Abstract
Background:
Uncontrolled hypertension (UHT) is associated with an increased risk of target organ damage (TOD). Matrix metalloproteinase-2 (MMP-2) plays a role in vascular remodeling, and the rs243866 (-1575G/A) polymorphism has been implicated in cardiovascular diseases.
Objective:
This study aimed to evaluate the association between rs243866 and TOD in UHT patients.
Methods:
A cross-sectional study was conducted on 134 UHT patients at two hospitals in Vietnam. Genotyping of rs243866 was performed using PCR, and TOD was assessed via echocardiography (left ventricular hypertrophy - LVH), renal function tests (eGFR, albuminuria), and carotid ultrasound (carotid atherosclerosis).
Results:
The genotypic distribution was GG (79.9%), GA (18.6%), and AA (1.5%), with allele frequencies of 89.2% (G) and 10.8% (A). The A allele was associated with higher risks of LVH (OR=2.553, 95% CI: 1.052-6.196, p=0.035), CKD (OR=2.639, 95% CI: 0.986-7.066, p=0.048), and carotid atherosclerosis (OR=6.806, 95% CI: 2.203-21.024, p<0.001). These associations remained significant after adjusting for confounders.
Conclusion:
The rs243866 polymorphism of MMP-2 is independently associated with TOD in UHT, particularly LVH, CKD, and carotid atherosclerosis. Genetic screening for rs243866 may provide insights into risk stratification and personalized hypertension management.
Keywords: Uncontrolled Hypertension, rs243866, MMP-2, Target Organ Damage, Left Ventricular Hypertrophy, Chronic Kidney Disease, Carotid Atherosclerosis
1. BACKGROUND
Uncontrolled hypertension (UHT) significantly increases the risk of cardiovascular events, contributing to morbidity and mortality worldwide (1). Despite optimal medical therapy, a subset of hypertensive patients fail to achieve target blood pressure (BP), leading to increased risks of left ventricular hypertrophy (LVH), chronic kidney disease (CKD), and carotid atherosclerosis (2).
Matrix metalloproteinase-2 (MMP-2) plays a crucial role in extracellular matrix remodeling and vascular pathology (3). The rs243866 (-1575G/A) polymorphism, located in the MMP-2 promoter region, influences gene expression and has been linked to various cardiovascular diseases (4, 5). However, its association with TOD in UHT remains poorly understood, particularly in Asian populations.
2. OBJECTIVE
This study aimed to evaluate the association between rs243866 polymorphism and TOD in UHT patients, providing insights into potential genetic markers for risk stratification.
3. MATERIAL AND METHODS
Study Design and Population
A cross-sectional study was conducted at Can Tho University of Medicine and Pharmacy Hospital and Can Tho Central General Hospital between March 2023 and May 2025.
Inclusion criteria
UHT diagnosis based on 2024 Vietnamese Society of Hypertension guidelines (6).
Age ≥18 years, on at least three antihypertensive drugs (including a diuretic), with uncontrolled BP (≥140/90 mmHg).
Exclusion criteria
Acute conditions (myocardial infarction, stroke, sepsis).
Autoimmune diseases, malignancies, end-stage renal disease.
Genotyping and Biochemical Assessments
Peripheral blood samples were collected for DNA extraction.
Genotyping of rs243866 was performed via PCR and sequencing (3500 Series Genetic Analyzer, Thermo Fisher, USA).
Biochemical parameters included eGFR (CKD-EPI equation) and albuminuria (ACR ≥30 mg/g) [7].
Imaging Assessments
Cardiac damage: LVH was diagnosed using echocardiography (LVMI >115 g/m2 in men, >95 g/m2 in women) [8].
Renal damage: CKD was defined as eGFR <60 mL/min/1.73m2 or albuminuria [7].
Vascular damage: Carotid atherosclerosis was identified by ultrasound (IMT ≥0.9 mm or plaques) [9].
Statistical Analysis
Genotypic and allelic distributions were analyzed using Chi-square tests.
Logistic regression was applied to evaluate associations between rs243866 and TOD, adjusting for confounders (age, BMI, diabetes, dyslipidemia, stroke history).
A p-value <0.05 was considered statistically significant.
4. RESULTS
Baseline Characteristics
A total of 134 UHT patients were included. Baseline characteristics are summarized in Table 1.
Table 1. Baseline Characteristics of Study Participants.
| Characteristic | Value (n=134) |
|---|---|
| Age (years) | 65,08 ± 14,614 |
| Male/Female | 44 (32.8%) / 90 (67.2%) |
| BMI ≥ 23 kg/m2 | 52 (38.8%) |
| Smoking | 65 (48.5%) |
| Type 2 Diabetes Mellitus | 59 (44%) |
| Dyslipidemia | 104 (77.6%) |
Genotypic and Allelic Distribution
The genotypic distribution of rs243866 is presented in Table 2.
Table 2. Genotypic and Allelic Distribution.
| Genotype | n (%) |
|---|---|
| GG | 107 (79.9) |
| GA | 25 (18.6) |
| AA | 2 (1.5) |
| Allele | n (%) |
| G | 239 (89.2) |
| A | 29 (10.8) |
Association Between rs243866 and Target Organ Damage
The A allele was associated with significantly higher risks of LVH, CKD, and carotid atherosclerosis (Table 3).
