A Common Tag Nucleotide Variant in MMP7 Promoter Increases Risk for Hypertension via Enhanced Interactions With CREB (Cyclic AMP Response Element-Binding Protein) Transcription Factor.

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  • Additional Information
    • Source:
      Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE
    • Publication Information:
      Publication: : Hagerstown, MD : Lippincott, Williams & Wilkins
      Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]-
    • Subject Terms:
      Genetic Predisposition to Disease*; Cyclic AMP Response Element-Binding Protein/*genetics ; Hypertension/*epidemiology ; Hypertension/*genetics ; Matrix Metalloproteinase 7/*genetics ; Polymorphism, Single Nucleotide/*genetics; Analysis of Variance ; Case-Control Studies ; Female ; Gene Expression Regulation ; Genetic Variation ; Genotype ; Humans ; India/epidemiology ; Male ; Predictive Value of Tests ; Prevalence ; Promoter Regions, Genetic/genetics ; Retrospective Studies ; Risk Assessment ; Urban Population
    • Abstract:
      MMP (matrix metalloproteinase)-7-a potent extracellular matrix degrading enzyme-is emerging as a new regulator of cardiovascular diseases. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we probed for the association of a tag single-nucleotide polymorphism in the MMP7 promoter (-181A/G; rs11568818) with hypertension in an urban South Indian population (n=1501). The heterozygous AG genotype significantly increased risk for hypertension as compared with the wild-type AA genotype (odds ratio, 1.60 [95% CI, 1.25-2.06]; P =2.4×10 -4 ); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than wild-type AA individuals. The study was replicated in a North Indian population (n=949) (odds ratio, 1.52 [95% CI, 1.11-2.09]; P =0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the CREB (cyclic AMP response element-binding protein) to the -181G promoter. In corroboration, overexpression/downregulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. The -181G promoter also displayed enhanced responses to hypoxia and epinephrine treatment. The higher promoter activity of -181G allele translated to increased MMP7 protein level, and MMP7 - 181AG heterozygous individuals displayed elevated plasma MMP7 levels, which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter polymorphism increased MMP7 expression under pathophysiological conditions (hypoxic stress and catecholamine excess) via increased interactions with CREB and enhanced the risk for hypertension in its carriers.
    • Contributed Indexing:
      Keywords: MMP7; catecholamine; hypertension; hypoxia; single nucleotide polymorphism; transcriptional regulation
    • Accession Number:
      0 (Cyclic AMP Response Element-Binding Protein)
      EC 3.4.24.23 (Matrix Metalloproteinase 7)
    • Publication Date:
      Date Created: 20191029 Date Completed: 20200522 Latest Revision: 20200522
    • Publication Date:
      20231215
    • Accession Number:
      10.1161/HYPERTENSIONAHA.119.12960
    • Accession Number:
      31656093