Vol.2, No.10, 1184-1190 (2010) Health
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Association of CYP2C19 genotype with type 2 diabetes
Carlos Hoyo-Vadillo1*, Jaime Garcia-Mena2, Adán Valladares3, Caterina R. Venturelli1, Niels
Wacher-Rodarte4, Jesús Kumate5, Miguel Cruz3
1Department of Pharmacology, Cinvestav-IPN Zacatenco, México City, Mexico; *Corresponding Author: citocromo@cinvestav.mx
2Departamento de Genética y Biología Molecular, Cinvestav-IPN Zacatenco, México City, Mexico
3Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI del IMSS, México
City, Mexico
4Unidad de Investigación Médica en Epidemiología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI de IMSS,
México City, Mexico
5Fundación IMSS, México City, Mexico
Received 4 July 2010; revised 13 July 2010; accepted 20 July 2010.
Background: CYP2C19 is a major isoform of
cytochrome P450 that metabolizes a number of
commonly prescribed drugs such as omepraz-
ole, diazepam, tolbutamide and propranolol. Its
expression is regulated by the constitutive and-
rostane receptor (CAR), involved in glucocorti-
coids synthesis. Since a number of crosslinks
have been described for CYPs and some horm-
ones, an association of CYP2C19 with type 2
diabetes is likely. Methods: Two groups were
studied, 352 diagnosed with type 2 diabetes
patients and 342 healthy volunteers form Mexi-
co City. Both groups were tested for CYP2C19*2
and *3 alleles. We carried out an allelic discri-
mination using TaqMan assay for *2, and used
FRET sensor and anchor probes for *3. Results:
Ninety one percent of the subjects had the wild
type allele, 9% have the *2 allele; no subject
presented the *3 allele. The CYP2C19*2 allele is
associated with type 2 diabetes (p = 0.012). Ad-
mixmap program was used to correct the adm-
ixture of this population and get the correlation.
This was further confirmed in a linear model
with a 67% power and by the method of Strom
and Wienker for association on subjects within
the mean range of Amerindian ancestry only (60%).
Conclusion: Type 2 diabetes patients have sign-
ificatly more *2 allele than healthy volunteers,
more evident for the patients with the homocyg-
ous genotype.
Keywords: Pharmacogenomics; CYP2C19; Type 2
Diabetes; Mexicans; Allele Frequency
The P450 Cytochrome gene super-family is involved in
the synthesis of steroids, as well as in the metabolism of
cholesterol [1]. Cytochrome genes exhibit a number of
mutations that alter their activity [2]. In the case of CYP-
2C19 the most common mutations *2 and *3 show no
enzymatic activity. For this isoform, CYP2C19, known
for metabolizing both, mephenytoin and omeprazole it
has been demonstrated to have the greatest genetic varia-
bility among human populations [3]. Some of them,
Asians for example [4], present a very high frequency of
mutations, Latin-Americans on the other hand, have a
small frequency of inactive alleles [5,6], while Eskimo
Inuits do not seem to present any mutations at all [7].
CYP2C19 metabolizes an estimated of 8% of all the-
rapeutic drugs in current use [8], knowing the variants
which do not present enzymatic activity is of huge inter-
est for physicians prescribing drugs such as tolbutamide,
omeprazole, proguanil, fluoxetine, citalopram, diazepam,
propanolol, diclofenac, indomethacine and others.
Previous studies have identified the presence of
CYP2C19*2 in Bolivians [5] and in Colombians [6].
Whereas in Inuits no mutations have been identified [7].
Asians have a high frequency of 2C19 mutations, actu-
ally they are so far the only population with 2C19*3
mutations. For this reason it is somehow obvious to look
for the presence of this allele in our Mexican subjects
since Amerindian populations came from Asia 30,000 to
45,000 years ago [9]. In addition, characterizing our
populations is an important advance towards a personal-
ized medicine.
Nuclear receptors are transcription factors that modu-
late cellular responses to small lipophyllic molecules such
as steroids and others. They also regulate the expres-
C. Hoyo-Vadillo et al. / Health 2 (2010) 1184-1190
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
sion of CYPs. Three of this nuclear receptors have been
described to regulate the expression of CYP2C19, CXR
(chicken xenobiotic receptor), PXR (pregnane X recep-
tor) and CAR [10]. All this elements are a linkage of
CYP2C19 with its role on cholesterol elimination and on
the physiology of other steroid hormones like cortisol.
