CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas.

7/24/2019 CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas.

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

CYP2D6 genetic polymorphisms in SouthernMexican Mayan Lacandones and Mestizos from

Chiapas

ARTICLE in PHARMACOGENOMICS NOVEMBER 2014

Impact Factor: 3.22 DOI: 10.2217/pgs.14.139 Source: PubMed

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9 AUTHORS, INCLUDING:

Eva Peas-LledUniversidad de Extremadura

53PUBLICATIONS 581CITATIONS

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Pedro DoradoUniversidad de Extremadura

77PUBLICATIONS 1,116CITATIONS

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Teresa Corona

Universidad Nacional Autnoma de Mxico


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Petra Yescas

Instituto Nacional de Neurologa y Neuroci


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Available from: Marisol Lpez

Retrieved on: 09 November 2015
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1859Pharmacogenomics(2014) 15(15), 18591865 ISSN 1462-2416

part of

PharmacogenomicsResearch Article

10.2217/PGS.14.139 2014 Future Medicine Ltd

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. CYP2D6alleles *2, *3, *4, *5, *6, *10, *17, *35and *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 CYP2D6PMs 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

BackgroundThe Mexican Genome Diversity Project(MGDP) showed genetic differences inMexicanMestizos (MM) from distant geo-graphical regions, which were due to differ-ent populations dynamics related to boththe intermixture proportions of differentancestral components, but also to demo-graphic conditions [1]. In particular, it is ofinterest to the polymorphic cytochrome

(CYP) P450. Interethnic differences in CYPpolymorphisms might be partially respon-sible for the variations in drug dispositionbetween populations. CYP2D6 is involvedin the biotransformation of several clini-cally important drugs, such as beta-block-ers, antidepressants and neuroleptics [2,3].The polymorphism of the enzyme results inpoor (PM), efficient or extensive (EM) andultrarapid (UM) metabolizers of CYP2D6substrates [4]. The worldwide distributionof PMs and UMs varies markedly [3,57].

Alleles CYP2D6*3, *4, *5 and *6 are non-functional, *10, *17 and *41 are associatedwith decreased activity, whereas duplica-tion (or multiplication) of CYP2D6*1, *2or*35 leads to the increased enzyme activityobserved in some UM individuals [8].

CYP2D6 genotyping studies in Mexi-canAmerindians populations have reportedvery low frequencies of PMs (Table 1). More-over, so far, UMs have only been analyzed in

Northern Mexicans [911]. The geographicalregion of the Mexican populations whereCYP2D6 allele frequencies has been inves-tigated is shown in Figure 1. A potentiallimitation of these data are the genotypingmethods used, since the decreased activityof *17and *41or the defective *5alleles wasnot always evaluated. Currently, the Mexicanpopulation is composed of Mestizos (90%)and a different ethno linguistic indigenouspopulation the Lacandones (MLs), who areMexican indigenous individuals that speak

CYP2D6genetic polymorphisms inSouthern Mexican Mayan Lacandones andMestizos from Chiapas

Marisol Lpez-Lpez1,Eva Peas-Lled2, PedroDorado2,3, Alberto Ortega1,Teresa Corona4, Adriana

Ochoa5, Petra Yescas5, ElisaAlonso5& Adrin LLerena*,21Department of Biological Systems,

Universidad Autnoma Metropolitana-

Xochimilco, Mexico City, Mexico2CICAB, Clinical Research Center,

Extremadura University Hospital &

Medical School, Badajoz, Spain3University of Extremadura, Plasencia,

Spain4Neurodegenerative Diseases Laboratory,

Instituto Nacional de Neurologa y

Neurociruga Manuel Velasco Surez,

Mexico City, Mexico5Department 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

[email protected]


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1860 Pharmacogenomics(2014) 15(15) future science group

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

Population

n

Normalalleles

(%)

Nullalleles

(%)

Reducedac

tivity

alleles(%)

Multiple

normal

alleles

(%)

Multiple

null

alleles

(%)

PM

(%)

UM

(%)

Ref.

*2

*35

*3

*4

*5

*6

*10

*17

*41

MexicanAmerican

349

22.8

n.e.

