基质金属蛋白酶-2 -735C/T基因多态性与巴西一家专科门诊的难治性高血压相关。

Matrix metalloproteinase-2 -735C/T polymorphism is associated with resistant hypertension in a specialized outpatient clinic in Brazil.

作者信息

Sabbatini Andrea R, Barbaro Natalia R, de Faria Ana Paula, Ritter Alessandra Mileni V, Modolo Rodrigo, Correa Nathália B, Brunelli Veridiana, Pinho Claudio, Fontana Vanessa, Moreno Heitor

机构信息

Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.

出版信息

Gene. 2017 Jul 15;620:23-29. doi: 10.1016/j.gene.2017.04.004. Epub 2017 Apr 5.

DOI:10.1016/j.gene.2017.04.004

PMID:28390988

Abstract

BACKGROUND

Matrix metalloproteinases (MMPs) are enzymes involved in cardiovascular (CV) remodeling and hypertension-mediated target organ damage (TOD). Genetic polymorphisms in matrix metalloproteinase 2 (MMP-2) gene [-1575G/A (rs243866); -1306C/T (rs243865); and -735C/T (rs2285053)] are associated with several CV conditions, however the relationship between MMP-2 polymorphisms and resistant hypertension (RH) is unknown. We evaluated whether these genetic single nucleotide polymorphisms (SNPs) in MMP-2 gene are associated with 1) MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) levels in RH and mild to moderate hypertensive (HT) subjects, 2) left ventricular hypertrophy (LVH) and arterial stiffness and 3) the presence of RH.

METHODS

One hundred and nineteen RH and 136 HT subjects were included in this cross-sectional study. Genotypes were determined by real-time PCR using TaqMan probes. Haplotypes were estimated using Bayesian method.

RESULTS

The levels of MMP-2 and TIMP-2 were similar among genotypes and haplotypes for the three studied polymorphisms in HT and RH groups. RH showed higher frequency for GCC haplotype and lower frequency of GCT and ATC haplotypes (-1575G/A, -1306C/T and -735C/T, respectively) compared to HT (0.77 vs. 0.64; 0.09 vs. 0.17; 0.13 vs. 0.19, p=0.003 respectively). GCC haplotype was associated to RH apart from potential confounders (odds ratio (OR)=2.09; 95% confidence interval (CI)=1.20-3.64; p=0.01). In addition, CC genotype (OR=2.93; 95% CI=1.22-7.01; p=0.02) and C allele (OR=2.81; 95% CI=1.26-6.31; p=0.01) for -735C/T polymorphism were independently associated with RH. GCT haplotype was associated with reduced probability of having RH (OR=0.35; 95% CI=0.16-0.79; p=0.01). Finally, no relationship was found between studied MMP-2 SNPs and left ventricular hypertrophy and arterial stiffness in both groups.

CONCLUSION

GCC haplotype carriers showed higher probability to have RH (odds ratio>1), while the GCT haplotype carriers showed lower probability to have RH, suggesting that the GCT haplotype may represent a protective genetic factor for the development of RH. These finds suggest that GCC and GCT haplotypes, and C allele and CC genotype of the -735C/T MMP-2 gene polymorphism may have a role in RH.

摘要

背景

基质金属蛋白酶（MMPs）是参与心血管（CV）重塑和高血压介导的靶器官损伤（TOD）的酶。基质金属蛋白酶2（MMP-2）基因的遗传多态性[-1575G/A（rs243866）；-1306C/T（rs243865）；以及-735C/T（rs2285053）]与多种心血管疾病相关，然而MMP-2多态性与顽固性高血压（RH）之间的关系尚不清楚。我们评估了MMP-2基因中的这些遗传单核苷酸多态性（SNP）是否与以下因素相关：1）RH和轻度至中度高血压（HT）患者的MMP-2和金属蛋白酶组织抑制剂-2（TIMP-2）水平；2）左心室肥厚（LVH）和动脉僵硬度；3）RH的存在。

方法

本横断面研究纳入了119例RH患者和136例HT患者。使用TaqMan探针通过实时PCR确定基因型。使用贝叶斯方法估计单倍型。

结果

在HT组和RH组中，所研究的三种多态性的基因型和单倍型之间的MMP-2和TIMP-2水平相似。与HT组相比，RH组中GCC单倍型的频率更高，而GCT和ATC单倍型（分别对应-1575G/A、-1306C/T和-735C/T）的频率更低（分别为0.77对0.64；0.09对0.17；0.13对0.19，p分别为0.003）。除潜在混杂因素外，GCC单倍型与RH相关（优势比（OR）=2.09；95%置信区间（CI）=1.20 - 3.64；p = 0.01）。此外，-735C/T多态性的CC基因型（OR = 2.93；95% CI = 1.22 - 7.01；p = 0.02）和C等位基因（OR = 2.81；95% CI = 1.26 - 6.31；p = 0.01）与RH独立相关。GCT单倍型与患RH的概率降低相关（OR = 0.35；95% CI = 0.16 - 0.79；p = 0.01）。最后，在两组中均未发现所研究的MMP-2 SNP与左心室肥厚和动脉僵硬度之间存在关联。