Both process are tightly involved in the development of
obesity and type 2 diabetes. This regulation of the
CYP2C19 is regulated by a complex crosslinking in-
volving cholesterol levels, glucocorticoid activity and
the action of other steroid hormones; therefore, the in-
terest to look for a possible association of CYP2C19
with type 2 diabetes.
2.1. Subjects
We included 367 men and 330 women (age range: 18-76
years old; body mass index averages of 28 for males and
30 for females, Table 1) from the DNA library of the
Biochemistry Research Unit of Medical Center 21st cen-
tury, IMSS, located in Mexico City. No relatives were
included in the groups. The corresponding ethics and
research committees approved the study. All participants
signed the informed consent. About half of the subjects
participating in this study were patients with type 2 diab-
etes, and because they were already part of other studies,
we had previously characterized their population ad-
2.2. Autosomal Ancestry-Informative
Markers (AIMs)
Stratification in the subjects of this study was corrected
using previously reported data [11], these markers have
large frequency differences among populations of Native
American (65%), European (30%), and West African
(5%) ancestry.
2.3. Biochemical Profile
Clinical evaluation was made after 12 h overnight fas-
ting. Blood samples were taken and used to measure gl-
ucose, triglycerides, total, high and low density choles-
terol levels were assayed using an ILab 350 Clinical Ch-
emistry System (Instrumentation laboratory, Mexico). All
participants were interviewed by a physician who colle-
cted data about their weight, height, systolic and diasto-
lic blood pressure. Quantitative measurements of fasting
plasma insulin were carried out using the chemilumines-
cence’s assay according to the manufacturer’s instruct-
tions (Immulite, France).
2.4. DNA Samples
DNA was extracted from blood cells using the Qiagen
columns according to the manufacturer’s recommenda-
tions (Qiagen, Chatsworth, CA, USA). Purity was veri-
fied by UV absorption at 260/280 nm and DNA integrity
was checked by electrophoresis in 0.8% agarose gels,
stained with ethidium bromide.
Table 1. General characteristics of the group studied.
Control T2D
Variable units Males Females Males Females
Number 259 93 107 235
Age years 41.6(8.2) 40.5(8.7) 57.8(9.9) 55.8(9.6)
Height m 1.68(0.07) 1.56(0.06) 1.64(0.08) 1.54(0.07)
Weight kg 77.9(10.5) 69.4(11.9) 76.1(11.3) 71.2(13.8)
Body Mass Index (BMI) kg/m2 27(3) 29(5) 29(5) 30(5)
Waist Hip Index 0.87(0.05) 0.84(0.07) 0.95(0.04) 0.89(0.07)
SBP mmHg 118(11) 114(8) 122(12) 124(15)
DBP mmHg 74(7) 73(8) 95(25) 92(24)
Glucose mg/dL 85.7(9.5) 84(8.7) 163.5(73.3) 154.2(60.9)
Insulin IU/ml 16(6.6) 15.6(7.6) 9.2(12.2) 8.4(11.5)
Glycosilated haemoglobin (A1c) % 4.2(0.6) 4(0.5) 7.6(2.4) 7.9(2)
Total cholesterol mg/dL 195(40) 189(36) 196(38) 206(46)
High density lipoprotein (HDL-C) mg/dL 51(23) 59(23) 40(16) 42(19)
Low density lipoprotein (LDL-C) mg/dL 106(46) 98(41) 119(39) 130(39)
Triglycerides mg/dL 173(102) 128(62) 225(134) 207(127)
Serum Creatinine mg/dL 1.00(0.16) 0.76(0.13) 0.93(0.98) 0.81(0.76)
Values are Mean (Standard Deviation).