Table 3. Multivariate Logistic Regression Analysis of TOD Risk.
| Organ Damage | OR (95% CI) | p-value |
|---|---|---|
| LVH | 2.553 (1.052-6.196) | 0.035 |
| CKD | 2.639 (0.986-7.066) | 0.048 |
| Atherosclerosis | 6.303 (2.129-18.661) | <0.001 |
5. DISCUSSION
Key Findings
This study is among the first to evaluate the association between the rs243866 polymorphism of the MMP-2 gene and target organ damage (TOD) in patients with uncontrolled hypertension (UHT). The key findings include:
The genotypic distribution of rs243866 was GG (79.9%), GA (18.6%), and AA (1.5%), with an A allele frequency of 10.8%.
Carriers of the A allele exhibited a significantly higher risk of left ventricular hypertrophy (LVH), chronic kidney disease (CKD), and carotid atherosclerosis compared to GG carriers.
Multivariate analysis confirmed the A allele as an independent risk factor for TOD, even after adjusting for age, BMI, diabetes, dyslipidemia, and stroke history.
These findings support the hypothesis that rs243866 influences MMP-2 activity, contributing to vascular remodeling and TOD in UHT patients.
Comparison with Previous Studies
Genotypic Distribution and Cardiovascular Risk
The allele frequencies observed in this study (89.2% for G and 10.8% for A) are consistent with previous reports from populations with hypertension (4, 5). A similar genotypic distribution was reported by Sabbatini et al. (2017) in a Brazilian cohort of hypertensive patients, where the A allele frequency was 13% (5).
rs243866 and Left Ventricular Hypertrophy
Our findings demonstrated that A allele carriers had a 2.553-fold increased risk of LVH (p=0.02), in agreement with previous studies showing an association between rs243866 and myocardial remodeling (4, 5). Increased MMP-2 expression in A allele carriers may lead to excessive extracellular matrix degradation, promoting myocardial fibrosis and LVH progression (10).
rs243866 and Chronic Kidney Disease
Patients carrying the A allele had a lower prevalence of CKD (25.6% vs. 74.4%, p = 0.048). This finding is consistent with Sabbatini et al. (2017), who reported an association between rs243866 and renal dysfunction as well as proteinuria in hypertensive patient (5). The underlying mechanism may involve MMP-2–mediated degradation of the glomerular basement membrane, leading to increased albumin permeability and progressive kidney damage (11).
rs243866 and Carotid Atherosclerosis
Carotid atherosclerosis was more common in A allele carriers (31.9% vs. 68.1%, p < 0.001), consistent with previous research linking rs243866 to vascular remodeling. MMP-2 overactivity is known to contribute to extracellular matrix degradation, destabilizing atherosclerotic plaques and increasing vascular stiffness (5).
Potential Mechanisms
The rs243866 polymorphism is located in the promoter region of the MMP-2 gene and is thought to enhance its transcriptional activity (4). The increased expression of MMP-2 may contribute to TOD through several mechanisms:
Cardiac remodeling: Excessive extracellular matrix degradation leading to myocardial fibrosis and LVH (12).
Renal injury: Basement membrane degradation, promoting albuminuria and glomerulosclerosis (13).
Vascular remodeling: Collagen and elastin degradation, facilitating atherosclerotic plaque formation (14).
These findings reinforce the role of MMP-2 in cardiovascular and renal pathology and suggest that rs243866 may be a genetic marker for TOD risk stratification.
Clinical Implications
Given the strong association between rs243866 and TOD, genetic screening for this polymorphism may help identify high-risk UHT patients. Early detection could allow for more aggressive BP control and tailored therapeutic strategies, potentially improving long-term outcomes. Moreover, targeting MMP-2 activity through pharmacological inhibition may represent a novel therapeutic approach.
Strengths and Limitations
Strengths
First study in Vietnam to evaluate the association between rs243866 and TOD in UHT patients.
Genotypic analysis performed using PCR and sequencing, ensuring high accuracy.
Multivariate logistic regression used to control for confounders.
Limitations
Small sample size (n=134); larger studies are needed to confirm findings.
Lack of MMP-2 serum level measurements, which could provide further insights into its role in TOD.
Environmental factors (diet, lifestyle) were not assessed.
Future Directions
Larger, multi-center studies to validate the association between rs243866 and TOD.
Investigation of MMP-2 serum levels in relation to genetic variants.
Clinical trials evaluating MMP-2 inhibitors as a potential therapy for TOD prevention in UHT patients.
6. CONCLUSION
This study demonstrates that the rs243866 polymorphism of MMP-2 is significantly associated with TOD in UHT patients, particularly LVH, CKD, and carotid atherosclerosis. Carriers of the A allele have a higher risk of these complications, supporting the role of MMP-2 in vascular and myocardial remodeling. Genetic screening for rs243866 may facilitate early risk assessment and personalized hypertension management. Further research is warranted to confirm these findings and explore therapeutic implications.
Author’s contribution:
The all authors were involved in all steps of preparation this article, including final proofreading.
Conflicts of interest:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Financial support and sponsorship:
This study did not receive funding from any individual or organization.
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