0.3

10.3

2.3

n.e.

7.4

0.7

n.e.

1.0

n.e.

2.3

2.0

[12]

264

18.0

n.e.

0.2

10.0

1.7

0.4

2.8

0.2

5.5

0.4

0.2

2.7

1.1

[13]

50

n.e.

n.e.

0

17.0

2.0

0

1.0

2.0

n.e.

3.0

n.e.

6.0

2.0

[14]

243

19.3

n.e.

1.4

11.2

2.7

n.e.

12.4

1.7

n.e.

4.5

0

2.1

6.2

[15]

112

10.7

4.1

0.9

13.1

1.3

0

2.3

n.e.

2.2

4.1

0

6.8

4.5

[9,1

0]

MexicanMestizo

96

25.5

n.e.

0

14.0

2.0

n.e.

2.6

0

n.e.

3.6

n.e.

3.1

3.6

[14]

125

n.e.

n.e.

1.2

5.6

n.e.

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

100

23.5

0

0

11

2.0

0

1.0

0

0

1.5

0

1.0

3.0

This

study

Tarahumaras

88

n.e.

n.e.

0

7.3

n.e.

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

Purpechas

85

n.e.

n.e.

0

2.9

n.e.

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

Tojolabales

43

n.e.

n.e.

0

1.2

n.e.

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

Tzotziles

56

n.e.

n.e.

0

2.7

n.e.

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

Tepehuanos

99

20.0

0

0

0.6

0.5

0

0

n.e.

1.0

1.5

0

0

1.0

[9,1

0]

Tzeltales

19

n.e

n.e

0

5,3

n.e

0

n.e.

n.e.

n.e.

n.e.

n.e.

0

n.e.

[16]

Mexicaneros

39

20.5

0

0

0

1.3

0

0

0

0

7.7

n.e.

0

15.4

[11]

Seris

19

5.3

0

0

21.1

0

0

0

0

0

5.3

n.e.

0

10.5

[11]

Guarijos

15

23.3

0

0

3.3

0

0

0

0

0

10

n.e.

0

20

[11]

Tepehuanos

129

18.8

0

0

0.4

0.4

0

0

0

0.4

2.7

n.e.

0

5.4

[11]

Mayos

44

10.2

0

0

8

0

3.4

0

0

3.4

9.1

n.e.

0

18.2

[11]

Huicholes

107

20.1

0

0

7.5

0.5

0

0

0

0

10.8

n.e.

0

20.6

[11]

Coras

81

26.5

0

0

1.2

1.2

0

0

0

1.2

4.3

n.e.

0

8.7

[11]

Tarahumaras

74

15.5

0

0

10.1

4.1

0

0.7

0

4.1

6.1

n.e.

1.4

10.8

[11]

MayanLacandones

154

20.8

0.3

0

10.4

0

0

0.6

0.0

1.3

1.3

0

0

2.6

This

study

n.e.:

Notevaluated;PM:Poormetabolizers,

individualswithzeroCYP2D6activegenes;UM:

Ultrarapidmetabolizers,

individualswithmorethantwoCYP2D6activegenes.

Table1.CYP2D6allelefrequenciesinthestudiedpopulationsand

comparisonwithseveralpreviouslyreportedMexicanpopulations.


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

future science group

CYP2D6genetic polymorphism in Mexican populations from Chiapas Research Article

Seris Guarijos Tarahumaras

Tepehuanos

Coras

Mayan

Lacandons

Tzotziles

Tojolabales

Purpechas

Mexicaneros,

Huicholes

Mayos

Tzeltales

USASeris Guarijos Tarahumaras

Tepehuanos

Coras

Mayan

Lacandons

Tzotziles

Tojolabales

Purpechas

Mexicaneros,

Huicholes

Mayos

zeltales

USA

Lacandon, a language from the Mayan linguistic fam-

ily. They inhabit the state of Chiapas, in particular theLacandon rain forest in the frontier between Mexicoand Guatemala.

The main aim of this study was to determine thefrequency of the PM and UM status evaluated from agenetic analysis of CYP2D6in two populations livingin Chiapas in order to evaluate previous data reportinga very low frequency of PMs among MexicanAmer-indians, and also to analyze the frequency of UMs inthese Southern Mexican populations.

