Mol. Hum. Reprod. Advance Access originally published online on May 6, 2005
Molecular Human Reproduction 2005 11(6):423-427; doi:10.1093/molehr/gah177
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The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China
1Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital and 2Department of Molecular Biology, Hebei Cancer Institute, Shijiazhuang, China
3 To whom correspondence should be addressed at: Hebei Cancer Institute, Hebei Medical University, Jiankanglu 12, Shijiazhuang 050011, China. Email: lykx1962{at}yahoo.com.cn
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Abstract |
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Matrix metalloproteinases (MMPs) may contribute to the development of endometriosis. Genetic variations in several MMP promoters may influence the transcription and expression of MMPs. The purpose of the present study was to assess how gene polymorphisms in the MMP1 and MMP3 promoters affect the risk of development of endometriosis. We genotyped 100 women with endometriosis and 150 control subjects in North China. There was a significant difference in frequency of the MMP1 genotype between cases and controls (P=0.03). The 2G homozygote in endometriosis and controls was significantly different (P=0.02). The frequency of the 2G allele among affected women (79%) was significantly higher than among the healthy controls (66.9%; P=0.003). However, the overall genotype and allelotype distribution of the MMP3 single nucleotide polymorphism (SNP) in patients was not different from that of controls (P
0.05). MMP1 and MMP3 polymorphisms were in linkage disequilibrium in cases and controls (D'=0.47; P=0.00). The haplotype frequency distribution derived from these two polymorphisms was significantly different between cases and controls (P=0.00). The haplotype analysis suggested an implication of both MMP1 and MMP3 polymorphisms in the susceptibility to endometriosis. We conclude that the MMP1 promoter SNP and MMP 2G/6A haplotype may modify susceptibility to endometriosis, but that the MMP3 promoter SNP is unlikely to be associated with endometriosis in the population of North China. Key words: endometriosis/matrix metalloproteinase/single nucleotide polymorphism/susceptibility
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Introduction |
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Endometriosis is an invasive but benign gynaecological disease characterized histologically by the presence of endometrial glands and stroma outside the uterine cavity. It is estimated that 10–20% of women of reproductive age (Goldman and Cramer, 1990
) are affected by endometriosis. The aetiology and pathogenesis of endometriosis are still unclear. Clinical evidence shows that endometriosis has a genetic basis (Kennedy, 1997) as suggested by the familial tendency (Kennedy et al., 1995). In recent years, research has focused on the identification of genes that influence susceptibility to endometriosis. A number of candidate genes have been studied (Zondervan et al., 2001). For example, associations have been reported between endometriosis and N-acetyl transferase 2 polymorphisms (Nakago et al., 2001) and glutathione S-transferase M1 gene polymorphism (Baranova et al., 1997). However, allelic polymorphisms of these genes can only partly explain the development of endometriosis, because multiple genes are involved.
Matrix metalloproteinase-1 (MMP1) and matrix metalloproteinase-3 (MMP3) can play a role in the development of endometriosis (Kokorine et al., 1997; Cox et al., 2001). MMP1 is an interstitial collagenase. Its expression by human endometrium is restricted to the perimenstrual period and to the stromal cells of the functional layer of the endometrium where it plays an essential role in the early stages of menstruation (Kokorine et al., 1996). This study showed that MMP1 is involved in tissue remodelling and bleeding, and possibly in the secondary shedding and reimplantation of endometriotic lesions (Kokorine et al., 1997). MMP3 (stromelysin-1) is known to lyse basal membrane collagen and to induce synthesis of other matrix metalloproteinases (MMPs) such as MMP1 and MMP9 (Brinckerhoff et al., 2000; Van Themsche et al., 2004). The MMP3 of ectopic endometrium may participate in the process of invasion and tissue remodelling that is hypothesized to occur in the pathogenesis of endometriosis (Cox et al., 2001).
