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9 AUTHORS, INCLUDING:
Eva Peas-Lled
Pedro Dorado
Universidad de Extremadura
Universidad de Extremadura
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Teresa Corona
Petra Yescas
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Research Article
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Pharmacogenomics
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] .
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
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
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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.
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
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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
Lacandones
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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
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11
12
13
14
15
Research Article
17
18
19
20
21
22
23
24
25
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