title: Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels.
abstract: BACKGROUND
  Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis.
  
  
  METHODS
  We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C(-1562)T, rs3918242; -90 (CA)(14-24), rs2234681; and Q279R, rs17576) were determined by Taqman® Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1.
  
  
  RESULTS
  Hemodialysis increased MMP-9 and TIMP-1 levels (P<0.05). Genotypes had no effects on baseline MMP-9 and TIMP-1 levels (P>0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C(-1562)T polymorphism (P<0.05), and increased MMP-9 levels in subjects with the QQ (but not QR or RR) genotype for the Q279R polymorphism (P<0.05), whereas the CA(n)(14-24) polymorphism had no major effects. While MMP-9 haplotypes had no effects on baseline MMP-9 levels (P>0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P=0.0012 and P=0.0045, respectively).
  
  
  CONCLUSIONS
  ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
authors.forename: Bernardo P
authors.initials: BP
authors.lastname: Marson
authors.forename: Riccardo
authors.initials: R
authors.lastname: Lacchini
authors.forename: Vanessa
authors.initials: V
authors.lastname: Belo
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Mattos
authors.forename: Bartira P
authors.initials: BP
authors.lastname: da Costa
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Poli-de-Figueiredo
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D006435:Renal Dialysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D055815:Young Adult
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9