C. Hoyo-Vadillo et al. / Health 2 (2010) 1184-1190
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
2.5. Allele-Specific TaqMan PCR for
DNA samples were analyzed for CYP2C19*2 using the
TaqMan PCR assay to detect G > A polymorphism acc-
ording to the manufacturer’s instructions. Amplification
and detection were made using the ABI PRISM 7000
(Applied Biosystems, USA) system with the following
profile: a denaturing cycle of 95ºC for 10 min and 40
cycles of 92ºC for 15 s, extension phase of 60ºC for 1
min. Samples were judged positive for *2 when the va-
lue of the emitted fluorescence was greater than the th-
reshold calculated by the instrument’s software. Display-
ed as an allelic discrimination plot. Wild type allele
CYP2C19*1 was labeled with VIC and *2 allele with
for ATTTCCCAGGAACCCA (SNP showed in bold-
2.6. CYP2C19*3 Evaluation by FRET
This polymorphism was identified following the method
described by Borlak and Thum [12] using fluorescence
resonance energy transfer (FRET) to assay genomic G >
A Sensor and anchor probes were labeled with fluoresce-
ein and Red640, respectively. PCR was run with a 5 min
denaturation step. Fifty cycles with 7 sec of annealing
(48ºC) and 14 sec of extension (72ºC) in a Light Cycler
(Model 1.2, Roche diagnostics, Germany). The melting
curve was done from 40ºC (with 30 sec of previous stab-
ilization) to 80ºC with a 0.1ºC/min slope. Tms were 61ºC
for the wild CYP2C19*1 type and 67ºC for the CYP2
C19*3 genotype. Software used was Light Cycler (Ro-
che, Version 4). Control probes for *1 and *3 were used
as validation of fusion points. The assay was validated
using standards provided by Roche.
2.7. Statistical Analysis
In order to correct the stratification of this population,
ADMIXMAP program was employed to look for case-
control (shown in Table 2) associations using logistic
regression and to measure the Hardy-Weinberg equilib-
rium. Iterations were tested to 4000, burning was sele-
cted to 200, “every” parameter to 7. The rest of parame-
ters were defaults. Co-variables were log of age and ge-
nder. Hardy-Weinberg equilibrium was also tested after
the Sasieni method implemented by Strom and Wienker
[13] (available at: http://ihg2.helmholtz-muenchen.de/
cgi-bin/hw/hwa1.pl) [14]. Proportions of genotypes were
compared by the Fisher exact test. Odds ratios and their
corresponding 95% confidence intervals were also esti-
mated. All p values < 0.05 were considered statistically
significant. The association between total cholesterol,
HDL-C, LDL-C levels with the CYP2C19*2 allele was
analyzed by the type III linear model with and without
co-variables, including the stratification of the population,
health, age, gender, height, body mass, waist-hip index,
and BMI. Linear models were also tested using model I
for interaction, with an Amerindian index as co-variable
as well as log of age and gender. In all tests significance
was considered for values less than 0.05.
3.1. Characteristics of the Sample and
Stratification of the Population
At total of 697 individuals were studied (Table 1). This
sample of Mexico City population had been previously
characterized for its ancestry informative makers by ad-
mixture mapping analysis, showing an estimated propor-
tion of 65% component of Amerindian, 30% European
Table 2. Linear model for CYP2C19 associtation with type 2 diabetes.
Source Type I Sum
of Squares df Mean Square F Sig. Noncent.
Corrected Model 48.1(b) 4 12,042 87,292 0.000 349,169 1,000
Intercept 94,616 1 94,616 685,863 0.000 685,863 1,000
Homocygotic 0.8 1 0.800 5800 0.016 5,800 0.671
Amerindian index 0.186 1 0.186 1,346 0.247 1,346 0.212
Sex 16,589 1 16,589 120,254 0.000 120,254 1,000
In (Age) 30,593 1 30,593 221,769 0.000 221,769 1,000
Error 58,216 422 0.138
Total 201,000 427
Corrected Total 106,384 426
a: Computed using alpha = 0.05; b: r Squared = 0.453 (Adjusted R Squared = 0.448).
Homocygotic referes to 2,2 genotype for CYP2C19.
Amerindian index was obteinded from admixmap and equals the integer of ameriandian component multiplied by 10 and divided by 4.
C. Hoyo-Vadillo et al. / Health 2 (2010) 1184-1190
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
and 5% West African. For this study, the stratification pl-
ays a critical role since the frequency of CYP2C19 is bi-
ased by ethnic admixture.
