ASSOCIATION OF NFKB1, NKX2-5, GATA4 AND RANKL
GENE POLYMORPHISMS WITH SPORADIC CONGENITAL
HEART DISEASE IN GREEK PATIENTS
Aidinidou L1, Chatzikyriakidou A1, Giannopoulos A2, Karpa V1, Tzimou I2, Aidinidou E3, Fidani L1,*
*Corresponding Author: Professor Liana Fidani, Department of General Biology, Medical School,
Aristotle University of Thessaloniki, University Campus, GR-54124, Thessaloniki, Greece. Tel.: +30-
231-099-9165. Fax: +30-231-099-9019. E-mail: sfidani@auth.gr
page: 15
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DISCUSSION
To date, several studies have reported that genetic
and epigenetic variations play a crucial role in CHD susceptibility,
however, the pathogenesis of disease is highly
complex and largely unknown. Mutations in genes controlling
cardiac development and regulation, such as GATA4,
NKX2-5, TBX5 [15], NOTCH1, TBX1, TBX20, CFC1,
CITED2, CRELD1, are associated with non syndromic
CHD [1]. In this case-control study, we examined the association
of variants in NFKB1, RANKL, GATA4 and NKX2-5
genes with risk of CHD in patients of Greek origin.
Up to the present, polymorphisms in NF-κB have
been implicated in the pathogenesis of CHD. The NFKB1
(–94ins/ delATTG) polymorphism (rs28362491) has been
broadly studied in cardiovascular diseases as a regulator
of various biological processes, such as inflammation,
proliferation and apoptosis. The NFKB1 gene encodes both
p50 and p105 subunits of NF-κΒ protein. Deletion of one
ATTG repeat in the promoter region of NFKB1 may result
in lower levels of p50 homodimer by reduced p50 synthesis
[16]. Partial depletion of p50 may decrease the antiinflammatory
response because the formation of the pro
inflammatory p65/p50 heterodimer depends on the concentration
of p50. Consequently, it may be that individuals
with carrying allele D are genetically determined toward
a higher inflammatory response [17]. A previous study
[17] recognized that D-allele carriers of NFKB1 (–94ins/
delATTG) are at increased risk of coronary heart disease,
and may therefore show that inflammation is a potential
mechanism for CHD development. Thus, it could reflect
a positive association between human carrying allele D
of rs28362491 and congenital cardiovascular anomalies.
In our study, we recognized a strong association
between rs28362491 with the susceptibility to CHD.
Individuals carrying allele D (ID/DD) of rs28362491, are
at higher risk for CHD compared to those without allele
D (II genotype) according to all six genetic models of
analysis. In contrast to our results, positive association of
the allele I with increased risk for development of an atrial
septal defect (ASD), as well as with a ventricular septal
defect (VSD), were demonstrated [1]. The discrepancy of
results among diverse populations may be related to the
racial and geographic differences.
In line with NFKB1, the genetic variant RANKL
(rs45311631) was also shown to be a significant variant
in predisposition to CHD in a Chinese population [10].
The RANKL gene is a member of TNF family is a type II
trans-membrane peptide. Furthermore, it is identified in numerous
cell types, such as T and B cells, mammary ligands,
vascular endothelial cells and synovial fibroblasts [18].
Decreased production of a RANKL significantly inhibited
the NF-κB signaling pathway and thus, may affect CHD
risk [10,11]. Consistent with these findings, RANKL may
also modulate CHD risk [10]. In the present study, no association
was detected between the variant rs45311631 of
the RANKL gene and CHD in the patients of Greek origin.
There are connections between normal heart structure
and multiple transcription factors, therefore, any mutation
in transcription factor may lead to abnormal cardiac development
and CHD. Transcription factor GATA4 contains a
zinc finger domain that binds to specific DNA. The GATA4
gene is highly conserved during evolution and plays a
critical role in cardiac stem cell differentiation and cardiogenesis [6]. In addition, mutations in the GATA4 gene can
cause congenital cardiac anomalies and thus, deletions or
duplications and point mutations of the gene, play a role in
CHD susceptibility [8]. Mutations throughout the GATA4
gene have been associated with many types of abnormal
heart structure such as VSDs, ASDs and pulmonary stenosis,
and different alterations in the same gene can cause
different CHD subgroups [6]. A previous study identified
association between the +1158 T allele in the 3’UTR of the
GATA4 gene (rs11785481) with a reduced risk for CHD in
a group of 146 Caucasian patients [8]. In our results, no
positive association was found, either in genotype or allele
frequencies of the GATA4 rs11785481 polymorphism,
indicating low mutation frequency of GATA4 in the Greek
population. A potential explanation for this discrepancy
may be related to the restricted group of CHD patients
and the geographic differences.
Furthermore, the GATA4 gene expression has a direct
impact on the embryonic and postnatal development
of heart and acts synergistically with other transcription
factors, such as NKX2-5 during cardiogenesis [8,19].
Cardiac transcription factor NKX2-5 acts in combination
with GATA4 in genetic, transcriptional and biochemical
processes during formation of the heart [3]. The NKX2-5
gene mutations regulate heart morphogenesis and function
and were detected in patients suffering from tetralogy
of Fallot. Also, GATA4 alterations were shown to impair
interactions with NKX2-5, causing CHD [3]. NKX2-5 is
an evolutionarily conserved homeobox protein gene and
was first identified to be implicated in diverse manifestations
of heart defects [5]. In the present study, our results
showed that a significant statistical association exists
between rs2277923 and CHD. Specially, the A allele of
rs2277923 in the NKX2-5 gene was found to be protective
in terms of CHD risk, as proved by the majority of models
of the statistical analysis. Likewise, Shi et al. [20] indicated
that individuals carrying the G allele of rs2277923 had
increased risk of developing VSD than those with an A
allele. In contrast to our association analysis, a previous
study identified that the rs2277923 SNP on the NKX2-5
gene is linked to the sporadic ASDs in the Chinese Yunnan
population and the A allele of rs2277923 is a potential risk
factor resulting in ASDs [5]. Nevertheless, there are some
different outcomes in CHD studies, which presented that
rs2277923 has no role in sporadic CHD pathogenesis in
Chinese patients [21,22]. The opposite research results
may be related to the races and region differences.
In conclusion, our findings suggest the NFKB1
(rs28362491) and NKX2-5 (rs2277923) gene polymorphism
as potential biomarkers of CHD in a Greek population.
However, further studies in more CHD patients
from different populations are needed to explore the association
between rs28362491, rs2277923, rs4531631 and
rs11785481 polymorphisms and CHD occurrence.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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