Materials & methods

SubjectsThe CYP2D6 genotype was analyzed in 100 MMsfrom Chiapas and 154 MLs unrelated healthy volun-teers. It was considered as MM only in those who fortwo generations, including their own, had been born inMexico, leaving in Chiapas and have Spanish-derivedlast names. ML subjects were recruited with the helpof community translators. To ensure their Lacandonorigin they were interviewed regarding their ancestralstatus for at least two previous generations. All gaveoral or written informed consent prior authoriza-tion from the community leader. The study was per-

formed according to the Helsinki Declaration and it

was approved by the Local Ethica l Committees of theinstitutions involved.

Genotyping procedure

For the genotyping, genomic DNA was obtained fromperipheral blood leukocytes by standard procedures.To detect the presence of allelic variants harboring aCYP2D6*5 gene deletion or gene duplication, longrange XL-PCR was performed as described in detailelsewhere [17]. Subjects positive for a duplication werefurther characterized for gene copy number. To dis-criminate between CYP2D6*1xN, *2xN and *4xN

alleles, a 10 kb long XL-PCR fragment was gener-ated from duplication-positive subjects and testedfor respective SNPs by an established PCR-RFLPapproach [17]. Genotype analysis for the CYP2D6*2,*3, *4, *5, *6, *10, *17, *35 and *41 allelic variantswas carried out on genomic DNA using commerciallyavailable TaqMan assay. The CYP2D6 genotype wasdetermined based on the presence of key SNPs asso-ciated with the alleles of interest (-1584C>G, 31G>A,100C>T, 1023C>T, 1707T>del, 1846G>A, 2549A>deland 2988G>A) as previously described [8]. CYP2D6*2alleles were defined by the presence of -1584C>G and


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CYP2D6*35alleles by -1584C>G and 31G>A; none ofthe subjects appeared to carry CYP2D6*2 alleles thatlacked the -1584C>G polymorphism.

PCR-RealTime genotyping was carried out usingTaqman and CYP2D6 CopyNumber assays

(Hs00010001_cn, Applied Biosystems, CA, USA)according to the manufacturers instructions, includingspecific primers and probes for these polymorphismsand the Universal PCR Master Mix, No AmpEraseUNG, which contains AmpliTaq Gold DNA poly-merase, dNTP, buffers and passive internal referencebased on ROXTM. The amplification conditions con-sisted of 10 min pre-incubation at 95C to activate theTaq DNA polymerase, followed by 40 cycles of dena-turation at 95C for 15 s, and then primer annealingand extension for 1 min at 60C. All assays were car-ried out in 96 well plates, with each plate including

negative (without DNA) and positive (heterozygousand/or homozygous) controls. The genotypes used forthe positive controls were from previous studies of ourgroup. Plates were read on an ABI 7300 instrument(Applied Biosystems, CA, USA). Hs00010001_cnspecifically targets CYP2D6 exon 9 sequences andwill not amplify CYP2D7 or CYP2D8 pseudogenes,or CYP2D6 alleles having CYP2D7 sequences inexon 9 (e.g. CYP2D6*36). The CYP2D6*1allele wasassumed when all CYP2D6alleles tested were absentsince we did not perform DNA sequencing.

The relationship between CYP2D6genotype and thepredicted metabolizer status was evaluated using the

activity score [7,18]. The value assigned to the referenceallele CYP2D6 *1, *2and *35was 1, to CYP2D6*3, *4,*4N, *5,and *6was 0, to CYP2D6*10, *17, *29,and*41was 0.5, and to multiplications of active CYP2D6(*1Nor *2N) was n (number of copies). The subjectswith zero and with more than two CYP2D6active geneswere classified as PMs and UMs, respectively, while therest were EMs.

Statistical analysis

The differences in CYP2D6 allele frequencies werecompared by using the 2 test and/or Fishers exact

test. p-values less than 0.05 were regarded as statisti-cally significant. Statistical analysis was performedusing STATISTICA 4.3 (StatSoft Inc., OK, USA) andGraphPad Prism 5.0 (GraphPad Software, Inc., CA,USA) programs.

