title: Matrix metalloproteinase-2 -735C/T polymorphism is associated with resistant hypertension in a specialized outpatient clinic in Brazil.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil. Electronic address: deia_sabbatini@hotmail.com.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Sabbatini
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Natalia R
authors.initials: NR
authors.lastname: Barbaro
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: de Faria
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Alessandra Mileni V
authors.initials: AMV
authors.lastname: Ritter
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Modolo
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Nathália B
authors.initials: NB
authors.lastname: Correa
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Veridiana
authors.initials: V
authors.lastname: Brunelli
authors.affiliation: Faculty of Medicine, Pontifical Catholic University of Campinas (Puccamp), Campinas, SP, Brazil.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pinho
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fontana
authors.affiliation: Laboratory of Cardiovascular Pharmacology, Faculty of Medical Sciences and Teaching Hospital, University of Campinas (Unicamp), Campinas, SP, Brazil.
authors.forename: Heitor
authors.initials: H
authors.lastname: Moreno
mesh_terms: D000368:Aged; D001938:Brazil; D016022:Case-Control Studies; D005260:Female; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D008875:Middle Aged; D010045:Outpatients; D020641:Polymorphism, Single Nucleotide
chemical_list: C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Genetic polymorphism; Refractory hypertension; Target organ damage; Tissue inhibitor of metalloproteinases 2