeltales
[19] (Table1) . The percentage of allele *4 is similar among
most MM populations reported, as well as for the MMs
and MLs informed here, but much higher than in Tepehuanos. The *5 allele frequency was found to be similar
in the MM group studied here, as well as in the other
MM [15,16] and MexicanAmerican populations reports
[1214] , but higher than in MLs where it was absent. The
classic plantanimal warfare thesis of P450 evolution
cannot be ruled out to explain the absence of PMs in
these populations [21] since the frequency of UMs is not

future science group

CYP2D6 genetic polymorphism in Mexican populations from Chiapas

Research Article

Table 2. Frequencies of CYP2D6 genotypes in 100 MexicanMestizo and 154 Lacandon individuals from Chiapas.
CYP2D6
genotype

Activity
score

MexicanMestizos
n

Frequency

95% CI

Frequency

95% CI

*4/*4

0.010

0.0000.0599

*4/*10

0.5

*4/*41

0.5

*2/*4

0.050

0.02520.1273

0.052

0.0250.101

*2/*5

0.010

0.0000.0599

*1/*5

0.034

0.00650.0883

*4/*35

*41/*41

*1/*4

14

0.140

0.08400.2226

24

0.156

0.1060.222

*10/*41

0.006

0.0000.040

*35/*41

1.5

*2/*41

1.5

0.006

0.0000.040

*1/*17

1.5

*2/*17

1.5

*1/*10

1.5

0.020

0.00110.0744

0.006

0.0000.040

*1/*41

1.5

0.013

0.0010.049

*2/*2

0.070

0.03660.1577

0.058

0.0300.109

*1x2/*4

*1/*1

37

0.370

0.28170.4679

67

0.435

0.3590.514

*1/*2

26

0.260

0.18360.3542

36

0.234

0.1740.307

*1/*35

0.006

0.0000.040

*2x2/*5

*1x2/*41

2.5

*1/*1x2

0.020

0.00110.0744

0.019

0.0040.058

*1/*2x2

0.010

0.0000.0599

*2x3/*41

3.5

*2/*2x4

0.006

0.0000.040

*1/*2x4

very high. The varying influence of European or Asian

ancestry in these populations may also explain the heterogeneity of these populations. Future studies analyzing
ancestry are required to understand such complexity.
These findings in Southern Mexican Mayans corroborate the low frequency of PMs in Amerindians and
resemble the high heterogeneity of the Mexican populations, both Mestizo and Amerindian, which could have
important implications for the clinical use of CYP2D6
drug substrates. For instance, it would also be of interest
to test if the low frequency of PMs in Mexican populations is associated with a low incidence of hospitalizations due to adverse events of CYP2D6 substrates.
Although, despite CYP2D6 PMs being qualitatively
different from the rest of EMs, as demonstrated by

future science group

Lacandones

bimodal distributions [4,7] , EMs may turn into PMs if

they are exposed to other xenobiotics, such as drugs or
traditional herbal medicines with alkaloid components,
known to be potent inhibitors of CYP2D6. Moreover,
since drugs and plants are metabolized by a myriad of
different enzymes that are encoded by their respective genes, substrate specificity and drug dosage seem
to be only two of many factors [22] contributing to a
drug response measured by quantitative variables such
as degree of efficacy or number/severity of side effects.
In support of that, despite the evidence about the relationship of CYP2D6 and drug response[6] , the combined use of parallel alternate metabolic CYP pathways
[23] that can compensate in the case of CYP2D6 PMs
to individualize treatments with certain CYP2D6 sub-

www.futuremedicine.com

1863

Research Article Lpez-Lpez, Peas-Lled, Dorado et al.

strates is, as yet, very limited, as is use of other genes
such as those encoding drug receptors also involved in
response [24] . Finally, individualized therapy to increase
drug safety in different populations will also largely
benefit from collecting and interrogating large genomics datasets in order to identify biological mechanisms
associated with observed outcomes [25] .
Future perspective
Interindividual variation in drug response poses a serious problem in clinical practice. Knowledge of the
distribution of common CYP2D6 alleles in the different ethnic groups that comprise the current Mexican
population represents relevant pharmacogenetic data of
clinical importance for a better therapeutic outcome.
This is especially true for CYP2D6 since it is responsible for the oxidative metabolism of 25% of commonly
prescribed drugs, and is codified by a highly polymorphic gene that shows marked interethnic variation.
Nevertheless, prospective clinical studies are needed
in order to establish pharmacogenetic based-dosing
for CYP2D6 substrate drugs, as well as studies on
the use of traditional plants by Mayans that may have
components with CYP2D6-inhibitory properties.

