MMP-1 Promoter Polymorphisms Research Articles

Matrix metalloproteinase 1, 3, and 9 polymorphisms and esophageal squamous cell carcinoma risk.

BackgroundMatrix metalloproteinases (MMPs) are multifunctional zinc-dependent proteinases that play a fundamental role in the pathogenesis of tumors. We have analyzed the association between 3 single-nucleotide polymorphisms (SNPs; MMP1 −1607 1G/2G, MMP3 −1612 5A/6A, and MMP9 −1562 C/T) and the risk of esophageal squamous cell carcinoma (ESCC).Material/MethodsWe investigated these 3 SNPs in 132 patients and 132 controls using polymerase chain reaction-restriction fragment length polymorphism methods. The MMP1 and MMP3 genes are located on the same chromosome. Haplotype analysis was performed to study the combined effect of the linked MMP polymorphisms on ESCC risk.ResultsThe MMP1 and MMP9 promoter polymorphisms were not associated with ESCC risk, while the MMP3 −1612 5A/6A polymorphism was significantly associated with susceptibility to ESCC. Patients carrying the 5A allele had a significantly higher risk for developing ESCC compared with individuals carrying the 6A allele (OR=1.93; 95% CI 1.34–2.77; p<0.01). The 2G-5A and 1G-5A haplotypes were associated with a significantly increased risk of ESCC as compared with the 2G-6A haplotype (OR=2.04, 95% CI 1.37–3.04 and OR=3.65, 95% CI 1.26–10.55, respectively).ConclusionsThese findings implicate this MMP3 polymorphism as a contributor to ESCC susceptibility.

Matrix metalloproteinase-1 promoter genotypes and haplotypes are associated with carotid plaque presence

ObjectivesMatrix metalloproteinase (MMP)-1 degrades fibrillar collagens suggesting important role in vascular remodeling. Data about MMP-1 promoter polymorphisms and carotid atherosclerosis (CA) are scarce. The aim of this study was to evaluate association of MMP-1 genotypes/haplotypes with carotid plaque (CP) presence in Serbian population. Design and methodsStudy enrolled a total of 702 participants: 274 controls and 428 consecutive patients with CA who underwent carotid endarterectomy. MMP-1 polymorphisms −1607 1G/2G, −519 A/G and −340 T/C were genotyped by PCR and RFLP methods. ResultsIndividuals carrying MMP-1 −1607 2G allele had significantly increased allele dose-dependent risk for CP presence (1G1G vs. 1G2G vs. 2G2G; OR=1; OR=1.87 95% CI 1.29–2.07; OR=3.49 95% CI 1.67–7.30, p=0.0009, respectively). Compared to the referent haplotype 2G−1607-T−340-A−519, the haplotypes 1G−1607-T−340-A−519, 1G−1607-T−340-G−519 and 2G−1607-C−340-A−519 had statistically significant protective effect on CP presence (OR=0.41, 95% CI 0.29–0.81, p=0.01; OR=0.56, 95% CI 0.44–0.89, p=0.01; OR=0.43, 95% CI 0.27–0.86, p=0.02, respectively). ConclusionsMMP-1 −1607 G/2G polymorphism solely and specific haplotypes of three analyzed promoter polymorphisms are significantly and independently associated with occurrence of CP. Replication studies in other populations are needed.

Analysis of the association of an MMP1 promoter polymorphism and transcript levels with chronic periodontitis and end-stage renal disease in a Brazilian population

Chronic periodontitis (CP) and end-stage renal disease (ESRD) are complex inflammatory conditions. Higher levels of MMP-1 were found in fluids and gingival tissues from CP patients and in the blood and tissues from ESRD patients. MMP1-1607 (1G/2G) is a functional polymorphism, as it alters MMP-1 expression. ObjectiveThe aim of this study was to investigate the association of the MMP1-1607 (1G/2G) polymorphism with CP and ESRD and evaluate differences in transcript levels between the groups. DesignA total of 254 individuals were divided into four groups: Group 1, without CP and without chronic kidney disease (CKD) (n=67); Group 2, with CP and without CKD (n=60); Group 3, without CP and with CKD stage 5 (ESRD) (n=52), and Group 4, with CP and with ESRD (n=75). The MMP1-1607 polymorphism was analysed by PCR-RFLP. MMP1 gene transcripts from gingival tissues were analysed by real-time PCR. ResultsNo association was found between the MMP1-1607 polymorphism and CP or ESRD. Increased levels of MMP1 transcripts were observed in CP patients with or without ESRD. No differences were observed in the transcript levels according to the genotypes. ConclusionIt was concluded that the MMP1-1607 polymorphism was not associated with either CP or ESRD. However, higher levels of MMP1 gene transcripts were found at gingival sites of CP in patients both with and without ESRD.