ResultsThe frequencies of the CYP2D6genotypes found in theMM and ML subjects studied are shown in Table 2. Thepercentages of CYP2D6alleles with normal, decreased,null or increased activity, as well as the predictive PMand UM metabolic phenotype in the Mexican popula-

tions from the present and previous studies to date areshown in Table 1. The percentage of individuals withzero CYP2D6 active genes (PM predicted phenotype)was 1.0% in MMs, while it was 0% in MLs. The fre-quency of UM were 2.6% and 3% for MLs and MMs,

respectively.

DiscussionTo the best of our knowledge, this is the first study ofCYP2D6 polymorphisms in Mexican Mayan Amer-indian Lacandones (MLs) and in a Mexican Mestizo(MMs) population from Southern Mexico. The absenceof PMs in the present population of MLs was similar tothose found in most previous Mexican-Amerindian pop-ulations [911,19]. There is only an exception in a group ofTarahumaras that also reported a very low frequency of1.4% [11]. The low PM frequency found in MMs from

Chiapas (1.0%) contrasts with higher percentages of PMsin other MM populations previously studied (Table 1).The UM frequency in both populations studied here

is lower than previous reports in European Caucasians [5]and other Mexican populations (Table 2). CYP2D6mul-tiplications, as well as copy number variations, were ana-lyzed in both populations. Previously, these analyses inMexican populations have been reported only for MMsfrom Central and Northern Mexico [10,15], and Amer-indians from Northern Mexico [10,11]. This is the firstanalysis of UMs among Southern-Mexican populations,specifically of Mayan groups. A possible explanation forthe variability in UMs frequencies could be the genetic

heterogeneity among Mexican Amerindian groups [20].However, another possibility is the genotyping method-ology employed in the different studies since the major-ity of previous reports did not discriminate multiplica-tion of nonfunctional CYP2D6 alleles, and UMs wereconsidered solely on multiplication status.

The percentages of alleles with diminished activity(*10, *17and *41) in MMs and MLs were similar to thosereported in other Mexican Mestizos and AmerindianTepehuanos [9,10]populations, respectively (Table 1). The*3and *6alleles (with null activity) in the MM and MLpopulations studied were absent. The low presence of

these alleles is similar to that observed in other Mexi-canMestizos [16], in Tepehuanos [9,10]and in Tzeltales[19](Table 1). The percentage of allele *4is similar amongmost MM populations reported, as well as for the MMsand MLs informed here, but much higher than in Tepe-huanos. The *5allele frequency was found to be similarin the MM group studied here, as well as in the otherMM [15,16]and MexicanAmerican populations reports[1214], but higher than in MLs where it was absent. Theclassic plantanimal warfare thesis of P450 evolutioncannot be ruled out to explain the absence of PMs inthese populations [21]since the frequency of UMs is not


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very high. The varying influence of European or Asianancestry in these populations may also explain the het-erogeneity of these populations. Future studies analyzing

ancestry are required to understand such complexity.These findings in Southern Mexican Mayans cor-

roborate the low frequency of PMs in Amerindians andresemble the high heterogeneity of the Mexican popula-tions, both Mestizo and Amerindian, which could haveimportant implications for the clinical use of CYP2D6drug substrates. For instance, it would also be of interestto test if the low frequency of PMs in Mexican popu-lations is associated with a low incidence of hospital-izations due to adverse events of CYP2D6 substrates.Although, despite CYP2D6 PMs being qualitativelydifferent from the rest of EMs, as demonstrated by

bimodal distributions [4,7], EMs may turn into PMs ifthey are exposed to other xenobiotics, such as drugs ortraditional herbal medicines with alkaloid components,

known to be potent inhibitors of CYP2D6. Moreover,since drugs and plants are metabolized by a myriad ofdifferent enzymes that are encoded by their respec-tive genes, substrate specificity and drug dosage seemto be only two of many factors [22] contributing to adrug response measured by quantitative variables suchas degree of efficacy or number/severity of side effects.In support of that, despite the evidence about the rela-tionship of CYP2D6 and drug response [6], the com-bined use of parallel a lternate metabolic CYP pathways[23]that can compensate in the case of CYP2D6 PMsto individualize treatments with certain CYP2D6 sub-

