J Med Biochem 2019; 38 (4) DOI: 10.

2478/jomb-2018-0046

UDK 577.1 : 61 ISSN 1452-8258

J Med Biochem 38: 461–467, 2019 Original paper

Originalni nau~ni rad

ASSOCIATION OF THE MTHFR 677C>T POLYMORPHISM WITH OBESITY AND

BIOCHEMICAL VARIABLES IN A YOUNG POPULATION OF MEXICO
POVEZANOST MTHFR 677C>T POLIMORFIZMA SA GOJAZNO[]U I BIOHEMIJSKIM
PROMENLJIVIMA U MLADOJ POPULACIJI MEKSIKA

Evelia Leal-Ugarte1, Valeria Peralta-Leal1, Juan Pablo Meza-Espinoza1, Jorge Durán-González1,

Nelly Macías-Gómez2, Anabel Bocanegra-Alonso3, José Ramón Lara-Ramos3
1Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de
Tamaulipas, Sendero Nacional km 3, Col San José, Matamoros, Tamps., México
2Centro Universitario del Sur, Universidad de Guadalajara, Av. Enrique Arreola Silva # 883,
Col Centro, Ciudad Guzmán, Jal., México
3Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas,
Calle 16 y Lago de Chapala, Col Aztlán, Reynosa, Tamps., México

Summary Kratak sadr`aj

Background: Methylenetetrahydrofolate reductase (MTHFR) Uvod: Polimorfizam genetske metilenetetrahidrofolat
gene polymorphisms have been associated with overweight reduktaze (MTHFR) je povezan sa prekomernom te`inom i
people and obesity. The goal of this study was to investigate gojazno{}u. Cilj ove studije bio je da se istra`i odnos
the relationship of the MTHFR 677C>T polymorphism MHTFR 677C>T polimorfizma sa gojazno{}u i bio-
with obesity and biochemical variables in young individuals hemijskim promenjivim kod mladih u Meksiku.
of Mexico. Metode: U studiju je uklju~eno ukupno 316 mladih osoba,
Methods: A total of 316 young individuals were included in 172 sa normalnom te`inom (NV) i 144 sa prekomernom
the study, 172 with normal weight (NW) and 144 with te`inom/gojaznih. Indeks telesne mase (BMI) je klasifiko-
over weight/obesity. Body mass index (BMI) was classified van kao NT (normalna te`ina), prekomerna te`ina i gojaz-
as NW, overweight, and obesity. Also, waist circumference nost. Tako|e, izmeren je obim struka. [tavi{e, odre|ena je
was measured. Moreover, glucose, total cholesterol, and i glukoza, ukupni holesterol i trigliceridi. Genotipizacija za
triglycerides were determined. Genotyping for MTHFR MTHFR 677C>T polimorfizam je izvedena metodom PCR-
677C>T polymorphism was performed by the PCR-RFLP RFLP.
method. Rezultati: Nije postojala razlika u distribuciji MHTFR
Results: There was no difference in the distribution of the 677C>T polimorfizma izme|u pojedinaca sa NT i preko-
MTHFR 677C>T polymorphism between individuals with mernom te`inom/gojaznih; ni u slu~aju kada su bili po-
NW and overweight/obesity; neither when they were deljeni na one sa prekomernom te`inom naspram NT, niti
divided by overweight vs NW, nor when we contrasted kada smo uporedili gojazne naspram onih normalne te`ine.
obese vs NW. However, an analysis stratified by gender Me|utim, analiza stratifikovana po polu je pokazala zna-
showed a significant protector effect of the TT genotype ~ajan za{titni efekat TT genotipa protiv gojaznosti kod
against obesity in males and elevated waist circumference mu{karaca i pove}anog obima struka kod `ena. Tako|e,

Address for correspondence:

Evelia Leal-Ugarte
Facultad de Medicina e Ingeniería en Sistemas
Computacionales de Matamoros, Universidad Autónoma
de Tamaulipas, Sendero Nacional km 3, Col San José, List of abbreviations: BMI, Body mass index; NW, normal
Matamoros, Tamps., México weight; CI, confidence interval; OR, Odds ratio; PCR-RFLP,
Phone: +52 868204 4000 Polymerase Chain Reaction-Restriction Fragment Length Poly-
Fax: +52 868204 4001 morphisms; bp, Base pairs; p, P value-Statistical significance;
e-mail: elugarteªdocentes.uat.edu.mx s, Second; min, Minute; HWE, Hardy-Weinberg Equilibrium.

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462 Leal-Ugarte et al.: MTHFR 677C>T and biochemical traits in youths

in females. Also, overweight/obese individuals with TT osobe sa preteranom te`inom/gojazne osobe sa TT geno-
genotype had less risk of high cholesterol or triglycerides tipom imale su manje rizika od visokog holesterola ili tri-
than overweight/obese subjects with the other genotypes. glicerida nego osobe prekomerne te`ine/gojazne osobe sa
Conclusions: These results suggest that the MTHFR 677T drugim genotipovima.
polymorphism might not be a risk factor for being over - Zaklju~ak: Ovi rezultati ukazuju na to da polimorfizam
weight/obesity. Rather, on the basis of our results, this MTHFR 677C>T mo`da nije faktor rizika za preveliku
variant could be a protector effect. However, further large- te`inu/gojaznost. Potpuno suprotno, na{i rezultati pokazuju
scale population-based studies are still necessary to clarify da ova varijanta mo`e imati za{titni efekat. Ipak, potrebne
the role of the MTHFR 677C>T polymorphism in over - su dodatne studije {irokog opsega da bi se pojasnila uloga
weight, obesity, and lipid profile level. MHTFR 677C>T polimorfizma u prekomernoj te`ini, go-
jaznosti i nivou lipidnog profila.
Keywords: MTHFR, 677C>T, obesity, overweight,
biochemical variables Klju~ne re~i: MTHFR 677C>T, gojaznost, prekomerna
te`ina, biohemijske promenljive

Introduction Academic Unit Reynosa Aztlán of the Autonomous

University of Tamaulipas, in Reynosa, Tamaulipas,
Overweight and obesity have become a serious
Mexico were enrolled in this study. Individuals were
public health problem worldwide since they increase
od the average age of 19, without apparent comor-
the risk of chronic diseases and early death (1).
bidities (hypertension, diabetes, or dyslipidemia). All
Overweight and obesity are disorders of energy
of them had their weight (kilogram; kg), and height
balance with excessive fat storage. According to the
(meter; m) measured. They were weighted in a
World Health Organization (WHO), obesity has
increased more than twofold in the last three decades precision balance with very light clothes and no
worldwide; in 2014, it was reported that more than shoes. Body mass index (BMI) was calculated as
1,900 million people over the age of 18 years were weight (kg) divided by height squared (m2). The BMI
overweight, and of those, over 600 million were was classified as normal weight (NW) (18.5–24.9
obese (2). In Mexico, in the most recent report by the kg/m2), overweight (25.0–29.9 kg/m2), and obesity
National Survey of Health and Nutrition, the (≥30.0 kg/m2) (2). Moreover, waist circumference
prevalence of overweight and obesity in people over was measured in all participants; in females, 88 cm
the age of 20, adolescents, and children was 72.5%, was considered normal, and ≥88 was considered
36.3% and 33.2%, respectively (3). Obesity is a elevated, in males, <102 cm (normal) and ≥102
multifactorial disease that involves environmental and (elevated). Glucose, cholesterol, and triglycerides
genetic factors (4). Candidate genes associated with were determined in an analyzer AutoKem II
obesity include the methylenetetrahydrofolate (KontroLab, Roma, Italy). Reference values (mmol/L
reductase gene (MTHFR), located in 1p36.3, of were as follows: for glucose, normal (≤5.55) and
which the rs1801133 polymorphism (677C>T; high (>5.55); for cholesterol, normal (≤5.2) and
A222V) is the most common and majorly studied (5). high (>5.2); for triglycerides, normal (≤1.71) and
MTHFR is a pivotal enzyme in folate metabolism, high (>1.71). This study was approved by the ethics
since catalyze 5,10-methylenetetrahydrofolate to 5- committee of each participating institute. Every
methyltetrahydrofolate. Moreover, it regulates the individual was asked for informed consent to take part
proportional usage of one-carbon units between in this research.
methylation reactions and nucleic acid synthesis. The
677TT genotype is associated with a reduction in the
availability of folate, high homocysteine levels, Genotyping by PCR-RFLP
reduced enzyme activity, and thermolabile enzyme Genomic DNA was isolated from peripheral
(6). Moreover, the 677T allele has been linked with blood by CTAB–DTAB (denaturing cationic deter-
overweight/obesity risk, dyslipidemias, and diabetes gents, to precipitate DNA) and Miller (salting out the
in several populations. However, so far, the studies
cellular proteins by dehydration and precipitation with
have been controversial (4, 5, 7–12, 14–30). Here,
a saturated NaCl solutions) methods (13). Geno-
we analyzed whether there is an association of the
typing was performed using PCR-RFLP with the
MTHFR 677C>T polymorphism with overweight and
following primers: 5’-TGAAGGAGAAGGTGTCTGCG
obesity, as well as its relationship with lipid profile,
GGA-3’ 5’-AGGACGGTGCGGTGAGAGTG-3’ a total
glucose level, and anthropometric measurements in a
of 100 ng genomic DNA was amplified in a 20 mL
young Mexican population.
PCR reaction, PCR buffer containing 3 mmol/L
MgCl2, 0.25 mmol/L dNTP’s (Bioline), 5 pmol of
each primer, 1 U Taq polymerase. The PCR cycles
Materials and Methods
were as follows: primary denaturation was carried at
Three hundred and sixteen students, 232 94 °C for 4 min followed by 35 cycles of 94°C for 30
females and 84 males, from the Multidisciplinary s, 61°C for 30 s, 72°C for 30 s. The final extension

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J Med Biochem 2019; 38 (4) 463

was carried out at 72 °C for 7 min (14). Thus, a metabolic traits was evaluated according to the
fragment of 198 base pairs (bp) was obtained; 10 mL genotype by Kruskal-Wallis test (available at
of the PCR product was digested by 4 hours at 37 °C http://vassarstats.net/kw3.html)
with the enzyme Hinf I (BioLabs, New England, USA);
the digestion products were separated in poly-
acrylamide gels. Homozygous individuals for the wild Results
allele (CC) result in a fragment of 198 base pair (bp);
heterozygous (CT) two fragments (198 bp and 175 One hundred and seventy-two individuals were
bp) and homozygous (TT) a fragment of 175 bp. NW, 74 overweight, and 70 obese. Allelic and
genotypic frequencies of the MTHFR 677C>T
polymorphism are shown in the Table I. Allele
Statistical analysis frequency in NW was consistent with HWE (p=0.65).
There was no difference in the distribution of this
Allelic and genotypic frequencies were polymorphism between NW and overweight/obese
established by counting and the distribution of the individuals [OR=0.94 (0.69–1.28); p=0.69], nor
genotypes between both groups was compared by when they were divided by NW vs overweight, or NW
Chi-square test. Hardy-Weinberg equilibrium (HWE) vs obese [OR=0.87 (0.59–1.3); p=0.47] and
was analyzed by Fisher exact test. Association was [OR=0.99 (0.67–1.47); p=0.96], respectively (Table
estimated by odds ratio (OR) and 95% confidence I). However, when the sample was stratified by
interval (CI) in SPSS v10.0 software (the C allele was gender, significant differences between NW males vs
taken as reference), p≤0.05 was considered obese males were observed (Table II), suggesting a
significant. Likewise, in overweight and obese protector effect for obesity of the T homozygotes.
individuals, risk factors such as glucose, triglycerides, Regarding the analysis of waist circumference,
and cholesterol were assessed. Moreover, analysis of stratified by gender, this showed that the females
means of anthropometric measurements and carrying the T allele had a minor risk of having

Table I Analysis of allelic and genotypic frequencies of the MTHFR 677C>T polymorphism between individuals with normal
weight, overweight/obese, overweight, and obese.

NW BMI <25 Overweight /obesity BMI ≥25

Genotype/allele OR (95% CI) *p value
n=172 n=144

C/C 43 34 Reference
C/T 90 84 1.18 (0.69–2.02) 0.55
T/T 39 26 0.84 (0.43–1.65) 0.62
C 176 152 Reference
T 168 136 0.94 (0.69–1.28) 0.69
Overweight
NW BMI<25
(≥25BMI <30)
n=172
n=74
C/C 43 16 Reference
C/T 90 49 1.46 (0.75–2.9) 0.27
T/T 39 9 0.62 (0.25–1.6) 0.31
C 176 81 Reference
T 168 67 0.87 (0.59–1.3) 0.47

NW BMI <25 Obesity BMI >30

n=172 n=70

C/C 43 18 Reference
C/T 90 36 0.96 (0.49–1.87) 0.89
T/T 39 16 0.98 (0.44–2.18) 0.96
C 176 72 Reference
T 168 68 0.99 (0.67–1.47) 0.96

*Chi square test.

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464 Leal-Ugarte et al.: MTHFR 677C>T and biochemical traits in youths

Table II Analysis of allelic and genotypic frequencies of the MTHFR 677C>T polymorphism between males with BMI <25 vs
BMI ³25 and females with waist circumference <88 cm vs ≥88 cm.

