MTHFR C677T Gene Polymorphism and Association with Disorders
ALEENA PARVEEN SHAIKH1, KRISTINE MAKHARADZE2, MARINA NAGERVADZE2,
MARINA KORIDZE2, RUSUDAN KHUKHUNAISHVILI2, SALOME GLONTI2
1Department of Clinical Medicine,
Batumi Shota Rustaveli State University,
Batumi,
GEORGIA
2Biology Department,
Batumi Shota Rustaveli State University,
Batumi,
GEORGIA
Abstract: - The Methylenetetrahydrofolate reductase (MTHFR) is a general and important enzyme in human
cells, which is responsible for the metabolism reactions of homocysteine and folate. The genetic material for
MTHFR enzyme synthesis is situated on 1 chromosome p arm in the 1p36.3 position. A lot of single nucleotide
mutations have been identified in this mentioned locus, but among them well-studied is the C677T gene
mutation. The C677T/MTHFR polymorphisms impact MTHFR enzyme activity, leading to alterations in
methionine and folate metabolism, homocysteine levels, and in most cases subsequent effects on DNA
methylation. This literature review compiles information about the MTHFR C677T polymorphism and explores
its potential association with various complex, multifactorial disorders, such as cancer, cardiovascular
complications, neurological conditions, and diabetes mellitus, among others. The review synthesizes findings
from diverse global populations, providing valuable insights for master's and doctorate students, as well as
researchers specializing in this field.
Key-Words: - MTHFR C677T Gene, polymorphism, multifactorial disorders, complication,
Methylenetetrahydrofolate reductase, Single nucleotide polymorphisms.
Received: April 19, 2023. Revised: December 5, 2023. Accepted: January 16, 2024. Published: March 14, 2024.
1 Introduction
methylenetetrahydrofolate to 5-
methyltetrahydrofolate, a key co-factor responsible
for adding methyl to homocysteine and after it is
converted into methionine. The genomic location of
the MTHFR gene is located on the 1st autosomal
chromosome, situated at the terminal part of the
short arm (1p36.6), [1], and this genomic region is
vital for controlling the folate metabolism, a
fundamental process in cell metabolism involving
the methylation of the vital macromolecules, such as
DNA, RNA, and as well proteins. This genetic
alteration results in the conversion of valine with
alanine at genetic codon 222, representing a very
general mutation that adversely affects the function
of the enzyme. MTHFR enzyme genetic makeup
involves two alleles. Presently, there are more than
20 gene mutations linked to this enzyme,
particularly single nucleotide polymorphisms
(SNPs) emphasis on the in-depth examination of the
C677T- rs1801133 and A1298C - rs1801131, [2].
The C677T allele has been well studied from the
scientific point of view and it is established that it
has high clinical significance too. The A1298C
variant is milder and less clinically significant.
In our current literature review, we will focus on
exploring the relationship of C677T SNP with
various types of complexes, and multifactorial
disorders, such as diabetes mellitus, cardiovascular
complications, cancer, and others (Table 1,
Appendix). The C677T MTHFR is intricately linked
with a range of diseases, including vascular
disorders, cancers, neurological conditions, diabetes,
psoriasis, and more [3], [4], [5], [6]. The prevalence
and distribution of the C677T polymorphism exhibit
geographical and ethnic variations, contributing to
its complex epidemiology, [7].
Homozygous mutations demonstrate increased
homocysteine levels, whereas individuals with
heterozygous (C/T) mutations exhibit slightly raised
homocysteine levels compared to controls, [8].
Increased levels of homocysteine, referred to as
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hyperhomocysteinemia, are recognized as a
developing susceptibility to several cardiovascular
diseases.
2 Function of
Methylenetetrahydrofolate
Reductase (MTHFR) and Its
Implications
The Methylenetetrahydrofolate reductase has a
crucial role in methionine and folate metabolism,
impacting the metabolism of the cell’s DNA and
ensuring the maintenance of appropriate
homocysteine levels in the body, [9].
C677T/MTHFR gene mutations lead to decreased
MTHFR enzyme activity, with individuals carrying
the heterozygous genotype (C/T) having 70% of
standard enzyme activity, and those with the T/T
homozygous genotype having just 30%, [10]. This
reduction interrupts the conversion of homocysteine
to methionine, leading to decreased serum folate
levels, increased homocysteine levels, and DNA
hypomethylation.
Homocysteine assumes a pivotal role in the
impairment of endothelial cells, expediting the
initiation and advancement of atherosclerosis. It
contributes to the development of unstable plaques
via mechanisms involving endoplasmic reticulum
stress, oxidative stress, inflammatory factors, and as
well immune responses. Furthermore, homocysteine
triggers injury to endothelial cells, initiates lipid
oxidation, as well accelerates the progression of the
atherosclerosis process, [11].
MTHFR is involved in the methylation
processes of DNA, RNA, purine, and thymidine
syntheses by acting as a methyl donor. These
processes contribute to the development of various
vascular diseases, [12]. The C677T/MTHFR
polymorphisms impact MTHFR enzyme activity,
leading to alterations in methionine and folate
metabolism, elevated homocysteine levels, and
subsequent effects on DNA methylation. The role of
homocysteine in endothelial damage and
atherosclerosis, coupled with the influence of
MTHFR in methylation processes, underscores the
complex interplay contributing to the development
of carotid atherosclerosis (CAS).
3 The C677T/MTHFR
Polymorphism Association with
Cardiovascular Disease
In [12], is studied 730 participants (516 males, 214
females) of Han ethnicity from Chongqing, China.
In individuals with carotid atherosclerosis, the
occurrence of heterozygotes (C/T) and homozygotes
(T/T) was notably high, and the rates of C/C
homozygotes and the C allele were markedly low (P
< 0.05) compared to the healthy controls. The
disease occurrence risk was higher for C/T
heterozygotes and T/T homozygotes (OR = 4.06, P
< 0.001 and OR = 3.14, P < 0.001), in comparison
to the C/C genotype. The mutation in the MTHFR
gene poses a risk factor for carotid atherosclerosis in
the Chinese population.
In a comprehensive study involving 3,247
participants aged 30 to 89 years (1,693 women,
1,554 men), it was revealed that the T/T
homozygous poses a risk for carotid stenosis
occurrence within the Japanese population, [13].
Another study corroborate these findings,
demonstrating that the incidence of a T allele in the
MTHFR gene significantly increases the risk of
intima-media thickness (IMT) thickening, thus
suggesting a link between C677T/MTHFR and
carotid atherosclerosis, [14].
However, the overall conclusions drawn from
various studies on this topic remain argumentative.
For instance, some authors showed that the MTHFR
gene's C/T polymorphism contributes to an elevated
homocysteine level. Surprisingly, they found no
significant correlation between this mutation and
carotid artery stenosis, [15].
The author’s group studies within the Georgian
population hold particular relevance for us as it
involves individuals from the same region as ours—
specifically, the Adjara region and Batumi city. The
study enrolled 101 patients with arterial thrombosis,
with a predominant male representation at 71.3%.
Notably, 83% of these patients had myocardial
infarction, and 13% had experienced ischemic
stroke. A comparison of the incidence between the
cases and controls revealed a significantly elevated
occurrence in the patient group (P < 0.05).
Specifically, the incidence of the C677T
polymorphism was 21.2% in the control group,
while the cases exhibited an incidence of 33.2%.
The considerable prevalence of MTHFR C677T
among individuals with arterial thrombosis proposes
a potential association, indicating an elevated risk of
arterial thrombosis in the mentioned population.
This association is further supported by the
statistically significant p-value, [16].
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Additionally, the study investigated in the Brazilian
adolescent population, the relationship between the
C677T polymorphisms and cardiovascular risk
factors. Among 115 adolescents, a prevalence of
hyper-homocysteinemia (19.1%) and alterations in
lipid profile were observed. Specifically, the
MTHFR C677T exhibited elevated levels of plasma
vitamin B6 and oxidized low-density lipoprotein
compared to the homozygous (CC) genotype
suggesting potential associations between this
genetic variation and certain biochemical markers
related to cardiovascular health, [17].
The inconsistencies in these conclusions may be
attributed to factors such as small sample sizes,
diverse racial backgrounds, and insufficient
modifications of confounding variables like
smoking, drinking, sleep quality, and dietary habits.
Therefore, it is suggested that the MTHFR variant
C677T may act as a relatively independent risk
factor for CAS or indirectly contribute to
atherosclerosis by elevating plasma homocysteine
levels. The varying outcomes across studies
highlight the need for further research with larger
and more diverse populations, precisely addressing
confounding factors, to gain a more conclusive
understanding of the link between MTHFR gene
polymorphisms and cardiovascular complication
risk.
4 The C677T/MTHFR Polymorphism
Association with Diabetes Mellitus
The link between MTHFR gene polymorphism and
individuals with diabetes mellitus type 2 has been
studied in various types of research. A study
investigating MTHFR gene polymorphism and
diabetic complications (retinopathy and
nephropathy) among Japanese individuals with type
2 diabetes found that incidence was higher of
677T/677T individuals with retinopathy than those
with the other genotypes. There was a notable
difference in genotype distribution, with frequencies
of 677C/677C at 41.9%, 677C/677T at 31.1%, and
677T/677T at 61.5% (P < 0.05). The retinopathy
occurrence of 677T/677T homozygotes was
clinically significant. The presence of the
677T/677T homozygous genotype is associated with
a higher likelihood of experiencing diabetic
retinopathy, particularly a specific type known as
non-proliferative retinopathy, in individuals with
hyperglycemia. Conversely, 677T/677T
homozygous failed to show any impact on
susceptibility to diabetic nephropathy, even in
subjects with hyperglycemia, [18].
MTHFR 677 TT genotype was found to be related
to both predisposition to Type 2 DM and its
complications, including diabetic retinopathy,
diabetic polyneuropathy, and ischemic heart disease
among the Egyptian population. In a research
involving 203 T2DM patients and 311 controls,
results showed that patients with MTHFR 677TT
genotype have higher susceptibility to diabetes.
Also indicated that this mutation confer
susceptibility to diabetic retinopathy, diabetic
polyneuropathy, and ischemic heart disease. The
study also found the potential role of MTHFR
1298C in the incidence of diabetic retinopathy. ACE
DD genotype exhibited a strong clinical correlation
to diabetic polynephropathy with a p value <0.001,
[19].
Another meta-analysis demonstrated a strong
association between Diabetic Nephropathy (DN) in
the Caucasian population with T2DM. MTHFR
677T genotype was found to be an important factor
in increased risk of DN. Additionally; p-values were
statistically significant for the results. In conclusion,
the Caucasian population has increased
susceptibility to DN in individuals with MTHFR
677T SNP, [20].
Another result showed that C677T mutation
might be a risk factor for nephropathy but not for
diabetes mellitus disease incidence in the Chinese
population. Meta-analysis from 12 studies
conducted in the Chinese population showed that
C677T polymorphism appears to show a higher
likelihood of DN in individuals with DM.
On the other hand, when examining the association
of the same polymorphism with T2DM, no
significant link was found, the p-value was 0.70,
which is higher than the conventional significance
threshold of 0.05, suggesting that the association
between the C677T gene polymorphism and
diabetes mellitus was not statistically significant,
[21].
5 The C677T/MTHFR Polymorphism
Association with Neurological
Conditions
MTHFR gene T allele may play a crucial role as a
key risk factor in the development of various
neurological conditions. In a comprehensive meta-
analysis, the research focused on exploring the
possible link between C/T gene polymorphism, and
the occurrence of hemorrhagic stroke (HS). The
analysis involved data from fifteen case-control
studies from various populations such as Chinese,
Turkish, and Dutch (2034 individuals with
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hemorrhagic stroke and 4485 control subjects). The
results consistently indicated a significant
correlation between the C/T genetic polymorphism
and an elevated risk of HS across various genetic
models, such as dominant, codominant, and
recessive, [22].
Potential genetic associations between MTHFR
polymorphisms and specific neurological conditions
such as migraine with aura, subacute combined
degeneration (SCD), and autism, particularly in
certain populations. When investigating the
association with migraine, studies showed no
overall significant difference between migraineurs
and controls. However, in the migraine with aura
subgroup, the TT allele showed an elevated
susceptibility compared to the CC genotype, [23]. A
noteworthy difference in genotype distribution was
observed between SCD patients and controls. SCD
patients displayed yet again an increased incidence
of the T allele. Results identified the TT and vitamin
B12 deficiency as a potential risk factor for SCD,
[24]. Contrary, autism and the MTHFR C677T
polymorphism gene also showed a noteworthy
association in the Chinese Han population,
particularly in the Northern Han subgroup, [25].
6 The C677T/MTHFR Polymorphism
Association with Cancer
The different types of cancers are associated with
polymorphisms of MTHFR. Numerous studies have
contributed valuable insights into the intricate
relationship between MTHFR gene polymorphism
and cancer risk, underscoring the importance of
population-specific factors and cancer types in
influencing outcomes. Breast cancer has high
prevalence characteristics among females and based
on WHO statistics is one of the major causes of
female mortality. Some scientific literature shows
the potential relationship between MTHFR gene
C677T and also A1298C single nucleotide
polymorphisms with breast carcinogenesis. The
study conducted by authors aimed to explore the
relationship between the MTHFR gene C677T
polymorphism and breast cancer in North Indian
women. Through genotyping, the researchers
observed noteworthy differences in the incidences
of the C/T genotype and the T allele amongst
individuals with breast cancer and those without.
These findings suggest a potential relation between
above-mentioned polymorphisms of the MTHFR
gene with an elevated genetic susceptibility to breast
cancer in this specific population, [26].
In contrast, a separate population study focused
on breast cancer in Mali did not reveal any
statistical correlation between C/T and susceptibility
to breast cancer. The genotypic analysis in the
Malian population did not show any clinically
significant differences in the distribution of C677T
genotypes between individuals with breast cancer
and those without, [27].
Individuals carrying certain variants of the
C677T polymorphism may have an altered
susceptibility to developing esophageal cancer
compared to those with different genotypes. When
comparing the T allele to the C allele and combining
individuals with TT and CT genotypes versus those
with the CC genotype, the study observed
significant associations with esophageal cancer risk,
[28].
The C677T polymorphism in the MTHFR gene
is more strongly linked to leukemias and
lymphomas than the A1298G polymorphism, as
suggested by studies with significant findings.
However, some research has not observed similar
connections, [29]. There were some scientific
publications about investigation the impact of gene
variations (C677T and A1298C) on chronic
lymphocytic leukemia (CLL) risk. Their study,
involving 832 CLL patients and 886 healthy
individuals, found that these gene variations did not
significantly increase the chances of developing
CLL. In simpler terms, having these specific genetic
differences doesn't appear to significantly contribute
to inheriting a risk for CLL, [30].
Another meta-analysis studied if MTHFR
C677T is linked to the incidence of stomach cancer.
After looking at information from 28 studies with
over 5,700 cases and 8,500 controls, results showed
a clear connection between this mutation and the
risk of stomach cancer overall. However, when
studied for different ethnic groups, the connection
was strong for Asians but not for Caucasians. In
simpler terms, this means the MTHFR C677T gene
might slightly raise the risk of stomach cancer in
Asians, but it doesn't seem to do the same in
Caucasians, [31].
Similar studies demonstrating differences in
cancer incidence were found for prostate cancer.
Researchers looked into the connection between
C677T and A1298C MTHFR genes and the risk of
prostate cancer. They analyzed data from 21 studies
involving over 21,000 participants. The overall
findings showed no significant link between these
gene variations and prostate cancer risk. However,
when studied for specific groups, results showed
that the C677T CT gene variation might increase
prostate cancer risk in East Asians. Also, the
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A1298C CC gene variation was linked to a slightly
lower risk in Europeans but a higher risk in Asians.
The study suggests that these gene-cancer
associations may differ in various populations, and
more large-scale studies are needed to confirm these
findings, [32].
7 Other Possible Associations
There are numerous scientific papers that show
other possible associations of different types of
disorders with MTHFR C677T gene polymorphism.
Among them is a potential link with venous
thromboembolism (VTE). The mentioned disorder
is a complex multifactorial disease, in which genetic
factors, especially several types of single nucleotide
mutations plays a crucial role. In the XXI century
many studies have been reported about a possible
link between MTHFR gene polymorphism and the
possible risk of VTE, but unfortunately they give us
alternative conclusions. Some of them suggested
that MTHFR C/T polymorphism is related to the
susceptibility to VTE, because the C/T genotype is a
significant risk factor for VTE, but some of the
published papers do not show any possible
correlation. There are very important review papers,
where 32 different studies are analyzed. There
mentioned studies included patients as Asian as
Caucasian population. 15 scientific papers were for
the Asian population, the majority of them belonged
to the Chinese population, and 17 papers were for
the Caucasian (South Korea, China, Russia,
Macedonia, Netherlands, America, Greece, Spain,
Egypt, Canada, Australia, Tunisia, Turkey, Mexico).
The publication year is from 1999 to 2019. The total
sample size contained 8223 patients and 10,859
controls. The study suggested that C/T
polymorphism may increase susceptibility to VTE
in the Asians, but not in the Caucasians, [33].
The Mexican population has highlighted an
elevated susceptibility of venous thromboembolism
(VTE) and thromboembolism in individuals with
C677T homozygous mutations (23%) compared to
those with heterozygous C677T-A1298C mutations
(16%), [34].Another research aimed to assess the
prevalence of methylenetetrahydrofolate reductase
variants in pulmonary hypertension patients and
investigate whether homozygous or compound
heterozygous variants correlate with the severity of
the disease. Medical records of 105 pulmonary
hypertension patients were retrospectively analyzed.
The rate of the minor alleles 677C > T and 1298A >
C was found to be 0.352 and 0.295, respectively.
Patients with these variants exhibited a markedly
elevated ratio of pulmonary to systemic vascular
resistance during the initial heart catheterization.
Moreover, a higher proportion of patients with
homozygous or compound heterozygous variants
had moderate to severe disease compared to those
without. The study suggests that these variants could
potentially influence disease progression or severity,
[35].
The authors suggested that MTHFR
polymorphisms could act as potential risk factors for
adverse pregnancy outcomes. As the frequency of
MTHFR gene polymorphisms increases, there are
higher chances of pregnancy losses, particularly
with the C677T polymorphism compared to
A1298C. Noteworthy were significant variations
observed in both perinatal complications and
occurrences of early pregnancy losses when the
study participants were categorized into different
groups based on their MTHFR gene
polymorphisms, [36]. In another research, when
investigating the link between the MTHFR C677T
genotype and various pregnancy-related factors it
was observed that pregnant women with the T allele
and those with the T/T genotype were linked to
severe intervillous fibrin and combined with
decidual thrombosis. In contrast, CC genotype
women exhibited a protective effect against the
above-mentioned pathologic variants. These
findings suggest a potential genetic influence on
specific pregnancy-related pathologies, [37].
When assessing the link between homocysteine
levels, assessed through the MTHFR C677T gene
variation, and the severity of COVID-19, the results
showed a significant association between the
presence of the MTHFR 677T allele, especially in
Latinos, and higher rates of COVID-19 incidence
and mortality compared to other ethnic groups.
Statistical analysis suggests a strong link between
the C677T gene variation and coronavirus-related
deaths (there was found to be a strong relationship
of 85% between the presence of the C677T gene
variation and death caused by coronavirus (p value=
0.03)), [38].
The authors identified a potential link between
COVID-19 and hypercoagulability in individuals
who have mutations in the MTHFR gene. Among
the COVID-19-infected patients, there was a
noteworthy incidence of MTHFR gene mutations,
affecting 30.3% of individuals. Additionally,
outcomes such as patient recovery (P value = 0.025),
and the severity of lung involvement, through CT (P
value = 0.009). Mortality and the presence of
radiological findings of thrombosis were statistically
significant. The findings imply that the presence of
MTHFR gene mutations may contribute to a
tendency for blood clot formation in individuals
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infected with COVID-19, raising concerns about the
potential impact on the risk of thrombotic events in
the Egyptian population, [39].
Interestingly, this association is noted even in
cases where there is no elevation in homocysteine
levels, a marker often associated with increased
clotting risk. An interesting case series on three
young females, previously healthy and aged 15-17,
who experienced spontaneous thromboembolic
diseases such as DVT and pulmonary emboli shortly
after contracting COVID-19. Despite being in the
normal range for homocysteine levels, these
individuals had either homozygous or heterozygous
mutations in the MTHFR gene. Suggesting an
interesting yet complex interplay of genetic and
environmental factors contributing to
thromboembolic events following COVID-19
infection, [40].
8 Conclusion
A comprehensive review of numerous scientific
studies has established a potential link between the
MTHFR C677T gene and various types of somatic
and infectious diseases. This connection is
particularly emphasized when examining the
MTHFR C677T polymorphism and its potential
links to complex disorders with multiple
contributing factors. These disorders include
cancers, cardiovascular complications, neurological
disorders, and among others. Notably, the most
significant associations are observed in
cardiovascular disorders, especially cases involving
venous thrombosis and diabetes mellitus. The
identification of an individual's homozygous or
heterozygous state for this gene is crucial for
effective disease treatment. Such information
enhances treatment efficacy and aids in preventing
further complications. The limitation of the study is
that there are also some studies which do not show
any significant association between the MTHFR
C677T gene and disorders.
References:
[1] Goyette P, Sumner JS, Milos R, Duncan A
M, Rosenblatt D S, Matthews R G, Rozen R.
Human methylenetetrahydrofolate reductase:
isolation of cDNA, mapping and mutation
identification. Nat Genet. 1994;7(2):195-200,
doi: 10.1038/ng0694-195
[2] 2. Sibani S, Christensen B, O’Ferrall
E, Saadi I, Hiou-Tim F, Rosenblatt D S,
Rozen R. Characteization of six novel
mutations in the methylenetetrahydrofolate
reductase (MTHFR) gene in patients with
homocystinuria. Hum Mutat. 2000;15(3):280-
287. doi: 10.1002/(SICI)1098-
1004(200003)15:3<280::AID-
HUMU9>3.0.CO;2-I
[3] Cho SE, Sook Hong K, Shin GJ, Chung WS.
The methylenetetrahydrofolate reductase
C677T gene mutation is associated with
hyperhomocysteinemia, cardiovascular
disease and plasma B-type natriuretic peptide
levels in Korea. Clin Chem Lab Med CCLM.
2006;44(9). doi:10.1515/CCLM.2006.194
[4] Li CX, Liu YG, Che YP, Jian-Lin Ou, Wen-
Cong Ruan, Yong-Lin Yu, Hai-Feng Li.
Association Between MTHFR C677T
Polymorphism and Susceptibility to Autism
Spectrum Disorders: A Meta-Analysis in
Chinese Han Population. Front Pediatr.
2021;9:598805. doi:
10.3389/fped.2021.598805
[5] Purnomo AF, Daryanto B, Seputra KP
Seputra KP, Budaya TN, Lutfiana NC,
Nurkolis F, Chung S, Suh JY, Park MN, Seo
BK, Kim B8. Methylenetetrahydrofolate
Reductase C677T (rs1801133) Polymorphism
Is Associated with Bladder Cancer in Asian
Population: Epigenetic Meta-Analysis as
Precision Medicine Approach. Cancers.
2023;15(17):4402. doi:
10.3390/cancers15174402
[6] Qi J, Zhang Y, Zhang L, Nie G. Association
between the MTHFR 677C/T Polymorphism
and Susceptibility to Psoriasis: An Updated
Meta-Analysis. J Clin Exp Dermatol Res.
2023;14(1):1-7. doi: 10.35841/2155-
9554.23.14.624
[7] Wang X, Fu J, Li Q, Zeng D. Geographical
and Ethnic Distributions of the MTHFR
C677T, A1298C and MTRR A66G Gene
Polymorphisms in Chinese Populations: A
Meta-Analysis. Wei QY, ed. PLOS ONE.
2016;11(4):e0152414. doi:
10.1371/journal.pone.0152414
[8] Castiglia P, Sanna V, Azara A, Miglio M,
Murgia L, Pira G, Sanges F, Fancellu A,
Carru C, Bisail M, Muroni MR.
Methylenetetrahydrofolate reductase
(MTHFR) C677T and A1298C
polymorphisms in breast cancer: a Sardinian
preliminary case-control study. Int J Med Sci.
2019; 16(8), 1089-1095. doi:
10.7150/ijms.32162.
[9] Leclerc D, Sibani S, Rozen R. Molecular
Biology of Methylenetetrahydrofolate
Reductase (MTHFR) and Overview of
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Volume 21, 2024
Mutations/Polymorphisms. In: Madame Curie
Bioscience Database, Landes Bioscience;
2013, [Online].
https://www.ncbi.nlm.nih.gov/books/NBK656
1/ (Accessed Date: December 26, 2023).
[10] Jain M, Pandey P, Tiwary N, Jain S. MTHFR
C677T polymorphism is associated with
hyperlipidemia in women with polycystic
ovary syndrome. J Hum Reprod Sci.
2012;5(1):52. doi:10.4103/0974-1208.97802
[11] Paganelli F, Mottola G, Fromonot J, Marlinge
M, Deharo P, Guieu R, Ruf J.
Hyperhomocysteinemia and Cardiovascular
Disease: Is the Adenosinergic System the
Missing Link? Int J Mol Sci. 2021;22(4):1690.
doi:10.3390/ijms22041690
[12] Peng X, Zhou Y, Wu X, Wang X, Bai H, Li
Y, Wang Z, Chen X, Wangcorresponding Y .
Association of methylenetetrahydrofolate
reductase (MTHFR) variant C677T and risk
of carotid atherosclerosis: a cross-sectional
analysis of 730 Chinese Han adults in
Chongqing. BMC Cardiovasc Disord.
2020;20(1):222. doi:10.1186/s12872-020-
01505-1
[13] Inamoto N, Katsuya T, Kokubo Y, Mannami
T, Asai T, Baba Sh, Ogata J, Tomoike H,
Ogihara T. Association of
Methylenetetrahydrofolate Reductase Gene
Polymorphism With Carotid Atherosclerosis
Depending on Smoking Status in a Japanese
General Population. Stroke. 2003;34(7):1628-
1633.
doi:10.1161/01.STR.0000075769.09092.82
[14] Kawamoto R, Kohara K, Tabara Y, Miki T,
Doi T, Tokunaga H, Konishi I . An
association of 5,10-methylenetetrahydrofolate
reductase (MTHFR) gene polymorphism and
common carotid atherosclerosis. J Hum
Genet. 2001;46(9):506-510.
doi:10.1007/s100380170031
[15] Dt P, Sm F, S S, S H. Association between
methylenetetrahydrofolate reductase
(MTHFR) polymorphism and carotid intima
medial thickness progression in post
ischaemic stroke patient. Ann Transl Med.
2015;3(21). doi:10.3978/j.issn.2305-
5839.2015.12.22
[16] Garakanidze S, Costa E, Bronze-Rocha E,
Santos-Silva A, Nikolaishvili G, Nakashidze
I, Kakauridze N, Glonti S, Khukhunaishvili R,
Koridze M, Ahmad S.
Methylenetetrahydrofolate Reductase Gene
Polymorphism (C677T) as a Risk Factor for
Arterial Thrombosis in Georgian Patients.
Clin Appl Thromb. 2018;24(7):1061-1066.
doi:10.1177/1076029618757345
[17] Morais CC, Alves MC, Augusto EM, Abdalla
DSP, Horst MA, Cominetti C. The MTHFR
C677T Polymorphism Is Related to Plasma
Concentration of Oxidized Low-Density
Lipoprotein in Adolescents with
Cardiovascular Risk Factors. Lifestyle
Genomics. 2015;8(3):105-113.
doi:10.1159/000439218
[18] Maeda M, Yamamoto I, Fukuda M,
Motomura T, Nishida M, Nonen Sh, Fujio Y,
Kasayama S, Azuma J . MTHFR gene
polymorphism is susceptible to diabetic
retinopathy but not to diabetic nephropathy in
Japanese type 2 diabetic patients. J Diabetes
Complications. 2008;22(2):119-125.
doi:10.1016/j.jdiacomp.2006.12.002
[19] Settin A, El-Baz R, Ismaeel A, Tolba W,
Allah WA. Association of ACE and MTHFR
genetic polymorphisms with type 2 diabetes
mellitus: Susceptibility and complications. J
Renin Angiotensin Aldosterone Syst.
2015;16(4):838-843.
doi:10.1177/1470320313516172
[20] Yang S, Zhang J, Feng C, Huang G. MTHFR
677T variant contributes to diabetic
nephropathy risk in Caucasian individuals
with type 2 diabetes: A meta-analysis.
Metabolism. 2013;62(4):586-594.
doi:10.1016/j.metabol.2012.10.004
[21] Is C677T Polymorphism in
Methylenetetrahydrofolate Reductase Gene a
Risk Factor for Diabetic Nephropathy or
Diabetes Mellitus in a Chinese Population?
Arch Med Res. 2012;43(1):42-50.
doi:10.1016/j.arcmed.2011.12.003
[22] Kang S, Zhao X, Liu L, Wu W, Zhang D.
Association of the C677T Polymorphism in
the MTHFR Gene with Hemorrhagic Stroke:
A Meta-Analysis. Genet Test Mol Biomark.
2013;17(5):412-417.
doi:10.1089/gtmb.2012.0295
[23] Rubino E, Ferrero M, Rainero I, Binello E,
Vaula G, Pinessi L. Association of the C677T
Polymorphism in the MTHFR Gene with
Migraine: A Meta-Analysis. Cephalalgia.
2009;29(8):818-825. doi:10.1111/j.1468-
2982.2007.01400.x
[24] Zhang X, Hou C, Liu P, Chen L, Liu Y, Tang
P, Li R. Methylenetetrahydrofolate Reductase
(MTHFR) C677T Polymorphism and
Subacute Combined Degeneration: Revealing
a Genetic Predisposition. Front Neurol.
2019;9:1162. doi:10.3389/fneur.2018.01162
WSEAS TRANSACTIONS on BIOLOGY and BIOMEDICINE
DOI: 10.37394/23208.2024.21.11
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E-ISSN: 2224-2902
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Volume 21, 2024
[25] Li CX, Liu YG, Che YP, Ou JL, Ruan WC,
Yu YL, Li HF. Association Between MTHFR
C677T Polymorphism and Susceptibility to
Autism Spectrum Disorders: A Meta-Analysis
in Chinese Han Population. Front Pediatr.
2021;9:598805.
doi:10.3389/fped.2021.598805
[26] Waseem M, Hussain SR, Kumar S,
Serajuddin M, Mahdi F, Sonkar SK, Bansal
Ch, Ahmad M K. Association of MTHFR
(C677T) Gene Polymorphism with Breast
Cancer in North India. Biomark Cancer.
2016;8:BIC.S40446. doi:10.4137/BIC.S40446
[27] Diakite B, Kassogue Y, Maiga M, Dolo G,
Kassogue O, Holl JL, Joyce B, Wang J, Cisse
K, Diarra F, Keita ML, Traore ChB, Kamate
B, Sissoko SB, Coulibaly B, Sissoko AS,
Traore Drissa, Sidibe FM, Bah S, Teguete I,
Ly M, Nadifi S, Dehbi H, Kim K, Murphy R,
Hou L. Lack of Association of C677T
Methylenetetrahydrofolate Reductase
Polymorphism with Breast Cancer Risk in
Mali. Khawar MB, ed. Genet Res.
2023;2023:1-7. doi:10.1155/2023/4683831
[28] Kumar P, Rai V. MTHFR C677T
polymorphism and risk of esophageal cancer:
An updated meta-analysis. Egypt J Med Hum
Genet. 2018;19(4):273-284.
doi:10.1016/j.ejmhg.2018.04.003
[29] Petrone I, Bernardo PS, Dos Santos EC,
Abdelhay E. MTHFR C677T and A1298C
Polymorphisms in Breast Cancer, Gliomas
and Gastric Cancer: A Review. Genes.
2021;12(4):587. doi:10.3390/genes12040587
[30] Rudd MF, Sellick GS, Allinson R, Matutes E,
Catovsky D, Houlston RS. MTHFR
Polymorphisms and Risk of Chronic
Lymphocytic Leukemia. Cancer Epidemiol
Biomarkers Prev. 2004;13(12):2268-2270.
doi:10.1158/1055-9965.2268.13.12
[31] Chen L, Lu N, Zhang BH, Weng L, Lu J.
Association between the MTHFR C677T
polymorphism and gastric cancer
susceptibility: A meta-analysis of 5,757 cases
and 8,501 controls. Oncol Lett.
2015;10(2):1159-1165.
doi:10.3892/ol.2015.3356
[32] Chen PL, Li WT, Wang J, Jiang Y D, Wu P ,
Chen T, Zheng S B . Association between
MTHFR gene polymorphisms (C677T,
A1298C) and genetic susceptibility to prostate
cancer: a meta-analysis. Genet Mol Res.
2015;14(4):19191-19202.
doi:10.4238/2015.December.29.29
[33] Gao M, Feng N, Zhang M, Ti X, Zuo X.
Meta-analysis of the relationship between
methylenetetrahydrofolate reductase C677T
and A1298C polymorphism and venous
thromboembolism in the Caucasian and
Asian. Biosci Rep. 2020;40(7):BSR20200860.
doi:10.1042/BSR20200860.
[34] López-Jiménez JJ, Porras-Dorantes Á, Juárez-
Vázquez CI, García-Ortiz J E, Fuentes-
Chávez C A , Lara-Navarro I J, Jaloma-Cruz
A R . Molecular thrombophilic profile in
Mexican patients with idiopathic recurrent
pregnancy loss. Genet Mol Res. 2016;15(4).
doi:10.4238/gmr.15048728
[35] Day RW, Mack GK, Barker AM, Rees TQ,
Jorgensen LO, Botto LD. Prevalence of
Variants in Methylenetetrahydrofolate
Reductase and the Severity of Pulmonary
Vascular Disease. Pediatr Cardiol.
2015;36(3):524-530. doi:10.1007/s00246-
014-1044-x
[36] Turgal M, Gumruk F, Karaagaoglu E, Beksac
M. Methylenetetrahydrofolate Reductase
Polymorphisms and Pregnancy Outcome.
Geburtshilfe Frauenheilkd. 2018;78(09):871-
878. doi:10.1055/a-0664-8237
[37] Mehandjiev TR, Tenno NM, Nakura Y,
Georgiev TP, Minekawa R, Wakimoto T,
Mimura K, Nakayama M, Kawakami K,
Kanagawa T, Tomimatsu T, Fujita T, Onouchi
Y, Takeuchi M, Kimura T, Yanagihara I.
Impact of maternal methylenetetrahydrofolate
reductase C677T polymorphism on
intervillous and decidual pathology with
pregnancy loss. J Obstet Gynaecol Res.
2019;45(1):78-85. doi:10.1111/jog.13798
[38] Ponti G, Pastorino L, Manfredini M, Ozben T,
Oliva G, Kaleci Sh, Iannella R, Tomasi A.
COVID‐19 spreading across world correlates
with C677T allele of the
methylenetetrahydrofolate reductase
(MTHFR) gene prevalence. J Clin Lab Anal.
2021;35(7):e23798. doi:10.1002/jcla.23798
[39] Abdelfattah EB, Abdelmaksoud SS, Shalaby
HM, Abo-zid ESh, Mahmoud MMY,
Elshebiny AA & Ezzelregal HG. Incidence of
thrombophilic gene polymorphism (MTHFR
C677T) in Egyptian COVID-19 patients and
its clinical implications. Egypt J Bronchol.
2023;17(1):72. doi:10.1186/s43168-023-
00246-x
[40] Does COVID-19 Infection Increase the Risk
of Hypercoagulability in Individuals with
MTHFR Gene Mutation? J Med Case Rep
Case Ser. Published online November 8,
2022.
WSEAS TRANSACTIONS on BIOLOGY and BIOMEDICINE
DOI: 10.37394/23208.2024.21.11
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115
Volume 21, 2024
doi:10.38207/JMCRCS/2022/DECD0316011
15
[41] He L, Shen Y. MTHFR C677T polymorphism
and breast, ovarian cancer risk: a meta-
analysis of 19,260 patients and 26,364
controls. OncoTargets Ther. 2017; Vol.
10:227-238. doi:10.2147/OTT.S121472
Abbreviations
MTHFR- Methylenetetrahydrofolate reductase
SNPs- Single Nucleotide Polymorphisms
IMT- Intima-Media Thickness
OR- Odds Ratio
CAS- Carotid Atherosclerosis
T2DM- Type 2 Diabetes Mellitus
ACE- Angiotensin converting Enzyme
DN- Diabetic Nephropathy
HS- Hemorrhagic Stroke
SCD- Subacute Combined Degeneration
CLL- Chronic lymphocytic leukemia
VTE- Venous Thromboembolism
COVID-19- Coronavirus disease 2019
DVT- Deep Venous Thrombosis
pHWE- P values for Hardy–Weinberg equilibrium
test
Contribution of Individual Authors to the
Creation of a Scientific Article (Ghostwriting
Policy)
- Aleena Parveen Shaikh – write the section 1 and 8
- Kristine Makharadze - write the section 2 and 3
- Marina Nagervadze - write the section 4 and 6
- Marina Koridze was supervising the writing
process
- Rusudan Khukhunaishvili – write the section 7
- Salome Glonti – write the section 5.
Sources of Funding for Research Presented in a
Scientific Article or Scientific Article Itself
Batumi Shota Rustaveli State University (BSU)
targeted the grant project «Possible associations of
MTHFR 677 C/T gene polymorphism with some
diseases in elderly people", 2023-2024.
Conflict of Interest
The authors have no conflicts of interest to declare
that are relevant to the content of this article.
Creative Commons Attribution License 4.0
(Attribution 4.0 International, CC BY 4.0)
This article is published under the terms of the
Creative Commons Attribution License 4.0
https://creativecommons.org/licenses/by/4.0/deed.en
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APPENDIX
Table 1. MTHFR C677T Gene polymorphism and association with disorders
Type of disease
Number of
studying
participants
Ethnicity
Potential association
References
Breast cancer
19,260 BC cases
and 23,364
controls
Asian and
Caucasian
Strong trend toward the risk for
BC in the TT and CT genotypes.
Increased risk in Asian and
Caucasian populations
[41]
Carotid atherosclerosis
730 participants
(516 males, 214
females)
China
The risk of disease occurrence
was higher for individuals with
C/T heterozygotes and T/T
homozygotes
[12]
Carotid stenosis
3,247
participants aged
30 to 89 years
(1,693 women,
1,554 men),
Japanese
population
MTHFR homozygous T/T poses
a risk for carotid stenosis
[13]
Diabetic Nephropathy
(DN) with T2DM
10 case-control
studies 1590
individuals (DN)
and 1555 T2DM
without DN.
Caucasian
population
The presence of the MTHFR 677
T variant was found to be a
factor contributing to an
increased risk of DN within this
particular population.
[20]
Venous
thromboembolism
(VTE)
The total sample
size is nearly
20,000,
containing 8223
patients and
10,859 controls
Caucasian and
Asian
MTHFR C677T polymorphism
may increase susceptibility to
VTE in the Asians, but not in the
Caucasian
[33]
T2DM
190 type 2
diabetic patients
Japanese
population
Incidence was higher of
677T/677T homozygous
individuals with retinopathy than
those with the other genotypes.
[18]
COVID-19
33 patients with
COVID-19 and
13 healthy
controls
Egyptian
population
COVID-19 patients with
MTHFR gene mutations (30.3%)
show significant links to
hypercoagulability, impacting
recovery, lung involvement,
mortality, and thrombosis.
[39]
Pulmonary hypertension
105 patients
USA
Homozygous or compound
heterozygous variants are
associated with a higher
proportion of moderate to severe
disease.
[35]
Hemorrhagic stroke
(HS)
6519 individuals
(2034 with
hemorrhagic
stroke and 4485
control subjects)
Various
populations
including
Chinese,
Turkish, and
Dutch
Significant associations between
MTHFR gene C677T
polymorphism and an elevated
risk of hemorrhagic stroke. The
associations were observed
across various genetic models.
[22]
Prostate cancer
Over 21,000
participants from
21 studies
Various
populations,
including East
Asians and
Europeans
No significant link. However,
subgroup analyses indicated that
the C677T CT gene variation
might increase prostate cancer
risk in East Asians. Additionally,
the A1298C CC gene variation
was associated with a slightly
lower risk in Europeans but a
higher risk in Asians.
[32]
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DOI: 10.37394/23208.2024.21.11
Aleena Parveen Shaikh, Kristine Makharadze,
Marina Nagervadze, Marina Koridze,
Rusudan Khukhunaishvili, Salome Glonti
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