CYP2D6

genotype

Activity

score

MexicanMestizos Lacandones

n Frequency 95% CI n Frequency 95% CI

*4/*4 0 1 0.010 0.0000.0599 0

*4/*10 0.5 0 0

*4/*41 0.5 0 0

*2/*4 1 6 0.050 0.02520.1273 8 0.052 0.0250.101

*2/*5 1 1 0.010 0.0000.0599 0

*1/*5 1 3 0.034 0.00650.0883 0

*4/*35 1 0 0

*41/*41 1 0 0

*1/*4 1 14 0.140 0.08400.2226 24 0.156 0.1060.222

*10/*41 1 0 1 0.006 0.0000.040

*35/*41 1.5 0 0

*2/*41 1.5 0 1 0.006 0.0000.040

*1/*17 1.5 0 0

*2/*17 1.5 0 0

*1/*10 1.5 2 0.020 0.00110.0744 1 0.006 0.0000.040

*1/*41 1.5 0 2 0.013 0.0010.049

*2/*2 2 7 0.070 0.03660.1577 9 0.058 0.0300.109

*1x2/*4 2 0 0

*1/*1 2 37 0.370 0.28170.4679 67 0.435 0.3590.514

*1/*2 2 26 0.260 0.18360.3542 36 0.234 0.1740.307

*1/*35 2 0 1 0.006 0.0000.040

*2x2/*5 2 0 0

*1x2/*41 2.5 0 0

*1/*1x2 3 2 0.020 0.00110.0744 3 0.019 0.0040.058

*1/*2x2 3 1 0.010 0.0000.0599 0

*2x3/*41 3.5 0 0

*2/*2x4 5 0 1 0.006 0.0000.040

*1/*2x4 5 0 0

Table 2. Frequencies of CYP2D6genotypes in 100 MexicanMestizo and 154 Lacandon individuals from Chiapas.


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strates is, as yet, very limited, as is use of other genessuch as those encoding drug receptors also involved inresponse [24]. Finally, individualized therapy to increasedrug safety in different populations will also largelybenefit from collecting and interrogating large genom-

ics datasets in order to identify biological mechanismsassociated with observed outcomes [25].

Future perspectiveInterindividual variation in drug response poses a seri-ous problem in clinical practice. Knowledge of thedistribution of common CYP2D6alleles in the differ-ent ethnic groups that comprise the current Mexicanpopulation represents relevant pharmacogenetic data ofclinical importance for a better therapeutic outcome.This is especially true for CYP2D6 since it is respon-sible for the oxidative metabolism of 25% of commonly

prescribed drugs, and is codified by a highly polymor-phic gene that shows marked interethnic variation.Nevertheless, prospective clinical studies are neededin order to establish pharmacogenetic based-dosingfor CYP2D6 substrate drugs, as well as studies onthe use of traditional plants by Mayans that may havecomponents 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 Na-

cional de Investigacin Cientca, Desarrollo e Innovacin

Tecnolgica (I+D+I) and Fondo Social Europeo of the Euro-

pean Union (FEDER), Instituto de Salud Carlos III-FIS ResearchGrants (PI10/02758; PI10/02010), by AEXCID Cooperacin

Extremea of the Junta de Extremadura (13IA001) to SIFF and

coordinated in the Network Red Iberoamericana de Farma-

cogentica y Farmacogenmica (RIBEF). The authors have no

other relevant afliations or nancial involvement with any

organization or entity with a nancial interest in or nancial

conict 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 institu-

tional 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 in-

volving human subjects, informed consent has been obtained

from the participants involved.

Executive summary

Background

CYP2D6polymorphisms contribute to interindividual differences in drug response of clinical importance.

Marked interethnic variation has been reported for the frequency of CYP2D6alleles.

Large interindividual variation in the enzyme activity of CYP2D6 has been described, which includesindividuals 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 CYP2D6polymorphisms 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.

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CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas.

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Transcript of CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas.