Cardiovascular diseases (CVD) have been the main cause of death worldwide in the past decade [1]. Efforts to overcome these diseases have gained crucial importance along with the increase in aging population. Screening of traditional risk factors could not provide sufficient information for CVD prediction. Approximately 25.0% of patients with CVD comprise asymptomatic individuals suffering from non fatal myocardial infarction or sudden death [2]. Therefore, in order to elucidate the causes of CVD, which lead to predisposition for this disease, new risk factors assessments have to be identified.
Arterial calcification affects the endothelial layer and the media of the vessel wall. Particularly, atherosclerotic vascular calcification is prevalent in the aging population, however atherosclerotic lesions can occur in earlier ages, even during fetal life, related with parental smoking [3]. Arterial calcification was found to progress with the differentiation of vascular smooth muscle cells (VSMCs) into osteoblast- and chondrocyte-like cells [4]. For this reason, the role of various bone related genes in atherosclerotic processes were investigated to clarify underlying mechanisms [5, 6, 7]. Matrix Gla protein (MGP), a vitamin K-dependent matrix protein, participate in regulatory mechanisms of vascular calcification. It is an 84-amino acid protein, mainly expressed in bone matrix, cartilage and VSMCs.
Matrix Gla protein contains nine glutamate residues and five of them can be γ-carboxylated by vitamin K-dependent reaction. Gla residues have high affinity to calcium phosphate (hydroxyapatite) compound. Knockout mouse model experiments have demonstrated that MGP-deficient mice exhibited abnormal and severe arterial and cartilage calcification within a few weeks after birth [6]. Moreover, single nucleotide polymorphisms (SNPs) of human
Previously, we investigated the associations of
Demographic and clinical data, including underlying diseases such as hypertension and diabetes mellitus (DM), smoking, alcohol consumption and family history were collected from medical records. Biochemical data related with CAD, such as serum glucose, triglyceride, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol and creatinine, were assayed using routine clinical methods. Table 1 represents demographic and biochemical profiles of participants.
The main characteristics of the coronary artery disease patients and controls. (Values are presented as mean ± SD and percent.)
Parameters | CAD Patients ( |
Controls ( |
|
---|---|---|---|
Gender (F; M) | F: 22; M: 90 | F: 30; M: 26 | <0.001 |
Age (years) | 62.63 ± 9.16 | 56.40 ± 9.40 | <0.001 |
Hypertension | 76 (67.9%) | 34 (60.7%) | 0.384 |
DMT2 | 52 (46.2%) | 20 (35.7%) | 0.244 |
Current smoker | 66 (58.9%) | 29 (51.8%) | 0.406 |
LDL-cholesterol (mg/dL) | 114.99 ± 43.28 | 104.67 ± 32.47 | 0.463 |
HDL-cholesterol (mg/dL) | 44.61 ± 13.49 | 41.33 ± 12.14 | 0.228 |
Total cholesterol (mg/dL) | 190.81 ± 52.96 | 176.42 ± 39.45 | 0.310 |
Triglycerides (mg/dL) | 176.22 ± 106.12 | 149.26 ± 68.27 | 0.234 |
Fasting glucose (mg/dL) | 122.21 ± 47.81 | 109.79 ± 24.89 | 0.215 |
eGFR (mL/min./1.73m3) | 90.37 ± 19.83 | 84.83 ± 22.81 | 0.051 |
sMGP (μg/L) | 0.82 ± 0.37 | 0.87 ± 0.42 | 0.426 |
CAD: coronary artery disease; DMT2: Diabetes mellitus type II; eGFR: estimated glomerular filtration rate; sMGP: serum MGP.
a Adjusted for age and gender status.
