This study aimed to determine possible association of eight polymorphisms of seven MMP genes with essential hypertension (EH) in a Caucasian population of Central Russia. Eight SNPs of the MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, and MMP12 genes and their gene–gene (epistatic) interactions were analyzed for association with EH in a cohort of 939 patients and 466 controls using logistic regression and assuming additive, recessive, and dominant genetic models. The functional significance of the polymorphisms associated with EH and 114 variants linked to them (r2 ≥ 0.8) was analyzed in silico. Allele G of rs11568818 MMP7 was associated with EH according to all three genetic models (OR = 0.58–0.70, pperm = 0.01–0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49–1.93, pperm < 0.02). Loci rs1320632 MMP8 and rs11568818 MMP7 contributed to the largest number of the models (12 and 10, respectively). The EH-associated loci and 114 SNPs linked to them had non-synonymous, regulatory, and eQTL significance for 15 genes, which contributed to the pathways related to metalloendopeptidase activity, collagen degradation, and extracellular matrix disassembly. In summary, eight studied SNPs of MMPs genes were associated with EH in the Caucasian population of Central Russia.
The aim of research. To study the association of polymorphic loci of matrix metalloproteinases with the development of essential hypertension (EH) in men of the Central Chernozem Region of Russia. Materials and methods. A study of 564 men with EH and 257 control men was performed. Analysis of the polymorphic loci of metalloproteinases rs11568818 MMР7, rs1320632 MMР8, rs11225395 MMР8, rs1799750 MMР1, rs3025058 MMР3 was performed using real-time PCR. The study of associations of SNPs and their haplotypes with the development of arterial hypertension was carried out using logistic regression analysis in the PLINK software (v. 2.050). The regulatory potential of polymorphic loci was analyzed in the HaploReg software (v. 4.1) (http://archive.broadinstitute.org). The effect of SNP on gene expression was studied using the data of the Genotype-Tissue Expression project (http://www.gtexportal.org/). Results. Haplotype including rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8 and rs1799750 MMP1 associated with a high risk of disease in men (OR=2,58, pperm=0,04). These polymorphisms located in region of promoter and enhancer histone marks and in the region of hypersensitivity to DNAse-1. They located in sites of proteins bound (TBP, CJUN, CFOS and GATA2) and they associated with the level of gene expression ММР7, ММР27 and RP11-817J15.3 (in peripheral blood, skeletal muscles, nervous tissue and other). Сonclusion. Haplotype G-A-C-1G for polymorphisms rs11568818 MMP7, rs1320632 MMP8, rs11225395 MMP8, rs1799750 MMP1 are associated with the development of essential hypertension in men in the Central Chernozem Region of Russia.
Cardiovascular diseases are the leading cause of death and disability in Russia and in the world, and hypertension is considered to be an independent predisposing factor in such complications as myocardial infarction, cerebral stroke, chronic renal failure and aneurysm. The study of the molecular genetic basis of hypertension is an important task of modern medicine and determines the prospects for its personalization. The aim of this review is to generalize the experimental data on genetic associations of matrix metalloproteinases (MMP) gene polymorphisms with the development of arterial hypertension and its complications. Materials and methods. The paper reviews the data on associations of polymorphisms of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12 with development of hypertension and its complications. The search and analysis of the literature data was carried out using the PubMed-NCBI databases (https: //preview.ncbi.nlm.nih.Gov/pubmed). Results of the study and conclusion. According to the latest data, the genes of matrix metalloproteinases (MMP) are involved in the etiopathogenesis of hypertension. This group of proteolytic enzymes with a wide range of biological functions, which are responsible for the hydrolysis of all components of the extracellular matrix. In the vascular wall, MMPs affect the migration, proliferation and apoptosis of smooth muscle, endothelial and inflammatory cells, thereby determining the formation of intima and arterial remodeling, as evidenced by clinical and transgenic studies. The facts about the role of MMP polymorphic markers in the development of arterial hypertension do not always agree with each other and differ in different populations, which can be explained by differences in the ethnic composition and size of the study groups and the design of the study.
Aim To study the involvement of cytokine polymorphous loci in development of arterial hypertension (AH) in men from the Central Black Earth region of Russia.Materials and methods 821 men were evaluated, including 564 patients with AH and 257 individuals of the control group. Analysis of 8 cytokine mononucleotide polymorphisms (MNP) was performed using the real-time polymerase chain reaction with TagMan probes. Statistical analysis was performed with the STATISTICA (v.10.0) and PLINK (v.1.06) software. The regulatory potential of MNP was analyzed with the HaploReg (v.4.1) service (http://archive.broadinstitute.org).Results The rs1061624 ТNFR2 polymorphous locus was associated with development of AH in men in recessive (odd ratio (OR), 0.33; 95 % confidence interval (CI): 0.18–0.61, рperm=0.0004) and additive (OR, 0.50, 95 % CI: 0.34–0.74, рperm=0.0006) genetic models and exerted a protective effect in development of AH. The rs1061624 MNP of the ТNFR2 gene has a regulatory significance; it is located in the DNA sites hypersensitive to the action of DNAase 1 and in binding sites for transcriptional factors and histones that mark enhancers and promoters in different organs and tissues.Conclusion The rs1061624 ТNFR2 gene polymorphism is involved in the development of AH in men of the Central Black Earth region of Russia.
Objectives. To study the interaction of polymorphic markers for matrix metalloproteinases (MMP) and chronic stress on formation of stroke on the background of hypertensive disease. Materials and methods. A total of 830 patients were studied: 303 patients with ischemic stroke on the background of hypertensive disease and 527 patients with hypertensive disease without stroke. SNP for metalloproteinases were studied using the real-time polymerase chain reaction. The functional signifi cance and infl uences of polymorphic loci on gene expression were studied using the HaploReg (v4.1) (http://archive.broadinstitute.org) and GTEx-portal (http://gtexportal.org) services. Results and conclusions. An association was found between the GG rs11568818 genotype of the MMP7 gene and a high risk of developing stroke in patients experiencing regular stress (odds ratio (OR) 1.71). The 5A allele and the 5A/5A genotype of rs3025058 of the MMP3 gene had protective effects on development of stroke in people without histories of chronic stress (OR 0.73 and OR 0.60, respectively). The SNP studied here were located in the histone protein H3K4me1 and H3K4me3 region, which is hypersensitive to DNase 1 and binds regulatory proteins and transcription factors, while the polymorphic rs11568818 locus is linked with the level of expression of the MMP7 gene.
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