ASSOCIATION OF GENETIC POLYMORPHISMS IN
THE Matrix Gla Protein (MGP) GENE WITH CORONARY
ARTERY DISEASE AND SERUM MGP LEVELS
Karsli-Ceppioglu S1,*, Yazar S2, Keskin Y3, Karaca M4, Luleci NE3, Yurdun T1
*Corresponding Author: Seher Karsli-Ceppioglu, Ph.D., Department of Toxicology, Faculty of Pharmacy,
Marmara University, Tibbiye Street No. 49, İstanbul 34668, Turkey. Tel: +90-216-414-2962.
Fax: +90-216-345-2952. E-mail: seher.karsli@marmara.edu.tr
page: 43
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DISCUSSION
In our study, we reported that serum MGP levels were
associated with rs4236 and rs1800802 SNPs of the MGP
gene with the occurrence of CAD. As results from the
studies investigating the relationship of MGP SNPs with
the serum MGP levels in CAD patients were inconclusive,
we believe our findings show evidence for this relationship.
We did not observe association between serum MGP levels
and MGP SNPs in CKD. Even though we demonstrated the
effect of rs4236 and rs12304 SNPs on CKD progression, in
the present study we did not find any significant correlation
between these SNPs and CAD risk. On the other hand, our
results demonstrated that investigated MGP variants might
affect serum MGP levels in CAD patients.
The MGP is considered as one of the important regulatory
proteins for inhibition of calcification in the vessel
wall and cartilage. The MGP gene SNPs are propounded
to alter MGP gene expression and serum MGP levels,
therefore increasing the risk of extracellular calcification
[13]. Numerous studies have demonstrated the relationship
between MGP SNPs and cardiovascular diseases in
relation with calcification [8,9,11,14]. Particularly, the role
of rs1800802 and rs4236 SNPs in cardiovascular diseases
has become prominent. The impact of the rs1800802 polymorphism
on transcription in VSMCs was demonstrated
in vitro, in addition to this result the differences in serum
concentrations of MGP was correlated with genotypic
variation [8].
The consequences of MGP genotype variants in CVD
are conflicting in clinical researches. For instance, the
role of MGP gene rs1800802 polymorphism on vascular
calcifications was investigated by numerous studies,
however, no significant association has been discovered
in an abdominal aorta of autopsy cases [15], coronary
arteries [14] or acute coronary syndrome and ischemic
stroke [11]. Although certain studies demonstrated the association
between the TT genotype of rs1800802 SNP and
all-cause mortality and CVD risk in hemodialysis patients
[16,17], our results did not show evidence linking the SNP
with disease status in hemodialysis patients with CKD
and CAD. On the other hand, the rs4236 polymorphism
was found to be associated with myocardial infarction in
low-risk individuals and assessed that this polymorphism
contributed to coronary artery calcification [9]. Cassidy-
Bushrow et al. [13] propounded that the rs4236 polymorphism
has been shown to affect the progression of coronary
artery calcification, however, it was not significantly associated
with incident calcification. In that study, MGP
genotypes were not involved in the quantity of coronary
artery calcification; contrary to this, Crosier et al. [16]
observed that rs1800802 or rs4236 SNPs were related to
decreased quantity of calcification. A recently published
meta-analysis, which evaluated the impact of MGP genetic
variants in the process of vascular calcification, revealed
that the rs1800801 (G7-A) polymorphism was associated
with the risk of vascular calcification and atherosclerotic
disease. However, rs800802 and rs4236 SNPs were not
correlated with these diseases [18].
Matrix Gla protein comprises five γ-carboxyglutamate
(Gla) amino acids and it is activated via γ-glutamate carboxylation
and serine phosphorylation [4]. The carboxy- lated MGP is asserted as a potent inhibitor of vascular calcification
[19,20]. The pathophysiological mechanisms
for protection from vascular calcification are: 1) to have
binding affinity to calcium-phosphate compound and prevent
their aggregation within arterial wall; 2) to stimulate
phagocytosis and apoptosis of the MGP-hydroxyapatite
complex by regulating the macrophages; 3) to inhibit
binding of bone morphogenetic protein-2 (BMP-2) to its
receptor in order to prevent the differentiation of vascular
smooth muscle cells (VSMCs) into osteoblast- and
chondrocyte-like cells [21]. The active form of MGP is
both phosphorylated and carboxylated, whereas inactive
forms are: uncarboxylated MGP (ucMGP), carboxylated
but not phosphorylated MGP (dpcMGP), phosphorylated
but uncarboxylated (pucMGP), and the fully inactive
un-carboxylated, dephosphorylated MGP (dpucMGP).
There are numerous studies that investigate the relationship
between serum MGP and/or inactive forms of
MGP levels, and vascular calcification in patients with
CKD and CVD diseases, however, whether MGP SNPs
have on effects serum MGP levels remain controversial
[19,22,23].
We propounded that MGP levels might be modified
in relation to the presence of polymorphic variants of the
MGP gene in circulation of patients with CAD. Serum
MGP levels were altered when associated with rs4236 and
rs1800802 SNPs with the occurrence of CAD. The MGP
levels increased when associated with the rs4236 variant,
on the other hand, MGP levels were found to be low in association
with the rs1800802 variant in the serum of CAD
patients. However, the distributions of serum MGP levels
were not statistically different between CAD patients and
controls. Research conducted on incidence of altered MGP
levels in vascular diseases are also contradictory.
In the meantime, the study of Wang et al. [24] is
compatible to our results, hence, the rs4236 polymorphism
found in association with higher MGP plasma levels
and rs1800802 with lower levels. Even Farzaneh-Far
et al. [8] propounded that the rs1800802 CC allele has
increased the transcriptional activity of the MGP gene,
direct or inverse relationship of the rs4236 or rs1800802
polymorphism with serum/plasma MGP concentrations
could not be established by certain investigations [14,25].
Furthermore, the association between serum MGP levels
and CAD has not been verified in clinical investigations.
The possible explanation is the activation of MGP occurring
with modifications including carboxylation and
phosphorylation; under-carboxylated MGP shows high
affinity for hydroxyapatite crystal, therefore, accumulates
in atherosclerotic lesions [19,20,26].
We evaluated the two-allelic haplotype distributions
in the studied SNPs and LD was not found to be significant
between control and patients. Crosier et al. [16] reported
that LD values of rs1800802, rs1800801 and rs4236 SNPs
were highly significant, otherwise Najafi et al. [14] did
not indicate haplotype distributions between rs1800802,
rs1800801 and rs1800799 SNPs.
The limitation of this study is that serum MGP levels
are inadequate to accurately reflect MGP tissue levels in
atherosclerotic lesions. Although the investigation was carried
out in a limited number of CAD patients, study groups
were classified by the presence of arterial calcification after
coronary diagnostic angiography, which was supposed to
improve the accuracy of study findings.
Our results revealed that rs4236 and rs1800802 variants
of the MGP gene were associated with serum MGP
levels in patients with CAD. However, genotype distributions
of three SNPs and serum MGP levels were not
correlated with the presence of CAD. As it is well known,
CVD are multifactorial disorders, therefore, development
of arterial calcification is affected by several conditions
including hypertension, hyperglycemia, hyperlipidemia
and aging. Consequently, MGP gene polymorphisms
might not directly influence the formation of CAD. Further
large-scale investigations will elucidate the contribution
of genetic variants of the MGP gene on formation and
progression of arterial calcification in CVD.
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