title: Higher risk of matrix metalloproteinase (MMP-2, 7, 9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants to gallbladder cancer.
abstract: BACKGROUND
  Matrix metalloproteinase belong to family of pericellular collagenases which degrade extracellular matrix (ECM), and is involved in the modulation and susceptibility of various cancers.
  
  
  METHODS
  The present study included 410 gallbladder (GBC) cases and 230 healthy controls from North India. Study examined the associations of polymorphisms of MMP-2c.735C>T (rs2285053), MMP-2c.1306 C>T (rs243865), MMP7c.181A>G (rs11568818), MMP-9p.R279Q (rs17556) MMP-9p.P574R (rs2250889), MMP-9 p.R668Q (rs17577) and TIMP2c.418 G>C (rs8179090) to GBC susceptibility. Genotyping was carried out by PCR-RFLP. Statistical analysis was performed by using SPSS ver16.
  
  
  RESULTS
  The MMP-2 c.735 [CT+TT], MMP-2c.1306 [CT+TT], MMP7 c.181 [AG+GG] and MMP-9 p.668 [RQ+QQ],TIMP2c.418 [GG+GC] genotypes were significantly associated with increased risk of GBC (P = 0.01; [OR]1.87, P = 0.02; [OR] 1.68, P = 0.02; [OR]=1.61, P = 0.002; [OR]=1.91,P = 0.01; [OR]=1.78 and (P = 0.03; [OR]=1.68; P = 0.01; [OR]=1.78 respectively). Haplotypes [C(-735) -T(-1306) ] and [T(-1306) -C(-735) ] of MMP-2 (P = <0.005; [OR] =1.78 P = <0.0001; [OR] =2.09) and haplotype [Q(279) -P(574) -Q(668) ]of the MMP-9 (P = 0.04; [OR] =2.75) were significantly associated with GBC risk. On stratification of GBC patients with/without gallstones, MMP-2 haplotypes were associated with higher GBC risk in patients accompanying gallstones whereas MMP-9 haplotypes showed risk in patients without stones. Combined effect of > 3 MMP/TIMP variant containing genotypes imparted increased risk of GBC (P < 0.0001; [OR] =3.36). Multivariate logistic regression results also supported association of MMP-2 (c.735C>T, c.1306 C>T), MMP-9 p.R668Q and TIMP2c.418G>C variants with GBC susceptibility.
  
  
  CONCLUSIONS
  This study suggests that genetic variants in MMP-2,7,9 and TIMP-2genes are associated with higher susceptibility of gallbladder cancer.
authors.affiliation: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Kiran L
authors.initials: KL
authors.lastname: Sharma
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Misra
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000328:Adult; D005260:Female; D005706:Gallbladder Neoplasms / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007194:India / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008956:Models, Chemical; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012307:Risk Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*
chemical_list: C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9