3.2. Genotypes
CYP2C19*2 genotypes were characterized for all subje-
cts. In our control subjects, 0.6% were homozygous and
15.6% heterozygous for *2. In T2D patients, 1.4% were
homozygous and 17.7% heterozygous for *2. These fre-
quencies were in Hardy-Weinberg equilibrium after Fi-
sher exact test (p = 1.000 for the control volunteers and
p = 0.384 for the T2D group. CYP2C19*3 genotypes
were not present in none of analyzed samples. The geno-
type frequencies are shown in Figure 1.
3.3. Allele Frequencies
Eight percent of the alleles in the control subjects, and
10% in T2D patients were CYP2C19*2 (Table 3). The
odds ratio was 1.22, with 95% confidence interval [0.81-
1.84], (p = 0.358), in a dominant model; and 2.57 with a
95% confidence interval of [0.44 - 19.26], (p = 0.431) in
a recessive model. The CYP2C19*3 allele was analyzed
in 460 subjects: 198 control volunteers and 262 type 2
diabetes patients and all of them had the wild type form
for the loci 636G > A (Table 2).
3.4. There is No Association between the
CYP2C19*2 Allele and HDL-C, LDL-C
and Total CYP2C19 Association with
Type 2 Diabetes
Admixmap program revealed a significance of 0.012 for
association of CYP2C19 genotypes with type 2 diabetes.
The power for this test is indirectly estimated to be 0.95,
using the G*power program. This was confirmed using
the linear model I. In this case ethnicity measured as Am-
erindian content in a 1 to 4 scale. This index was calcu-
lated by scaling the results of Amerindian ancestry. Log
of age and gender as co-variables were also included.
The significance was of 0.016 for subjects with recessive
homozygous genotype. The statistical power for this test
was 0.67. When subjects with Amerindian index of 3
were selected, an association was detected using the
Sasieni procedure; however in this case type 2 diabetes
subjects were not in Hardy-Weinberg equilibrium. Odds
ratio for that group is shown in Table 4.
Classical approach using linear model also show the
association for CYP2C19 with type 2 diabetes, see Ta-
ble 2. In that case age and sex were taken as covariables,
and the significance was 0.016.
Our finding of the *2 allele association with type 2 diab-
Figure 1. Observed frequency of CYP2C19
genotypes on case (T2D) and control (healthy)
groups. Note that the slight higher frequency of
*1/*2 genotype together with the much higher
frequency of *2/*2 in case group are respon-
sible for the association of CYP2C19 genotype
with type 2 diabetes (T2D).
etes is apparently due to the homozygous genotype gr-
oup as seen in the raw database. Of six subjects present-
ing this genotype five were type 2 diabetes patients vers-
us only one in the control group. The only healthy *2/*2
carrier was a young male (40 years) who is probably in
high risk for developing type 2 diabetes. Type 2 diabetes
is a multifactor disease; the role of CYP2C19 in this
pathogenesis can be linked by its interaction with CAR
and PXR [15,16]. Interestingly Kohalmy [17] have des-
cribed a CYP2C19 relationship with DHEA which at the
same time is related to type 2 diabetes. Type 2 diabetes
patients present increased CYP2E1 activity, measured as
a decrease of the area under the curve after chlorzoxazo-
ne administration. CYP2E1 mRNA, in blood mononucl-
ear cells, was found increased as well [18]. On the other
hand, it has been previously suggested that free radicals
are a risk factor for type 2 diabetes. One source for the
suppression of free radicals happens to be CYP activity.
Among the involved isoforms, the CYP2C family can
play a major role [19].
It has to be pointed out that CYP2C19*2 comprises an
haplotype with at least four mutations: 99C > T; 681G >
A; 990C > T; 991A > G [20]. It has four variants: 2A,
2B, 2C and 2D; the last three, besides the mentioned
four mutations also have other substitutions: 276 G > C,
481 G > C and 1213 G > A, respectively. For CYP2C19*2
the 681G > A, SNP was included in the taqman assay.
CYP2C19*3 have two haplotypes: 3A (636G > A; 991A
> G; 1251A > C) and 3B (636G > A; 991A > G; 1078G
> A; 1251A > C) [20]. For CYP2C19*3 the SNP of 636
G > A was the one included for the Light Cycler system.