Figure 1
The structure of the human

Genotype and allele distributions of
Genotype/Allele | CAD Patients ( |
Controls ( |
|
---|---|---|---|
rs1800802 | |||
Genotype: TT | 42 (37.5%) | 22 (39.3%) | |
TC | 55 (49.1%) | 29 (51.8%) | 0.701 |
CC | 15 (13.4%) | 5 (8.9%) | |
Allele: T | 139 (62.0%) | 73 (65.2%) | |
C | 85 (38.0%) | 39 (34.8%) | 0.822 |
rs4236 | |||
Genotype: Thr/Thr | 37 (33.0%) | 12 (21.4%) | 0.267 |
Thr/Ala | 57 (50.9%) | 35 (62.5%) | |
Ala/Ala | 18 (16.1%) | 9 (16.1%) | |
Allele: Thr | 131 (58.5%) | 59 (52.7%) | |
Ala | 93 (41.5%) | 53 (47.3%) | 0.119 |
rs12304 | |||
Genotype: Glu/Glu | 89 (79.5%) | 44 (80.0%) | 0.936 |
Glu/X | 23 (20.5%) | 11 (20.0%) | |
X/X | 0 (0.0%) | 0 (0.0%) | |
Allele: Glu | 201 (89.7%) | 99 (90.0%) | 0.936 |
X | 23 (10.3%) | 11 (10.0%) |
CAD: coronary artery disease.
Figure 2
Histograms of the serum MGP concentrations (μg/L) relative to

Odds ratios and their 95% confidence intervals for alleles of
Genotypes | CAD Patients ( |
Single-Vessel Disease ( |
Two-Vessel Disease ( |
Three-Vessel Disease ( |
||||
---|---|---|---|---|---|---|---|---|
OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |||||
rs1800802: TT |
||||||||
TT+CC | 0.927 (0.480-1.792) | 0.822 | 0.736 (0.346-1.567) | 0.426 | 1.182 (0.481-2.905) | 0.716 | 1.264 (0.451-3.457) | 0.655 |
rs4236: Thr/Thr |
||||||||
Thr/Ala+Ala/Ala | 1.809 (0.854-3.829) | 0.121 | 1.878 (0.821-4.294) | 0.135 | 1.833 (0.680-4.943) | 0.231 | 1.571 (0.498-4.962) | 0.441 |
rs12304: Glu/Glu |
||||||||
Glu/X+X/X | 0.967 (0.433-2.162) | 0.936 | 0.857 (0.352-2.086) | 0.734 | 1.625 (0.469-5.631) | 0.444 | 0.750 (0.224-2.512) | 0.641 |
CAD: coronary artery disease; OR: odds ratio; 95% CI: 95% confidence interval.
a Control group is the reference category.
The allele distributions of SNPs were further evaluated to view the association of
The baseline distribution characteristics of
Parameters | rs1800802 | rs4236 | rs12304 | sMGP (μg/L) | |||
---|---|---|---|---|---|---|---|
TT+TT |
Thr/Thr/Ala+Thr Ala/ |
Glu/Glu/Glu X+X/ |
Correlation | ||||
Gender (F; M) | F:22; M: 30; F: 42; M: 74 | 0.452 | F: 9; M: 43; F: 40; M: 76 | 0.024 | F: 39; M: 12; F: 94; M:22 | 0.500 | 0.043 |
LDL-cholesterol (mg/dL) | 106.81±38.62; 113.93±41.19 | 0.701 | 117.61±42.17; 108.47±39.26 | 0.394 | 112.15±37.40; 112.21±53.30 | 0.878 | 0.222 |
HDL-cholesterol (mg/dL) | 44.69±16.78; 43.13±11.31 | 0.556 | 46.87±14.79; 41.72±11.76 | 0.049 | 44.29±8.53; 41.25±8.53 | 0.361 | 0.145 |
Total cholesterol (mg/dL) | 188.28±46.01; 185.56±51.14 | 0.344 | 195.10±45.91; 181.37±51.04 | 0.245 | 187.45±48.46; 185.10±53.94 | 0.939 | 0.085 |
Triglycerides (mg/dL) | 170.81±83.15; 166.67±102.21 | 0.769 | 177.05±119.29; 162.67±81.21 | 0.528 | 162.09±84.13; 199.42±139.30 | 0.115 | 0.903 |
Fasting glucose (mg/dL) | 121.31±42.67; 117.13±42.46 | 0.544 | 125.54±51.81; 114.28±35.63 | 0.539 | 117.80±39.23; 121.63±56.52 | 0.653 | 0.588 |
eGFR (mL/min./1.73m3) | 85.5786.75±±23.6220.99 ; | 0.835 | 88.8085.81±±22.0121.97 ; | 0.405 | 85.9888.70±±21.3724.28 ; | 0.377 | 0.015 |
sMGP, serum MGP; eGFR, estimated glomerular filtration rate.
a Adjusted for age and gender status.