The MMP1 and MMP3 genes are located near each other on chromosome 11 and the level of expression of these genes can be influenced by single nucleotide polymorphisms (SNPs) in the promoter region of their respective genes (Spurr et al., 1988; Ye et al., 1996; Rutter et al., 1998). The promoter region of MMP1 contains a guanine insertion/deletion polymorphism (1G/2G polymorphism) at position –1607. This 2G allele results in increased transcriptional activity (Rutter et al., 1998) because the guanine insertion creates a binding site for a member of the Ets transcription factor family (Tower et al., 2002). The 2G allele may contribute to increased invasiveness of endometrial carcinomas (Nishioka et al., 2000), to the development of ovarian cancer (Yasunobu et al., 1999) and lung cancer (Zhu et al., 2001). The promoter region of MMP3 is characterized by a 5A/6A promoter polymorphism at position –1171 in which one allele has six adenosines (6A) and the second has five adenosines (5A) (Ye et al., 1995). The 6A allele has a lower promoter activity than the 5A allele in vitro (Ye et al., 1996). The MMP3 SNP has been reported to be associated with both susceptibility to and the invasiveness of breast cancer (Ghilardi et al., 2002).
In the present study, we conducted a hospital-based case control study to explore the role of the MMP1 and MMP3 promoter SNPs in the development of endometriosis in a population of North China. As both MMP genes are located on the same chromosome, linkage disequilibrium was also investigated.
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Materials and methods |
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Study participants
Blood was obtained from the following two groups and DNA was extracted for genotyping: (i) healthy female blood donors aged 25–50 years (n=150) and (ii) endometriosis inpatients (cases) in the Fourth Affiliated Hospital, Hebei Medical University between 2001 and 2003 (n=100). The endometriosis patients with clinically, endoscopically and histologically confirmed diagnoses were studied. All the endometriosis patients who had not taken hormone treatment were at stage III–IV. The patients were staged according to the revised American Fertility Society classification (AFS, 1985). General patient information was recorded in detail on their respective medical notes.
The control group consisted of women of reproductive age without any malignant disease as confirmed by surgical exploration during voluntary abortion, caesarean section or pathologically confirmed after hysterectomy was performed for benign menstrual disorders. General information about the healthy controls was extracted from their medical notes. The study was approved by the Ethics Committee of the Hebei Obstetrics and Gynecology Institute and informed consent was obtained from all recruited subjects.
DNA extraction
Venous blood (5 ml) was drawn from each subject into Vacutainer tubes containing EDTA and stored at 4°C. Genomic DNA was extracted within one week after sampling using proteinase K (Merck, Darmstadt, Germany) digestion followed by a salting out procedure according to the method of Miller et al. (1988).
MMP1 promoter SNP genotyping
The MMP1 genotyping was determined by PCR–restriction fragment length polymorphism (PCR–RFLP) assay. The PCR primers used for amplifying the MMP1 polymorphism were: forward 5'-TGACTTTTAAAACATAGTCTATGTTCA-3' and reverse 5'-TCTTGGATTGATTTGAGATAAGTCATAGC-3' (Zhu et al., 2001). The reverse primer was specially designed to introduce a recognition site of restriction enzyme AluI (AGCT) by replacing a T with a G at the second position close to the 3'-end of the primer. The 1G allele has this recognition site, whereas the 2G allele destroys the recognition site by inserting a guanine. PCR was performed in a 20 µl volume containing 100 ng of DNA template, 2 µl of 10x PCR buffer, 1.5 mmol of MgCl2, 1 U of Taq DNA polymerase (BioDev-Tech., Beijing, China), 200 µmol of dNTPs and 200 nmol of sense and antisense primer. The PCR cycling conditions were 5 min at 94°C followed by 35 cycles of 30 s at 94°C, 30 s at 58°C and 30 s at 72°C, and with a final step at 72°C for 5 min to allow for the complete extension of all PCR fragments. An 8 µl aliquot of PCR product was digested overnight at 37°C in a 10 µl reaction containing 10 U of AluI (TakaRa Biotechnology Co. Ltd, Dalian, China) and 1x reaction buffer. After overnight digestion, the products were resolved and separated on a 4% agarose gel stained with ethidium bromide. After electrophoresis, homozygous 2G alleles were represented by a DNA band with size at 269 bp, homozygous 1G alleles were represented by DNA bands with sizes at 241 and 28 bp, whereas heterozygotes displayed a combination of both alleles (269, 241 and 28 bp) (Figure 1). For a negative control, each PCR reaction used distilled water instead of DNA in the reaction system.
