| Objective:Endometriosis (EMs) and adenomyosis are common gynecological diseases, which are produced by multiple gene loci interacting with each other and with the environment. These two diseases can bring chronic pelvic pain and infertility for women of reproductive age. Although there are various methods to cure them, the result is unsatisfactory, and the reason due to the fact that aetiology and pathogenesis are not completely understood to date. It is the widely accepted that endometriosis is caused by the blood of menstruate countercurrented, while adenomyosis is caused by the decreased capacity of recovery for the muscular wall of the uterus. However, the endometrial cells implant either outside the uterine cavity or within the myometrial wall of the uterus, if implantation of these cells intends to be successful, one of the preconditions must be the degradation and turnover of extracellular matrix (ECM) and basement membrane (BM), in which the matrix metalloproteinases (MMPs) play important roles. MMP-2, of several members in the MMP family, is especially interesting because of its universal expression and multiple functions. The single nucleotide polymorphisms (SNPs) of MMP-2 may modify the transcriptional activity and protein expression of MMP-2, and further contribute to the development of some diseases. In addition, the tissue inhibitor of metalloproteinase-2 (TIMP-2) is the most important endogenous inhibitor of MMP-2. The SNPs of TIMP-2 promoter region may also modify the transcriptional activity and further influence protein expression of TIMP-2 and MMP-2. Thus, SNPs of MMP-2 and TIMP-2 promoter region may influence the risk of developing endometriosis and adenomyosis by modifying protein expression of MMP-2. The aim of the present study was to investigate association of MMP-2 -1306C/T and TIMP-2 -418G/C SNPs with the risk of endometriosis and adenomyosis.Methods:This case-contral study included 478 patients (298 with endometriosis and 180 with adenomyosis) and 324 frequency-matched healthy control women. Five milliliter of venous blood from each subject was drawn in Vacutainer tubes containing EDTA and stored at 4℃, while the information of every subject was obtained. 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 and TIMP-2 genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis was performed using SPSS11.5 software package. A probability level of 5% was considered significant. The age difference of cases and frequency-matched controls was analyzed by the t-test. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in study groups using Chi-square test. Comparison of the MMP-2 genotype and 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. The interactive influences of MMP-2 and TIMP-2 were analysed by likelihood ratio test.Results1 Age, menarche age, gravidity and parity among endometriosis, adenomyosis and control women had no significant difference (P>0.05). The genotype frequencies of MMP-2 and TIMP-2 in healthy controls did not significantly deviate from that expected for a Hardy-Weinberg equilibrium (P>0.05).2 The frequencies of the MMP-2 C and T allele among endometriosis patients and healthy controls were 88.9%, 11.1% and 87.0%, 13.0%, respectively; No significant difference in the MMP-2 allele distribution was shown between endometriosis patients and controls (P>0.05). The distribution of the C/C, C/T and T/T genotypes between endometriosis patients (79.2%, 19.5% and 1.3%, respectively) and controls (75.7%, 22.8% and 1.5%, respectively) also had no significant difference (P>0.05). Compared with the C/T+T/T genotypes, the C/C genotype could not increase the risk of developing endometriosis, the odds ratio was 1.23 (95%CI=0.84~1.79).3 The frequency of the MMP-2 C allele among adenomyosis patients (92.2%) was significantly higher than those in the healthy controls (87.0%) (P<0.05). The frequencies of the C/C, C/T and T/T genotypes among adenomyosis patients (85.0%, 14.4% and 0.6%, respectively) were significantly different from those in healthy controls (75.7%, 22.8% and 1.5%, respectively) (P<0.05). Compared with the C/T+T/T genotypes, the C/C genotype could significantly increase the risk of developing adenomyosis, the odds ratio was 1.83 (95%CI=1.13~2.96).4 The frequencies of the TIMP-2 G and C allele among endometriosis patients and healthy controls were 83.7%, 16.3% and 81.3%, 18.7%, respectively; No significant difference in the TIMP-2 allele distribution was shown between endometriosis patients and controls (P>0.05). The frequency of the C/C homozygote in endometriosis patients (0.7%) was significantly lower than that in the controls (3.7%) (P<0.05). Compared with the G/C+C/C genotypes, the G/G genotype could not increase the risk of developing endometriosis, the odds ratio was 1.08 (95%CI=0.78~1.52). 5 The frequencies of the TIMP-2 G and C allele among adenomyosis patients and healthy controls were 82.2%, 17.8% and 81.3%, 18.7%, respectively; There was no significant difference in the TIMP-2 allele distribution between adenomyosis patients and controls (P>0.05). The frequencies of the TIMP-2 G/G, G/C and C/C genotypes among adenomyosis patients and healthy controls were 67.2%, 30.0%, 2.8% and 66.4%, 29.9%, 3.7%, respectively; No significant difference in the TIMP-2 genotype distribution was shown between adenomyosis patients and controls (P>0.05). Compared with the G/C+C/C genotypes, the G/G genotype could not modify the risk of developing adenomyosis, the odds ratio was 1.04 (95%CI=0.71~1.53).6 The combined effect of MMP-2 -1306C/T and TIMP-2 -418G/C genotypes showed that the -1306C/C&-418G/G was the most frequent combined genotype in the population, which was 51.5% in controls. Compared with the -1306C/T+T/T&-418G/C+C/C genotype, the other combined genotypes could not modify the risk of developing endometriosis; However, the -1306C/C&-418G/G and -1306C/C&-418G/C+C/C genotypes could significantly increase the risk of developing adenomyosis, the odds ratio were 2.37 (95%CI=1.05~5.35) and 2.53 (95%CI=1.08~5.95), respectively.Conclusions1 The MMP-2 -1306C/T SNP might not be related to the risk of endometriosis development. The MMP-2 C/C genotype did not significantly increase the risk of the endometriosis development compared to C/T+T/T genotypes.2 The MMP-2 -1306C/T SNP was associated with the risk of developing adenomyosis. The subjects carrying C/C genotype could be associated with the increased risk of developing adenomyosis.3 Although no association of the TIMP-2 -418G/C SNP with the risk of endometriosis development was showed, the frequency of the C/C homozygote in endometriosis patients was significantly lower than that in the controls, which might be a protective factor for the development of endometriosis.4 There was no significant association between the TIMP-2 -418G/C SNP and the risk of developing adenomyosis.5 The combined effect of MMP-2 and TIMP-2 genotypes indicated that the -1306C/C&-418G/G was the most frequent combined genotype in the population, which was 51.5% in controls. Compared with the -1306C/T+T/T&-418G/C+C/C genotype, although the other genotypes could not modify the risk of developing endometriosis, the -1306C/C&-418G/G and -1306C/C&-418G/C+C/C combined genotypes could significantly increase the risk of developing adenomyosis... |
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