C. Hoyo-Vadillo et al. / Health 2 (2010) 1184-1190
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Table 3. Observed frequencies of CYP2C19*2 and *3.
Healthy T2D Healthy T2D Healthy T2D
Genotype Number of subjects Observed Frequency H-W Expected freq.
*1/*1 295 279 83.8% 80.9% 83.9% 80.5%
*1/*2 55 61 15.6% 17.7% 15.4% 18.5%
*2/*2 2 5 0.6% 1.4% 0.7% 1.1%
*1/*3 0 0 0% 0% 0% 0%
*2/*3 0 0 0% 0% 0% 0%
*3/*3 0 0 0% 0% 0% 0%
Allele *1 91.6% 89.7%
Allele *2 8.4% 10.3%
Allele *3 0% 0%
Table 4. Odds ratio for genotypes in healthy males (control) versus diabetic males.
Risk allele 2
[1]<->[2] [11]<->[12] [11+]<->[22] [11]<->[12+22] Common odds ratio
Odds_ratio = 1.992 Odds_ratio = 1.724Odds_ratio = 5.663 Odds_ratio = 1.907Odds_ratio = 2.741
C.I. = [1.084-3.659] C.I. =
C.I. =
C.I. =
chi2 = 5.09 chi2 = 2.78 chi2 = 2.54 chi2 = 4.00 chi2 = 4.88
p = 0.02404 (Pearson) p = 0.09571 p = 0.11067 p = 0.04543 p = 0.02711
Risk allele 1
[2]<->[1] [22]<->[12] [22]<->[11] [11+12]<->[22] Common odds ratio
Odds_ratio = 0.502 Odds_ratio = 0.298Odds_ratio = 0.177 Odds_ratio=0.193 Odds_ratio=0.543
C.I. = [0.273-0.922] C.I. =
[0.016-5.714] C.I. = [0.010-3.227] C.I. =
chi2 = 5.09 chi2 = 1.46 chi2 = 2.54 chi2 = 2.33 chi2 = 4.88
p = 0.02404 (Pearson) p = 0.22749 p = 0.11067 p = 0.12663 p = 0.02711
For both alleles just one SNP was included as the stan-
dard technique proceeds, because SNPs always come
together for a given haplotype, in other words, one SNP,
the one shared for all variants, is enough to characterize
the haplotype.
Complex networks of nuclear receptors, where PXR
and CAR are outstanding representatives, regulate the ex-
pression of CYP3A4 and CYP2C19. The latter is modu-
lated by glucocorticoids which at the same time interact
with insulin for energy balance altogether with the part-
icipation of the neuropeptide Y.
Since it has been demonstrated that CAR also regu-
lates the expression of CYP2C19 [21] the CYP2C family
can be considered part of the xenosensing mechanism in
charge of the regulation of cholesterol, bile acids and in-
directly the uptake of dietary cholesterol as Handschind
[16] describes it. Furthermore, the crosstalk between all
the orphan nuclear receptors has been pointed out by
several authors [22,23]. After all CYPS are not very
substrate specific and the interesting conclusion of the
Meyer group that the organism manages xenobiotics and
drugs as toxic bile salts [24]. These changes suggest a
crosstalk between the factors deriving in type 2 diabetes
and the regulation of cytochromes P450. At the moment
the regulation of CYP2C19 has been demonstrated but
the inverse can be only assumed as part of a feedback
In conclusion our work shows that the mexican popu-
C. Hoyo-Vadillo et al. / Health 2 (2010) 1184-1190
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Figure 2. Frequencies of main alleles of CYP2C19 on different
populations. Colombians, Bolivians and Mexicans have the lo-
wer frequencies for *2 allele. But Inuits have no presence of
them. While Asians have the greatest frequencies for the *2 and
only they present *3.
lation of Mexico City has the same frequencies for CY-
P2C19 wild and *2 alleles than the populations reported
in Bolivia and Colombia (Figure 2). The *3 allele was
not detected in our population just as in other Latin-
The collaboration of Dr. Esteban Parra is fully acknowledged for get-
ting the ancestry informative proportions of our population and with
the use of ADMIXMAP. Financial support from Fundación IMSS and
from Cinvestav are greatly appreciated
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