MMP1-1607(1G&gt;2G) polymorphism and the risk of lung cancer in Lebanon

CONTEXT:Matrix metalloproteinases (MMPs) are a family of enzymes that degrade various components of the extracellular matrix and are involved in the development and progression of cancer. Lung cancer is the most commonly diagnosed cancer in Lebanon. MMP1 is responsible for degrading stromal collagens, which enhance the ability of neoplastic cells to cross basal membrane of both the endothelium and the vascular endothelium. A recent meta-analysis has suggested that the MMP1-1607 2G allele may be associated with an increased risk for certain types of cancers.AIM:This study was undertaken to investigate the association between guanine insertion polymorphism in the MMP1 promoter and the susceptibility to lung cancer in the Lebanese population.SETTINGS AND DESIGN:This case-control study was conducted on 41 patients with lung cancer and 51 age-matched healthy controls, recruited from different regions of Lebanon.METHODS:Cases were histologically confirmed lung cancer patients obtained from different hospitals in Lebanon. Controls were healthy unrelated individuals with no history of cancer or genetic diseases. All subjects were genotyped for MMP1 -1607(1G>2G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP).RESULTS:No statistically significant differences were found when genotype and allele distribution of MMP1 -1607(1G>2G) polymorphism were compared between patients with lung cancer and controls [P= 0.6 by chi-squared test on a 3×2 contingency table; allelic P=0.61, OR (95% CI) = 1.18 (0.60-2.31)].CONCLUSION:Our data shows that MMP1 promoter polymorphism is not associated with lung cancer susceptibility in the Lebanese population.

Matrix metalloproteinase 1 promoter polymorphisms and risk of myocardial infarction: a case–control study in a Spanish population

Inherited and acquired risk factors contribute to the development of the atherosclerotic lesion and its most common clinical manifestation, myocardial infarction (MI). Multiple studies have suggested a role for matrix metalloproteinases (MMPs) in atherosclerosis, and several functional polymorphisms in the MMP-1 gene have been linked to the risk of MI. The aim of this study was to evaluate the association between MMP-1 promoter polymorphisms and early MI in a Spanish cohort. We carried out a case-control study with 261 unrelated patients who had suffered an MI before 55 years of age and 194 healthy controls, all male and smokers. The genotypes for the three MMP-1 promoter polymorphisms -1607 1G/2G, -519 A/G, and -340 T/C were determined through PCR-restriction fragment length polymorphism. Allelic, genotypic, and haplotypic frequencies were statistically compared between groups. Frequencies of the three polymorphisms did not differ between patients and controls. The -1607 1G/2G and -519 A/G variants were in linkage disequilibrium. Analysis of the haplotype frequencies showed significant associations of the 2G(-1607)-G(-519)-T(-340) (odds ratio = 2.40; 95% confidence interval = 1.27-4.55; P<0.006) and 1G(-1607)-G(-519)-T(-340) (odds ratio = 0.68; 95% confidence interval = 0.50-0.94; P<0.05) haplotypes with the risk of early MI. MMP-1 promoter polymorphisms are associated with the risk of early MI in a Spanish population of smoking males.

Polymorphism of matrix metalloproteinase genes (MMP1andMMP3) in patients with varicose veins

Several risk factors for varicose veins have been identified: female gender, combined with obesity and pregnancy, occupations requiring standing for long periods, sedentary lifestyle, history of deep-vein thrombosis and family history. However, no specific gene variants related to a wide prevalence of varicosities in general population have been identified. Extracellular matrix composition, predominantly maintained by matrix metalloproteinases (MMPs), may affect the vein-wall structure, which may lead to dilation of vessels and cause varicosities. MMP-1 (tissue collagenase I) and MMP-3 (stromelysin I) expression was found to be raised in varicose veins compared with normal vessels. Therefore, a study was conducted to evaluate a potential association between MMP1 and MMP3 promoter polymorphisms and a risk of varicose veins. Genotyping for the presence of the polymorphisms -1607dupG (rs1799750) in MMP1 and -1171dupA (rs3025058) in the MMP3 promoter region was performed using PCR and restriction-fragment length polymorphism assays in a group of 109 patients diagnosed with varicose veins and 112 healthy controls. The frequencies of the MMP1 and MMP3 alleles (minor allele frequency 0.440 in patients vs. 0.451 in the controls for MMP1-1607*G and 0.514 vs. 0.469 for MMP3-1171*dupA, respectively) and of genotypes did not differ significantly between patients and controls. The MMP1-1607dupG and MMP3-1171dupA promoter polymorphisms are not valuable markers of susceptibility for varicose veins.

Polymorphism +17 C/G in Matrix Metalloprotease MMP8 decreases lung cancer risk

BackgroundMatrix metalloproteases (MMPs) constitute a family of enzymes capable of degrading different components of the extracellular matrix and are implicated in the invasion of tumor cells through the basement membrane. Polymorphisms in MMP genes may result in changes in the expression of MMPs being associated with the development and progression of cancer. We have investigated the association between three polymorphisms (-1607 1G/2G, +17 C/G and -77 A/G) in the human collagenases MMP1, MMP8 and MMP13 and the risk of development or progression of lung cancer.MethodsA hospital-based case-control study was designed including 501 lung cancer patients and 510 controls matched. Genotypes were determined by PCR-RFLP. Results were analyzed using unconditional logistic regression, Cox's proportional hazard regression, and the Kaplan-Meier method.ResultsThe MMP1 and MMP13 promoter polymorphisms were not associated with lung cancer risk, while the C/G polymorphism in MMP8 was associated with a statistically significant decreased risk of developing lung cancer (ORadj = 0.65; 95%CI = 0.45–0.93). The Kaplan-Meier analysis showed that the polymorphisms in MMP1, MMP8 and MMP13 not seem to modify the overall survival. Multivariate analysis revealed that MMP1, MMP8 and MMP13 polymorphisms are not independent prognostic factors for overall survival.ConclusionThis study suggests that the polymorphism in MMP8 is associated with a decreased lung cancer risk, which can be used as a prognostic marker in lung cancer.

Aseptic Loosening of Total Hip Arthroplasty: Preliminary Genetic Investigation

Femoral and acetabular loosening can be attributed different factors, but the causes and mechanism of early failure are still obscure. The objective of this study was to investigate the relationship between gene polymorphisms and early implant failure. Fifty-eight patients older than 50 years was recruited for analysis of MMP-1 promoter polymorphisms in early osseointegrated implant failure. The results showed in control group a frequency of 20.97% of 2G allele and 67.74% the genotype 1G/1G whereas, in the test group, a frequency of 83.33% of 2G allele and 66.66% the genotype 2G/2G. These results indicate that the polymorphism in the promoter of the MMP-1 gene could be a risk factor for early implant failure of total hip arthroplasty.

A single‐nucleotide polymorphism in the matrix metalloproteinase‐1 promoter enhances bladder cancer susceptibility

To explore the association between the promoter polymorphism (that influences the transcriptional level) of matrix metalloproteinase-1 (MMP-1, associated with tumour cell invasion and metastasis) and bladder cancer in a Turkish population. The MMP-1 polymorphism was assessed in 102 transitional cell carcinomas of the bladder (50 Ta, 52 T2-4) and in 94 age-, smoking- and gender-matched healthy volunteers. The polymerase chain reaction (PCR) assay was used to determine the MMP-1 genotypes. Genomic DNA used for the assay was extracted from peripheral blood lymphocytes. The frequency of the MMP-1 2G/2G genotype, which results in the highest MMP-1 transcriptional level, was compared to that of the 1G/1G plus 1G/2G genotypes. Of the 102 cases with bladder cancer, 49 (48%) showed the 2G/2G genotype, whereas it was found in 22 of the 94 controls (23%); this difference was statistically significant (P < 0.01; odds ratio 2.79, 95% confidence interval, CI, 1.53-5.60). However, there was no significant association between the 2G/2G genotype and tumour grade and pathological stage. We assessed the interaction between smoking status (former and current smokers, by their median pack years) and 2G/2G genotype; there was a significantly increased risk in heavy smokers (P < 0.001; odds ratio 3.21; 95% CI 1.33-5.60). These results suggest that the MMP-1 promoter polymorphism might be linked to susceptibility for bladder cancer.

Matrix Metalloproteinase-1 and -9 Promoter Polymorphisms and Endometrial Carcinoma Risk in a Japanese Population

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases that degrade all the components of the extracellular matrix (ECM). Several studies have demonstrated association between MMP gene polymorphisms and various cancers. The object of this study was to investigate whether the MMP-1 and MMP-9 gene promoter polymorphisms are associated with endometrial carcinomas in a Japanese population. We compared the allele frequencies and genotype distributions of each single nucleotide polymorphism in the promoter regions of MMP-1 (-1607 1G/2G) and MMP-9 (-1562 C/T) in 107 endometrial carcinoma cases and 213 controls using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. The allele frequencies of MMP-1 -1607 2G and MMP-9 -1562T were 64.0% and 10.7% in the cases and 70.0% and 16.7% in the controls, respectively. No significant differences in the allele frequencies or genotype distributions were found between cases and controls for the MMP-1 -1607 1G/2G polymorphism. However, a small but significant difference in the allele frequency of the MMP-9 -1562T allele was noted between cases and controls (P = .046; odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.01 to 2.73). Stratification by histology revealed a significant difference in the frequency of the MMP-9 -1562T allele between endometrioid carcinoma cases (10.2%) and controls (P = .043; OR = 1.76; 95% CI, 1.02 to 3.03); we did not find a significant difference in the frequency of the MMP-9 -1562T allele between non-endometrioid carcinoma cases (13.2%) and controls. These results suggest that the MMP-9 -1562 C/T polymorphism may be associated with susceptibility to endometrioid carcinoma in the Japanese population.

Genetic polymorphisms in the MMP‐1 and MMP‐3 gene may contribute to chronic periodontitis in a Brazilian population

Matrix metalloproteinase-1 and -3 (MMP-1, MMP-3) represent proteinases that degrade macromolecules of the extracellular matrix. These enzymes play a fundamental role during destruction of periodontal tissues. Genetic polymorphisms were characterized in the promoter region of the MMP-1 and MMP-3 genes. The aim of this study was to investigate the relationship between these genetic variations with chronic periodontitis in a Brazilian population. Non-smoking subjects (n = 114) exhibiting sites > or = 5 mm clinical attachment loss were recruited for study. Control subjects (n = 109) should not exhibit clinical signals of periodontitis. MMP-1 (-1607 1G/2G, -519 A/G) and MMP-3 (-1612 5A/6A) gene promoter polymorphisms were genotyped using PCR-RFLP methods. Analysis of polymorphisms showed no differences in distribution of the -1607 1G/2G and -519 A/G variants in the MMP-1 gene between the healthy and periodontitis group (p > 0.05). However, the distribution of genotype frequencies of the -1612 5A/6A polymorphism in the MMP-3 gene showed that the 5A/5A genotype was significantly more frequent in the periodontitis group (p = 0.008). The same was not observed in the 5A/6A genotype once only one 5A allele is carried. We also observed a trend to increase the frequency of the MMP-1/MMP-3 haplotype (2G/5A) in the periodontitis group (p = 0.08). On the basis of the results, no significant association is found for the MMP-1 polymorphisms with susceptibility of periodontitis, while the MMP-3 gene polymorphism may contribute to periodontal tissue destruction during periodontitis in Brazilian subjects.

Matrix Metalloproteinase-1 and -9 Promoter Polymorphisms Are Not Associated With an Increased Risk of Uterine Leiomyomas in a Japanese Population

Matrix metalloproteinases (MMPs) play an important role in modeling and remodeling the extracellular matrix in leiomyomas. Hence, we investigated whether associations exist between leiomyomas and promoter polymorphisms in the MMP-1 and MMP-9 genes in a Japanese population. We compared the distribution of polymorphisms in the promoter regions of MMP-1 (-1607 1G/2G) and MMP-9 (-1562 C/T) in 267 leiomyoma patients and 184 control patients using polymerase chain reaction-fragment-length polymorphism (PCR-RFLP) analysis. The allele frequencies of the MMP-1 -1607 2G and MMP-9 -1562 T polymorphisms were 74.6% and 18.6% in leiomyoma patients, and 71.3% and 18.6% in control patients, respectively. No significant differences in allele frequencies or genotype distributions were found between leiomyoma and control patients. Moreover, no associations were found between MMP-1 and MMP-9 genotypes and leiomyoma size or a family history of the condition. These findings suggest that MMP-1 and MMP-9 promoter polymorphisms are unlikely to be associated with an increased risk of uterine leiomyomas in Japanese women.

A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the prognosis of patients with ovarian cancer

The enzyme matrix metalloproteinase (MMP)-1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP-1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women. The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data. No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involvement (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient's age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04). Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.

Matrix metalloproteinase-1 and -3 gene promoter polymorphisms in Japanese patients with periodontitis.

Matrix metalloproteinase (MMP)-1 and MMP-3 have important roles in the connective tissue remodelling and destruction processes in periodontitis. MMP-1 1G/2G (-1607) and MMP-3 5A/6A (-1171) polymorphisms have been identified and appear to influence the transcription of the genes. The aim of this study was to investigate whether these gene promoter polymorphisms were associated with the susceptibility to periodontitis. Genomic DNA was obtained from 37 generalised aggressive, 205 slight-to-severe generalised chronic-periodontitis patients and 142 healthy subjects. All subjects were non-smoking Japanese. We genotyped by using TaqMan PCR assay. The statistics were analysed by chi2-test. We found no significant differences in genotype distributions, allele frequencies, carriage rates and haplotype frequencies in the MMP-1 and the MMP-3 gene promoter polymorphisms among all groups. The distributions of MMP-1 and MMP-3 genotypes in our study were different from those of previously reported in Caucasians or Brazilians, but consistent with previously reported in Japanese. Our data did not support the hypothesis that MMP-1 and/or MMP-3 gene promoter polymorphisms influenced the susceptibility to periodontitis in Japanese patients, indicating MMP-1 and MMP-3 expressions were regulated by complex processes such as cytokine network in periodontal disease rather than gene polymorphisms.

Association of matrix metalloproteinase-1 and -3 promoter polymorphisms with clinical subsets of Norwegian primary sclerosing cholangitis patients

Background/Aims Primary sclerosing cholangitis (PSC) is considered an immune mediated liver disease of multifactorial and multigenetic aetiology. Concomitant ulcerative colitis (UC) is seen in many PSC patients, but the pathogenetic link between these disorders is unknown. Due to association with inflammation, fibrosis, and cancer development, the matrix metalloproteinases MMP-1 and MMP-3 are candidate genes for predisposition to both PSC, UC and cholangiocarcinoma. Methods We investigated the association of MMP-1 and MMP-3 promoter polymorphisms in 165 Norwegian PSC patients compared to 118 UC patients and 346 healthy controls. Results There were no differences in MMP-1 and MMP-3 frequencies between PSC patients and UC patients or healthy controls. PSC patients with UC showed an increased frequency of the MMP-3 allele 5A compared to PSC patients without UC (60% vs. 45%; P c=0.01). All patients (100%) with cholangiocarcinoma carried MMP-1 allele 1G, compared to only 72% of PSC patients without cholangiocarcinoma. Conclusions We found no general associations of the MMP-1 and MMP-3 genes to PSC or UC among Norwegian patients, but specific alleles were associated to subsets of PSC patients with UC and cholangiocarcinoma. The results support the theory of genetic heterogeneity among PSC patients.

Association of matrix metalloproteinase-1 and -3 promoter polymorphisms with clinical subsets of Norwegian primary sclerosing cholangitis patients

Background/Aims Primary sclerosing cholangitis (PSC) is considered an immune mediated liver disease of multifactorial and multigenetic aetiology. Concomitant ulcerative colitis (UC) is seen in many PSC patients, but the pathogenetic link between these disorders is unknown. Due to association with inflammation, fibrosis, and cancer development, the matrix metalloproteinases MMP-1 and MMP-3 are candidate genes for predisposition to both PSC, UC and cholangiocarcinoma. Methods We investigated the association of MMP-1 and MMP-3 promoter polymorphisms in 165 Norwegian PSC patients compared to 118 UC patients and 346 healthy controls. Results There were no differences in MMP-1 and MMP-3 frequencies between PSC patients and UC patients or healthy controls. PSC patients with UC showed an increased frequency of the MMP-3 allele 5A compared to PSC patients without UC (60% vs. 45%; Pc=0.01). All patients (100%) with cholangiocarcinoma carried MMP-1 allele 1G, compared to only 72% of PSC patients without cholangiocarcinoma. Conclusions We found no general associations of the MMP-1 and MMP-3 genes to PSC or UC among Norwegian patients, but specific alleles were associated to subsets of PSC patients with UC and cholangiocarcinoma. The results support the theory of genetic heterogeneity among PSC patients.

Association of matrix metalloproteinase (MMP)-1 promoter polymorphism with head and neck squamous cell carcinoma

To explore the relation of the MMP-1 1G/2G and MMP-3 5A/6A promoter polymorphisms with head and neck squamous cell carcinoma (HNSCC), DNA specimens extracted from peripheral blood cells of HNSCC patients and healthy controls were genotyped. The frequency of the MMP-1 2G/2G genotype was significantly higher in HNSCC patients ( n=140) than in age- and sex-matched controls ( n=223) ( P=0.042; OR, 1.56). In the MMP-3 polymorphism, there was no significant difference in the genotype distribution between patients and controls. These data suggest that the MMP-1 promoter polymorphism may be associated with HNSCC.

MMP-1 promoter polymorphism: association with chronic periodontitis severity in a Brazilian population.

A single nucleotide polymorphism was described in the promoter region of the human MMP-1 gene, and this polymorphism has been associated with risk of cancer metastasis and inflammatory diseases. In this paper, we studied the possible relationship between the MMP-1 promoter polymorphism and the severity of chronic periodontitis. Genomic DNA from oral mucosa was amplified by PCR and analyzed by restriction endonuclease. The alleles were separated by polyacrylamide gel electrophoresis. The significance of the differences in observed frequencies of polymorphism in moderate and severe disease and healthy groups was assessed by Chi-squared test. In the healthy group, the 2G allele was observed with a frequency of 48.7%, while in severely diseased patients the 2G allele was seen in 69.2% (P = 0.0344). The genotype 2G/2G was found in 46.15% of the group with severe periodontitis, and 24.3% and 25.0%, respectively, of the healthy and moderate groups (P = 0.0647). These results show that a polymorphism in the promoter region of MMP-1 gene is associated with the severe chronic periodontitis phenotype in non-smokers.

Association of functional polymorphisms of matrix metalloproteinase (MMP)‐1 and MMP‐3 genes with colorectal cancer

Matrix metalloproteinase (MMP)-1 and MMP-3 genes are associated with tumor cell invasion and metastasis with their promoter polymorphisms influencing the level of transcription. Our study explored the association of these polymorphisms with colorectal cancer risk in a Japanese population. DNA was extracted from peripheral blood of 101 patients with colorectal cancer and 127 age- and gender-matched healthy volunteers. Genotyping was carried out using PCR-RFLP and direct sequencing. In the MMP-1 gene polymorphism, the frequency of the 2G/2G genotype that is associated with higher enzyme activity was significantly increased in colorectal cancer patients when compared to controls (p = 0.0067; OR = 2.077; 95% CI = 1.221-3.534). With regard to the MMP-3 polymorphism, unexpectedly, the frequency of the 6A/6A genotype causing lower enzyme activity was significantly increased in patients (p = 0.0129; OR = 2.110; 95% CI = 1.165-3.822). Because the loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium between the 2 loci using expectation-maximization algorithm. We found that the 2 loci were in linkage disequilibrium and that 2G-6A haplotype was significantly increased in patients compared to controls (p = 0.0010; OR = 1.949; 95% CI = 1.305-2.911). Our present data suggest that the MMP-1 and MMP-3 promoter polymorphisms may be associated with a colorectal cancer susceptibility in Japanese.