Figure 3
Linkage disequilibrium block structures of

In our study, we reported that serum MGP levels were associated with rs4236 and rs1800802 SNPs of the
The MGP is considered as one of the important regulatory proteins for inhibition of calcification in the vessel wall and cartilage. The
The consequences of
Matrix Gla protein comprises five γ-carboxyglutamate (Gla) amino acids and it is activated
We propounded that MGP levels might be modified in relation to the presence of polymorphic variants of the
In the meantime, the study of Wang
We evaluated the two-allelic haplotype distributions in the studied SNPs and LD was not found to be significant between control and patients. Crosier
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
Figure 1

Figure 2

Figure 3
![Linkage disequilibrium block structures of MGP gene polymorphisms was performed by Haploview (version 4.2) [12]. Numbers in squares (D’ values) indicate the pairwise correlation between polymorphisms. Color scheme from red to white represent higher to lower LD values.](https://sciendo-parsed-data-feed.s3.eu-central-1.amazonaws.com/6006b6c4e797941b18f33eee/j_bjmg-2019-0020_fig_003.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20230130T080731Z&X-Amz-SignedHeaders=host&X-Amz-Expires=18000&X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20230130%2Feu-central-1%2Fs3%2Faws4_request&X-Amz-Signature=8327978f8fb7a27ce78515191fba5e2c91162f2803f55eb66b60badebcd1d5f5)
The baseline distribution characteristics of MGP alleles and their correlation with serum MGP concentrations. (Values are presented as mean ± SD.)
Parameters | rs1800802 | rs4236 | rs12304 | sMGP (μg/L) | |||
---|---|---|---|---|---|---|---|
TT+TT |
Thr/Thr/Ala+Thr Ala/ |
Glu/Glu/Glu X+X/ |
Correlation | ||||
Gender (F; M) | F:22; M: 30; F: 42; M: 74 | 0.452 | F: 9; M: 43; F: 40; M: 76 | 0.024 | F: 39; M: 12; F: 94; M:22 | 0.500 | 0.043 |
LDL-cholesterol (mg/dL) | 106.81±38.62; 113.93±41.19 | 0.701 | 117.61±42.17; 108.47±39.26 | 0.394 | 112.15±37.40; 112.21±53.30 | 0.878 | 0.222 |
HDL-cholesterol (mg/dL) | 44.69±16.78; 43.13±11.31 | 0.556 | 46.87±14.79; 41.72±11.76 | 0.049 | 44.29±8.53; 41.25±8.53 | 0.361 | 0.145 |
Total cholesterol (mg/dL) | 188.28±46.01; 185.56±51.14 | 0.344 | 195.10±45.91; 181.37±51.04 | 0.245 | 187.45±48.46; 185.10±53.94 | 0.939 | 0.085 |
Triglycerides (mg/dL) | 170.81±83.15; 166.67±102.21 | 0.769 | 177.05±119.29; 162.67±81.21 | 0.528 | 162.09±84.13; 199.42±139.30 | 0.115 | 0.903 |
Fasting glucose (mg/dL) | 121.31±42.67; 117.13±42.46 | 0.544 | 125.54±51.81; 114.28±35.63 | 0.539 | 117.80±39.23; 121.63±56.52 | 0.653 | 0.588 |
eGFR (mL/min./1.73m3) | 85.5786.75±±23.6220.99 ; | 0.835 | 88.8085.81±±22.0121.97 ; | 0.405 | 85.9888.70±±21.3724.28 ; | 0.377 | 0.015 |
Odds ratios and their 95% confidence intervals for alleles of matrix Gla protein genotypes for coronary artery disease.
