Higher risk of matrix metalloproteinase ( MMP-2, 7, 9) and tissue inhibitor of metalloproteinase ( TIMP-2) genetic variants to gallbladder cancer.

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), MMP 7c.181A>G (rs11568818), MMP -9p.R279Q (rs17556) MMP -9p.P574R (rs2250889), MMP -9 p.R668Q (rs17577) and TIMP 2c.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] , MMP 7 c.181 [ AG+ GG] and MMP -9 p.668 [ RQ+ QQ] , TIMP 2c.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 [Q279-P574-Q668]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 TIMP 2c.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. [ABSTRACT FROM AUTHOR]