| Objective:Although endomembrane invaded different places, endometriosis (EMs) and adenomyosis were considered as the same qualitative disease in the past. It was called internal endometriosis for that adenomyosis invaded myometrium. In recent years, it has been found that compared with EMs, internal endometriosis has significant differences in development, diagnosis and treatment, so it was called adenomyosis in stead. But the two diseases are similar in pathology, besides, in the clinic about 15% adenomyosis patients suffer from EMs at the same time. Present studies have shown that the two diseases are semblable in pathogenesis and susceptibility. As frequently- occurring disease of child-bearing period women, the aetiology and pathogenesis of EMs are still unclear. In 1997, Kennedy pointed out that EMs was an inherited disease which was produced by multiple gene loci interacting with each other and with the environment. Like carcinoma, EMs has the unique characteristics of invasion and metastasis though it is a benign disease, it has hereditary feature which is similar with malignant tumor, furthermore, it is reported that EMs can develop into ovarian cancer (OVCA). Many studies hint that a number of candidate genes of OVCA may be the candidate genes of endometriosis, such as MMPs. EMs, adenomyosis and OVCA are common diseases of gynecology. Present studies have shown that genetic factor plays an important role in the development of the three diseases. So here, we studied the association between the MMP SNP and the susceptibility of EMs, adenomyosis and epithelial ovarian cancer.The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, which are required for the degradation of the proteins composing the extracellular matrix (ECM) and basement membrane (BM). MMP activity is known to play a key role in physiological and pathologic process. Single nucleotide polymorphisms (SNP) in several MMP promoters may influence transcription and expression of MMPs. In recent years, our study group has done a series of researches on the association of some polymorphic sites of MMP family and EMs, adenomyosis, epithelial ovarian cancer, and we have made successful achievement. This study was designed to investigate the association between the MMP-2 promoter -735bpC/T SNP and the susceptibility of endometriosis, adenomyosis and epithelial ovarian cancer in North Chinese Women.Methods : All the patients were recruited from the gynecology and obstetrics department of the Fourth Affiliated Hospital of Hebei Medical University from December 2002 to December 2006, including 271 cases of endometriosis, 162 cases of adenomyosis, and 235 cases of epithelia ovarian cancer. All the patients were histologically confirmed. 245 cases of healthy volunteers who had no clinical evidence of endometriosis, adenomyosis, ovarian cancer or any other malignant tumours were randomly selected from Chinese blood donors as control subjects. All cases and controls were from Chinese Han population. The informed consent was got from all the recruited subjects. The information of healthy controls was obtained by questionnaire. Five milliter of venous blood from each subject was drawn in Vacutainer tubes containing EDTA and stored at 4℃. The genomic DNA was extracted within one week after bleeding by using proteinase K digestion followed by a salting out procedure. Genotypes of the MMP-2 gene were analyzed by PCR-restriction fragment length polymorphism analysis (RFLP). Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Comparison of the MMP-2 genotype, allelotype distribution in patients and healthy controls was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model and adjusted by age.Results:The allelotype frequencies and the genotype frequencies of MMP-2 in the group of healthy controls were found in Hardy-Weinberg equilibrium (P>0.05). 1 Association between the MMP-2 -735bpC/T SNP in promoter region and the susceptibility of endometriosis: The C and T allele frequency of MMP-2 in the endometriosis patients was 76.2% and 23.8%, respectively. Compared with the controls (76.3%, 23.7%), there was no significant difference between the patients and controls (χ~2=0.002,P=0.962). The distribution of the C/C, C/T+T/T genotypes in the case was 58.3%, 41.7%, respectively. Compared with the controls (57.6%, 42.4%, respectively), there was no significant difference between the patients and controls (χ~2=0.360,P=0.863). Compared with the C/T+T/T genotypes, the C/C genotype carriers could not increase the risk of developing endometriosis, the odds ratio was 1.031 (95%CI=0.727~1.463). 2 Association between the MMP-2 -735bpC/T SNP in promoter region and the susceptibility of adenomyosis: The C and T allele frequency of MMP-2 in the adenomyosis patients was 73.8% and 26.2%, respectively. Compared with the controls, there was no significant difference between the patients and controls (χ~2=0.688,P=0.407). The distribution of the C/C, C/T+T/T genotypes in the case was 51.9%, 48.1%, respectively. Compared with the controls, there was no significant difference between the patients and controls (χ~2=1.281,P=0.258). Compared with the C/T+T/T genotypes, the C/C genotype carriers could not increase the risk of developing adenomyosis, the odds ratio was 0.794 (95%CI=0.533~1.184). 3 Association between the MMP-2 -735bpC/T SNP in promoter region and the susceptibility of epithelial ovarian cancer: The C and T allele frequency of MMP-2 in the ovarian cancer patients was 81.0% and 19.0%, respectively. Compared with the controls, there was no significant difference between the patients and controls (χ~2=2.864,P=0.091). The distribution of the C/C, C/T+T/T genotypes in the case was 66.7%, 33.3%, respectively. Compared with the controls, there was significant difference between the patients and controls (χ~2=3.978 , P=0.046). Compared with the C/T+T/T genotypes, the C/C genotype carriers could increase the risk of developing ovarian cancer, the adjusted odds ratio was 1.475 (95%CI=1.006~2.163). 4 The ovarian cancer patients were divided into early stage group and advanced stage group by clinical stage: The distribution of C/C, C/T+T/T genotypes in the advanced stage group was 67.2%, 32.8%, respectively. Compared with the early stage group (65.9%, 34.1%, respectively), there was no significant difference between the two groups (χ~2=0.039 , P=0.844). Compared with the C/T+T/T genotypes, the C/C genotype carriers could not significantly modify the risk of the stage of ovarian cancer, the adjusted odds ratio was 1.060 (95%CI=0.594~1.890). 5 The ovarian cancer patients were divided into four groups by pathological characteristics: The distribution of the C/C, C/T+T/T genotypes of MMP-2 in the serous ovarian cancer group was 67.5%, 32.5%,respectively, which was 77.8%, 22.2% in the mucinous ovarian cancer group, 66.7%, 33.3% in the endometriod cancer group and 53.6%, 46.4% in the undifferentiated cancer group, respectively. Compared with each other, there was no significant difference among the four groups (χ~2=3.685, df=3, P=0.298). But compared the four groups respectively with the controls, the difference of the distribution of C/C, C/T+T/T genotypes between the mucinous ovarian cancer group and the control group was significant (χ~2=4.131, P=0.042). Compared with the C/T+T/T genotypes, the C/C genotype carriers could significantly increase the risk of developing mucinous ovarian cancer, the adjusted odds ratio was 2.582 (95%CI=1.006~6.622) (χ~2 value and P value were according to the table 8).Conclusions: 1 The MMP-2 -735bpC/T SNP may not play a role in the genetic susceptibility to the development of endometriosis and adenomyosis. The MMP-2 C/C genotype did not significantly increase the risk of the development of these two diseases. 2 The MMP-2 -735bpC/T SNP was associated with the susceptibility of epithelial ovarian cancer. Compared with the C/T+T/T genotypes, the C/C genotype could increase the risk of developing ovarian cancer, the adjusted odds ratio was 1.475 (95%CI=1.006~2.163). But there was no association between this polymorphism and the stages of epithelial ovarian cancer. But the polymorphism may be associated with the risk of developing mucinous ovarian cancer, compared with the C/T+T/T genotypes, the C/C genotype carriers could significantly increase the risk of developing mucinous ovarian cancer, the adjusted odds ratio was 2.582 (95%CI=1.006~6.622).
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