Genotypes | CAD Patients ( |
Single-Vessel Disease ( |
Two-Vessel Disease ( |
Three-Vessel Disease ( |
||||
---|---|---|---|---|---|---|---|---|
OR (95% CI) | OR (95% CI) | OR (95% CI) | OR (95% CI) | |||||
rs1800802: TT |
||||||||
TT+CC | 0.927 (0.480-1.792) | 0.822 | 0.736 (0.346-1.567) | 0.426 | 1.182 (0.481-2.905) | 0.716 | 1.264 (0.451-3.457) | 0.655 |
rs4236: Thr/Thr |
||||||||
Thr/Ala+Ala/Ala | 1.809 (0.854-3.829) | 0.121 | 1.878 (0.821-4.294) | 0.135 | 1.833 (0.680-4.943) | 0.231 | 1.571 (0.498-4.962) | 0.441 |
rs12304: Glu/Glu |
||||||||
Glu/X+X/X | 0.967 (0.433-2.162) | 0.936 | 0.857 (0.352-2.086) | 0.734 | 1.625 (0.469-5.631) | 0.444 | 0.750 (0.224-2.512) | 0.641 |
Genotype and allele distributions of matrix Gla protein gene rs1800802, rs4236, and rs12304 polymorphisms.
Genotype/Allele | CAD Patients ( |
Controls ( |
|
---|---|---|---|
rs1800802 | |||
Genotype: TT | 42 (37.5%) | 22 (39.3%) | |
TC | 55 (49.1%) | 29 (51.8%) | 0.701 |
CC | 15 (13.4%) | 5 (8.9%) | |
Allele: T | 139 (62.0%) | 73 (65.2%) | |
C | 85 (38.0%) | 39 (34.8%) | 0.822 |
rs4236 | |||
Genotype: Thr/Thr | 37 (33.0%) | 12 (21.4%) | 0.267 |
Thr/Ala | 57 (50.9%) | 35 (62.5%) | |
Ala/Ala | 18 (16.1%) | 9 (16.1%) | |
Allele: Thr | 131 (58.5%) | 59 (52.7%) | |
Ala | 93 (41.5%) | 53 (47.3%) | 0.119 |
rs12304 | |||
Genotype: Glu/Glu | 89 (79.5%) | 44 (80.0%) | 0.936 |
Glu/X | 23 (20.5%) | 11 (20.0%) | |
X/X | 0 (0.0%) | 0 (0.0%) | |
Allele: Glu | 201 (89.7%) | 99 (90.0%) | 0.936 |
X | 23 (10.3%) | 11 (10.0%) |
The main characteristics of the coronary artery disease patients and controls. (Values are presented as mean ± SD and percent.)
Parameters | CAD Patients ( |
Controls ( |
|
---|---|---|---|
Gender (F; M) | F: 22; M: 90 | F: 30; M: 26 | <0.001 |
Age (years) | 62.63 ± 9.16 | 56.40 ± 9.40 | <0.001 |
Hypertension | 76 (67.9%) | 34 (60.7%) | 0.384 |
DMT2 | 52 (46.2%) | 20 (35.7%) | 0.244 |
Current smoker | 66 (58.9%) | 29 (51.8%) | 0.406 |
LDL-cholesterol (mg/dL) | 114.99 ± 43.28 | 104.67 ± 32.47 | 0.463 |
HDL-cholesterol (mg/dL) | 44.61 ± 13.49 | 41.33 ± 12.14 | 0.228 |
Total cholesterol (mg/dL) | 190.81 ± 52.96 | 176.42 ± 39.45 | 0.310 |
Triglycerides (mg/dL) | 176.22 ± 106.12 | 149.26 ± 68.27 | 0.234 |
Fasting glucose (mg/dL) | 122.21 ± 47.81 | 109.79 ± 24.89 | 0.215 |
eGFR (mL/min./1.73m3) | 90.37 ± 19.83 | 84.83 ± 22.81 | 0.051 |
sMGP (μg/L) | 0.82 ± 0.37 | 0.87 ± 0.42 | 0.426 |
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