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  • Title: Higher risk of matrix metalloproteinase (MMP-2, 7, 9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants to gallbladder cancer.
    Author: Sharma KL, Misra S, Kumar A, Mittal B.
    Journal: Liver Int; 2012 Sep; 32(8):1278-86. PubMed ID: 22621753.
    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. METHODOLOGY: 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. CONCLUSION: This study suggests that genetic variants in MMP-2,7,9 and TIMP-2genes are associated with higher susceptibility of gallbladder cancer.
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