Financial & competing interest disclosure

This study was supported by Consejo Nacional de Ciencia y
Tecnologa de Mxico (CONACYT #167261) and by Plan Nacional de Investigacin Cientfica, Desarrollo e Innovacin
Tecnolgica (I+D+I) and Fondo Social Europeo of the European Union (FEDER), Instituto de Salud Carlos III-FIS Research
Grants (PI10/02758; PI10/02010), by AEXCID Cooperacin
Extremea of the Junta de Extremadura (13IA001) to SIFF and
coordinated in the Network Red Iberoamericana de Farmacogentica y Farmacogenmica (RIBEF). The authors have no
other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles
outlined in the Declaration of Helsinki for all human or animal
experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained
from the participants involved.

Executive summary
Background
CYP2D6 polymorphisms contribute to interindividual differences in drug response of clinical importance.
Marked interethnic variation has been reported for the frequency of CYP2D6 alleles.
Large interindividual variation in the enzyme activity of CYP2D6 has been described, which includes
individuals with efficient or extensive metabolism (including ultrarapid metabolizers [UMs]) and poor
metabolism status.
Previous studies in MexicanAmerindians revealed a very low frequency of poor metabolizers (PMs), while
UMs have only been informed in groups from Northern Mexico.

Aims
Herein, we evaluated the hypothesis of low frequency of PMs in MexicanAmerindians in Southern Mexican
populations from Chiapas (Lacandones [ML] vs Mestizos [MM]), and determined the frequency of UMs in
these populations.

Results
This is the first study of CYP2D6 polymorphisms in Mexican Mayan Amerindian Lacandones and in Mexican
Mestizo populations from Southern Mexico.
The PM predicted phenotype was absent in Lacandones, while it was 1.0% in Mexican Mestizos from Chiapas.
The observed frequency of UMs was similar for Lacandones (2.6%) and Mexican Mestizos (3%).

Conclusion
These findings in Southern Mexican Mayans corroborate the low frequency of PMs in Amerindians and
resemble the high heterogeneity of the Mexican populations, both Mestizo and Amerindian.

References
Papers of special note have been highlighted as:
of interest
1

1864

Silva-Zolezzi I, Hidalgo-Miranda A, Estrada-Gil J

etal. Analysis of genomic diversity in Mexican Mestizo
populations to develop genomic medicine in Mexico. Proc.
Natl Acad. Sci. USA 106(21), 86118616 (2009).

Pharmacogenomics (2014) 15(15)

This is one of the first genome-wide genotyping studies of a

Mexican Mestizo population.

Zanger UM, Raimundo S, Eichelbaum M. Cytochrome

P450 2D6: overview and update on pharmacology, genetics,
biochemistry. Naunyn Schmiedebergs Arch. Pharmacol.
369(1), 2337 (2004).

Dorado P, Suarez-Kurtz G, LLerena A. Pharmacogenetics

of cytochrome P450 in Hispanic populations.

future science group

CYP2D6 genetic polymorphism in Mexican populations from Chiapas

In:Pharmacogenomics in Admixed Populations. Suarez-Kurtz

G (Ed.). Landes Bioscience, Austin, 6074 (2007)
4

LLerena A, Cobaleda J, Martnez C, Bentez J. Interethnic

differences in drug metabolism: influence of genetic and
environmental factors on debrisoquine hydroxylation
phenotype. Eur. J.Drug. Metab. Pharmacokinet. 21(2),
129138 (1996).

Bradford LD. CYP2D6 allele frequency in European

Caucasians, Asians, Africans and their descendants.
Pharmacogenomics 3(2), 229243 (2002).

Zhou S-F, Liu J-P, Chowbay E. Polymorphism of human

cytochrome P450 enzymes and its clinical impact. Drug
Metab. Rev. 41(2), 89295 (2009).

LLerena A, Dorado P, Ramrez R etal. CYP2D6 genotype

and debrisoquine hydroxylation phenotype in Cubans and
Nicaraguans. PharmacogenomicsJ. 12 (2), 176183 (2012).