Male BMI <25 Male BMI ≥25

Genotype/allele OR (95% CI) *p value
n=37 n= 47

C/C 7 18 Reference
C/T 21 23 0.43 (0.15–1.22) 0.10
T/T 9 6 0.26 (0.07–1.00) <0.05
C 35 59 Reference
T 39 35 0.53 (0.29–0.99) <0.05
Female <88 cm Female ≥88 cm
Genotype/allele OR (95% CI) *p value
n=155 n=77
C/C 36 43 Reference
C/T 79 22 0.23 (0.12–0.45) <0.001
T/T 40 12 0.25 (0.12–0.55) <0.001
C 151 108 Reference
T 159 46 0.40 (0.27–0.61) <0.001

Table III Analysis of allelic and genotypic frequencies of the MTHFR 677C>T polymorphism between overweight/obese
individuals depending on the level of triglycerides, cholesterol, and glucose.

Overweight /obesity Overweight /obesity

Genotype/alleles triglycerides ≤1.71 mmol/L triglycerides >1.71 mmol/L OR (95% CI) *p value
n=109 n=35
C/C 25 12 Reference
C/T 60 21 0.73 (0.31–1.70) 0.47
T/T 24 2 0.17 (0.04–0.86) 0.02
C 110 45 Reference
T 108 25 0.57 (0.32–0.99) 0.04
Overweight /obesity Overweight /obesity
cholesterol ≤5.2 mmol/L cholesterol >5.2 mmol/L
n=126 n=18
C/C 30 6 Reference
C/T 70 12 0.86 (0.29–2.50) 0.78
T/T 26 0 0.09 (0.01–1.65) 0.02
C 130 24 Reference
T 122 12 0.53 (0.26–1.11) 0.09
Overweight /obesity glucose Overweight /obesity glucose
≤5.55 mmol/L >5.55 mmol/L
n=111 n=33
C/C 28 9 Reference
C/T 65 18 0.86 (0.35–2.15) 0.75
T/T 18 6 1.04 (0.32–3.41) 0.95
C 121 36 Reference
T 101 30 0.99 (0.58–1.73) 0.99
*Chi square test.

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J Med Biochem 2019; 38 (4) 465

Table IV Analysis of anthropometric measurements, lipid, and glycemic traits in 316 Mexican youths according the MTHFR
677C>T genotype.

Trait CC CT TT p value*
n 80 172 64
Age (years) 19.5 ± 1.9 19.7 ± 1.8 20.0 ± 3.6 0.34
BMI (kg/m2) 25.9 ± 6.4 25.8 ± 5.9 25.8 ± 7.8 0.63
Hip circumference (cm) 99.2 ± 13.0 99.7 ± 13.7 98.5 ± 12.8 0.68
Waist circumference (cm) 89.9 ± 22.9 90.1 ± 21.0 98.5 ± 17.4 0.03
**Waist hip ratio 0.84 ± 0.7 0.84 ± 0.7 0.83 ± 0.7 0.79
Systolic pressure (mm Hg) 108.6 ± 18.5 106.5 ± 13.5 104.3 ± 14.9 0.63
Diastolic pressure (mm Hg) 75.6 ± 10.0 74.8 ± 10.1 72.7 ± 9.6 0.33
Total cholesterol (mmol/L) 4.18 ± 1 4.04 ± 1.93 3.88 ± 0.75 0.22
Triglycerides (mmol/L) 1.19 ± 0.69 1.17 ± 0.4 1.04 ± 0.49 0.18
Glucose (mmol/L) 4.8 ± 0.79 4.93 ± 1.18 4.85 ± 0.82 0.88

Data are expressed as mean ± standard deviation. BMI: body mass index. *Kruskal-Wallis test (available at
http://vassarstats.net/kw3.html). **Genotypes of waist hip ratio were 73, 148, and 61 for CC, CT, and TT, respectively.

