The Association Of MMP-12MMP-13Polymorphism With The Risk Of Colorectal Cancer

Objective: In the promoter region of MMP-12MMP-13gene exists SNPsmutation, these SNPs loci related to the expression and regulation of MMP-12,MMP-13,and associated with susceptibility to colorectal cancer. This studyinvestigates the relationship between MMP-12, MMP-13gene rs2276109A/Gand rs2252070A/G polymorphism and genetic susceptibility to colorectalcancer, providing a molecular basis for screening,diagnosis and treatment ofpopulation with high risk of colorectal cancer.Methods: This population-based case-control study included129CRCpatients who admitted in the Fourth Affiliated Hospital of Hebei MedicalUniversity from2012March to2013March and74healthy controls. Thegenomic DNA was extracted by using proteinase K digestion followed by asalting out procedure, Genotypes of the genotype frequency of rs2276109A/Gand rs2252070A/G SNP loci allele in MMP-12MMP-13gene were analyzedby polymerase chain reaction-ligase detection reaction (PCR-LDR) method.Statistical analysis was performed by using SPSS11.5software packageVer.13.0. A probability level of lower than5%was considered significant forall statistical analyses. Hardy-Weinberg equilibrium analysis was performedby comparing the observed and expected genotype frequencies in controlgroups using Chi-square test. Comparisons of allele and genotype distributionin cases and controls were performed by means of two-sided contingencytables using Chi-square test.The MMP haplotype frequencies and linkagedisequilibrium coefficient were estimated by using EH linkage software and2LD software. The odds ratio (OR) and95%confidence interval (CI) werecalculated via unconditional logistic regression model.Results：1Genotype distribution frequency of MMP-12rs2276109A/G MMP-13rs2252070A/G obeys the Hardy-Weinberg equilibrium in the control group (P> 0.05).2The analysis on polymorphism of MMP-12gene rs2276109A/G and pert-inence of CRC:The frequencies of alleles A and G on the MMP-12rs2276109A/G are98.7%and1.4%respectively in the case group, while among colon cancerpatients they are99.0%and1.0%respectively. There was no significantdifference between the two groups’ comparison in statistics.(P＞0.05). Amongcolon cancer patients in experimental group, the frequencies of genotypes A/A,A/G and G/G are98%、2.0%and0%, respectively, while in the control groupthey are97.3%、2.7%and0%respectively. There was no significant differencebetween the two groups’ comparison in statistics.(P＞0.05). Compared withthe A/A genotype, there is no pertinence between the individual who has thegenotype A/G and the risk of colon cancer (OR=0.345,95％CI=0.019-6.145).While in the experimental group of rectal cancer patients, the frequencies ofalleles A and G are93.6%and6.4%, which has significant difference betweenthe two groups（P=0.049）. This shows that the increasing frequency of alleleG on MMP-12rs2276109A/G could increase the risk of rectal cancer. Thefrequencies of the genotypes A/A、A/G、G/G between rectal cancer patients are87.2%、12.8%and0%respectively which has significant difference comparedwith the control group (P=0.044). The individual who has genotype A/Gsuffers more risky of rectal cancer than that who has the genotype A/A(OR=10.193,95％CI=1.552-66.939）.3The analysis of correlation between MMP-13gene rs2252070A/G polym-orphism and CRC.The frequencies of the alleles A and G on MMP-13rs2252070A/G amongexperimental colon cancer patients are47.1%and52.9%, while in the controlgroup they are32.4%and67.6%respectively; There was significantdifference between the two groups (P=0.019). This shows that the increasingfrequency of allele A on MMP-13rsrs2252070A/G will add the risk ofcolon cancer.The frequencies of the genotypes A/A、A/G、G/G in coloncancer patients (15.7%,62.7%and21.6%respectively) and in controls (13.5%,37.8%and48.6%respectively) have significant difference in statistics(P=0.007). Compared with the genotype G/G,the genotype A/G couldsignificantly increase the risk of developing colon cancer (OR=6.787,95％CI=2.392-19.253）, while the genotype A/A is no related to the risk ofdeveloping colon cancer (OR=3.378,95％CI=0.912-12.514）. However in theexperimental group of rectal cancer patients,the frequencies of alleles A and Gare42.3%and57.7%, which has no significant difference between the twogroups (P＞0.05). The frequencies of the genotypes A/A、A/G、G/G in rectalcancer patients (21.8%、41.0%and37.2%, respectively) and in controls had nosignificant difference (P＞0.05). Compared with the genotype G/G,thegenotypes A/G and A/A could not increase the risk of developing rectal cancer(OR=1.475,95%CI=0.656-3.317, OR=2.404,95%CI=0.871-6.640).4The combined analysis on SNPs of rs2276109A/G and rs2252070A/G inMMP-12, MMP-13gene was carried out by software EH and2LD.The resultsshowed that：4.1In colon cancer patients of control group and experimental group,MMP-12, there is strong chain imbalance between MMP-13geners2276109A/G and rs2252070A/G (D’=0.992).The result showed that thehighest frequency of haplotype is rs2276109A-2252070G(66.2%), followedby rs2276109A-2252070A(32.4%), rs2276109G-2252070G (1.4%) andrs2276109G-2252070A(0%),(probably related to the small amount ofsample and missing the haplotype).The rs2276109A-2252070A haplotype willincrease the risk of colon cancer（OR=1.783,95%CI=1.060-2.997) while thers2276109A-2252070G, rs2276109G-2252070G haplotypes will reduce therisk of it（OR=0.573,95％CI=0.342-0.961、OR=0.023,95％CI=0.001-0.454）.Due to the small sample size of rs2276109G-2252070A haplotype, haplotypedetection will be missed.4.2In rectal cancer patients of controls and experimental group, there isweaker chain imbalance between MMP-12, MMP-13gene rs2276109A/G andrs2252070A/G polymorphisms (D’<0.001). The rs2276109A-2252070Ghaplotype could reduce the risk of rectal cancer （OR=0.615,95％ CI=0.387-0.978）. Due to the small sample size of rs2276109G-2252070Ahaplotype, haplotype detection will be missed. Two other haplotypesdistribution may have no influence on the risk of rectal cancer whose OR are0.1.329（95％CI=0.829-2.128) and2.290（95％CI=0.432-12.138）respectively.Conclusions:1The MMP-12rs2276109A/G SNP might not be associated with the riskof developing colon cancer, but it was associated with the risk of developingrectal cancer. Compared with the genotype A/A, the genotype A/G couldsignificantly increase the risk of rectal cancer.2The MMP-13rs2252070A/G SNP was associated with the risk ofdeveloping colon cancer. Compared with the genotype G/G, genotype A/Gcould significantly increased the risk of colon cancer. The genotype A/A wasnot associated with the risk of developing colon cancer. But the locus SNP onA/A might not be associated with the risk of developing rectal cancer.3The loci of rs2276109A/G and rs2252070A/GSNPs in MMP-12,MMP-13gene had strong chain disequilibrium in colon cancer (D ’=0.992);The two alleles had weak chain disequilibrium in rectal cancer (D ’<0.001).