Human Cytochrome P450 (CYP) Allele Nomenclature

Committee.
www.cypalleles.ki.se/cyp2d6.htm

Sosa-Macas M, Elizondo G, Flores-Prez C etal. CYP2D6

genotype and phenotype in Amerindians of Tepehuano
origin and Mestizos of Durango, Mexico. J.Clin. Pharmacol.
46(5), 527536 (2006).

10

Sosa-Macas M, Dorado P, Alanis-Bauelos RE, LLerena

A, Lares-Asseff I. Influence of CYP2D6 deletion,
multiplication, -1584C>G, 31G>A and 2988G>A gene
polymorphisms on dextromethorphan metabolism among
Mexican tepehuanos and mestizos. Pharmacology 86(1),
3036 (2010).

11

Lazalde-Ramos BP, Martinez-Fierro ML etal. CYP2D6 gene

polymorphism and predicted phenotypes in eight indigenous
groups from northwestern Mexico. Pharmacogenomics 15(3),
339348 (2014).

Report on CYP2D6 polymorphism in indigenous groups

from northwestern Mexico.

12

Mendoza R, Wan YJ, Poland RE etal. CYP2D6

polymorphism in a Mexican American population. Clin.
Pharmacol. Ther. 70(6), 552560 (2001).

13

Luo HR, Gaedigk A, Aloumanis V, Wan YJ. Identification of

CYP2D6 impaired functional alleles in Mexican Americans.
Eur. J.Clin. Pharmacol. 61(11), 797802 (2005).

14

Casner PR. The effect of CYP2D6 polymorphisms on

dextromethorphan metabolism in Mexican Americans.
J.Clin. Pharmacol. 45(11), 12301235 (2005).

15

Lpez M, Guerrero J, Jung-Cook H, Alonso ME. CYP2D6

genotype and phenotype determination in a Mexican

future science group

Research Article

Mestizo population. Eur. J.Clin. Pharmacol. 61(10),

749754 (2005).
16

Contreras AV, Monge-Cazares T, Alfaro-Ruiz L etal.

Resequencing, haplotype construction and identification
of novel variants of CYP2D6 in Mexican Mestizos.
Pharmacogenomics 12(5), 745756 (2011).

Report on CYP2D6 polymorphism in Mexican Mestizos

from Northwestern and Central-Pacific states of Mexico.

17

Dorado P, Cceres M, Pozo-Guisado E, Wong ML, Licinio

J, Llerena A. Development of a PCR-based strategy for
CYP2D6 genotyping including gene multiplication of
worldwide potential use. Biotechniques 39(Suppl.10),
571574 (2005).

18

Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy

MJ, Leeder JS. The CYP2D6 activity score: translating
genotype information into a qualitative measure of
phenotype. Clin. Pharmacol. Ther. 83(2), 234242 (2008).

19

Salazar-Flores J, Torres-Reyes LA, Martnez-Corts G etal.

Distribution of CYP2D6 and CYP2C19 polymorphisms
associated with poor metabolizer phenotype in five
Amerindian groups and western Mestizos from Mexico.
Genet. Test Mol. Biomarkers 16(9), 10981104 (2012).

20

Rangel-Villalobos H, Muoz-Valle JF, Gonzlez-Martn

A, Gorostiza A, Magaa MT, Pez-Riberos LA. Genetic
admixture, relatedness, and structure patterns among
Mexican populations revealed by the Y-chromosome. Am.
J.Phys. Anthropol. 135(4), 448461 (2008)

21

Nebert DW. Polymorphisms in drug-metabolizing enzymes:

what is their clinical relevance and why do they exist? Am.
J.Hum. Genet. 60(2), 265271 (1997).

22

Nebert DW, Zhang G, Vesell ES. From human genetics and

genomics to pharmacogenetics and pharmacogenomics: past
lessons, future directions. Drug Metab. Rev. 40(2), 187224
(2008).

23

Peas-Lled E, Guillaume S, Naranjo ME etal. A combined

high CYP2D6-CYP2C19 metabolic capacity is associated
with the severity of suicide attempt as measured by objective
circumstances. PharmacogenomicsJ. doi:10.1038/tpj.2014.42
(2014) (Epub ahead of print).

24

Daly AK. Individualized drug therapy. Curr. Opin. Drug

Discov. Devel. 10(1), 2936 (2007).

25

Vivar JC, Pemu P, McPherson R, Ghosh S. Redundancy

control in pathway databases (ReCiPa): an application for
improving gene-set enrichment analysis in Omics studies and
Big data biology. OMICS 17(8), 414422 (2013).

www.futuremedicine.com

1865