elevated waist circumference, both CT genotype and population. Similarly, Di Renzo et al. (7) studied 56
TT homozygote; but this was not observed in males obese individuals who underwent a diet and observed
(Table II). Testing between overweight/obese individuals that before starting the regime there were more
based on glucose, cholesterol, and triglycerides obese who carried the T (+) genotype (CT or TT) and
levels, showed that the TT genotype was more less with T (-) genotype (CC carriers). They found that
common in subjects with triglycerides ≤1.71 mmol/L after twelve weeks the subjects who carried the T (-)
and cholesterol ≤5.2 mmol/L (Table III). As for the genotype (CC homozygote) decreased more weight
analysis of quantitative variables according to than the T allele carriers (CT or TT) (5). Others re-
genotype, only significant differences were detected searchers suggest that overweight/obese individuals
for waist circumference, and individuals with TT with MTHFR 677TT genotype are at increased risk
genotype had a larger waist circumference than CC for type 2 diabetes mellitus (30).
and TT subjects (p=0.03; Table IV).
To our knowledge, the finding that carrier
females of the MTHFR 677T allele have a minor risk
of elevated waist circumference has not been
Discussion reported in healthy people, but Wang et al. analyzed
Besides known causes involved in overweight/ this parameter between patients with metabolic
obesity development (poor eating habits, lack of syndrome from China and they found a trend towards
physical activity, and psychological disorders), gene- a protector effect against elevated waist
tics plays a very important role, since it represents up circumference in the patients with the TT genotype
to 70% of factors associated with overweight/obesity [OR=0.60 (0.27–1.32); p=0.204] (31), which is in
(4). The results of this study showed no statistical accordance with our observations. On the other
differences about the prevalence of the MTHFR hand, the analysis of means of anthropometric
677C>T polymorphism between NW and over - measurements showed that waist circumference was
weight/obesity individuals, which agrees with the increased in individuals with TT genotype. Although
majority of researches (4, 8, 10–12, 14, 17, 18, 20, this looks like a contradiction, it could be explained by
22, 29). However, opposite findings have also been an unequal distribution of the people with abdominal
described; so Lambrinoudaki et al. (9) observed that obesity and the size sample.
healthy postmenopausal women carrying the 677CT Regarding lipid profiles, the MTHFR 677T allele
or 677TT genotype had central adiposity and waist is associated in non-obese patients with unfavourable
higher hip ratio compared with women carrying the serum lipid profiles in several studies (15, 18, 21, 24,
677CC genotype. Tabassum et al. (19) reported 26, 28). In this study, we detected low levels of
association of 677C>T polymorphism with over - triglycerides and cholesterol in overweight/obese
weight/obesity [1.24 (1.01–1.52) p=0.04] in Indian individuals carrying the TT genotype. In contrast to

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466 Leal-Ugarte et al.: MTHFR 677C>T and biochemical traits in youths

our observation, Zhi et al. (27) found that over - gender differences, sample size, statistical analysis
weight/obese females carrying the TT genotype had criteria, and the participation of other genes that
high triglycerides levels (p=0.0007), and in over - coding enzymes involved in the homocysteine
weight/obesity males, the CT carriers had significantly pathway. We only investigated one polymorphism and
higher LDL-cholesterol levels than the TT carriers did did not have data on other environmental factors,
(p=0.018) in Chinese population. Moreover, Di such as physical activity, dietary habits, alcohol
Renzo et al. (23) studying obese women with consumption and cigarette smoking. We consider that
metabolic syndrome who underwent a diet, found identification of polymorphisms associated with
that CC carriers had lower triglycerides and minor obesity and overweight in young individuals will allow
fasting glucose (p≤0.05). the detection of people in risk at an early age, which
could to permit to take preventive actions.
On the other hand, it is known that the TT
genotype is associated with high homocysteine levels In conclusion, these results suggest that the
(6). Moreover, the significant increment of cholesterol MTHFR 677T polymorphism might not be a risk
has been detected in diet-induced hyperhomo- factor for being overweight/obese. Rather, on the
cysteinemic rats (32). Accordingly, it has been basis of our results, this variant could be a protector
suggested that elevation of homocysteine increases effect. However, further large-scale population-based
HMG-CoA reductase expression, which in turn studies are still necessary to clarify the role of the
activates three transcription factors: sterol regulatory MTHFR 677C>T polymorphism in overweight,
element-binding protein 2 (SREBP-2), cyclic adeno- obesity, and lipid profile level.
sine monophosphate response element-binding
Acknowledgements. Research supported by
protein (CREB), and nuclear factor Y (NF-Y), and
Universidad Autónoma de Tamaulipas through grant
likely increases cholesterol biosynthesis, with
UAT10-SAL-0306. JRRL was supported by CONACyT
subsequent hypercholesterolemia (32). In this study,
fellowship.
we did not evaluate the plasma homocysteine levels.
Contradictorily, our results suggest that individuals
carrying the TT genotype have a minor risk to
develop high levels of triglycerides, and cholesterol. Conflict of interest statement

Discordances observed among studies may be The authors stated that they have no conflicts of
occasioned by several factors such as differences in interest regarding the publication of this article.
dietary, physical activity habits, genetic background,

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Received: October 4, 2018

Accepted: December 5, 2018

Unauthentifiziert | Heruntergeladen 03.10.19 19:19 UTC