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MMP3 promoter SNP genotyping
The MMP3 genotype was determined by the PCR–RFLP assay. The PCR primers used for amplifying the MMP3 polymorphism were: 5'-GGTTCTCCATTCCTTTGATGGGGGGAAAgA -3' (forward primer mutated from A to G at the second nucleotide close to the 3'-end to create a Tth111I recognition site in the case of a 5A allele) and 5'-CTTCCTGGAATTCACATCACTGCCACCACT-3' (reverse primer) (Gnasso et al., 2000
). PCR was performed in a 20 µl volume containing 100 ng of DNA template, 2 µl of 10x PCR buffer, 1.5 mmol of MgCl2, 1 U of Taq DNA polymerase (BioDev-Tech., Beijing, China), 200 µmol of dNTPs and 200 nmol of sense and antisense primer. The PCR cycling conditions were 5 min at 94°C followed by 35 cycles of 30 s at 94°C, 30 s at 65°C and 30 s at 72°C, and with a final step at 72°C for 5 min to allow for the complete extension of all PCR fragments. An 8 µl aliquot of PCR product was digested at 65°C for 4 h in a 10 µl reaction containing 10 U of Tth111I (TakaRa Biotechnology Co. Ltd, Dalian, China) and 1x reaction buffer. After digestion, the products were separated on a 3% agarose gel stained with ethidium bromide. After electrophoresis, the 5A alleles were represented by DNA bands with sizes at 97 and 32 bp, the 6A alleles were represented by a DNA band with size at 129 bp, whereas the heterozygotes displayed a combination of both alleles (129, 97 and 32 bp) (Figure 2). For a negative control, each PCR reaction used distilled water instead of DNA in the reaction system.
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Statistical analysis
Statistical analysis was performed using SPSS10.0 software package (SPSS Company, Chicago, IL, USA). Hardy–Weinberg analysis was performed to compare the observed and expected genotype frequencies using the chi-square test. Comparison of the MMP1 and MMP3 genotype distribution in the study groups was performed by means of two-sided contingency tables using the chi-square test. The MMP1 and MMP3 haplotype frequencies and linkage disequilibrum coefficient were estimated using the EH linkage software (version 1.2, Rockefeller University, New York). The odds ratio (OR) and 95% confidence interval (CI) were calculated using an unconditional logistic regression model and adjusted by age and sex accordingly. A probability level of 5% was considered significant.
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Results |
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MMP1 promoter SNP with susceptibility to endometriosis
The distribution of the MMP1 genotypes in healthy controls and endometriosis patients did not significantly deviate from that expected for a Hardy–Weinberg equilibrium (
2=4.43 and 0.814, P=0.109 and 0.666). The frequency of the 2G allele among endometriosis patients (79%) was significantly higher than the healthy controls (66.9%) (2=8.53, P=0.003). The frequencies of the 2G/2G, 2G/1G and 1G/1G genotypes were significantly different from those in healthy controls (2=6.99, P=0.03; Table I). The frequency of the 2G homozygotes in endometriosis was higher than in the controls (2=5.26, P=0.02). Compared with the 1G/1G genotype, both the 2G/2G and in combination with the 1G/2G genotype significantly modified the risk of developing endometriosis. The adjusted ORs were 3.65 (95%CI=1.41–9.43) and 3.25 (95%CI=1.29–8.23), respectively (Table II).
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MMP3 promoter SNP with susceptibility to endometriosis
The distribution of the MMP3 genotypes in healthy controls and endometriosis patients were consistent with the Hardy–Weinberg equilibrium (
2=0.58 and 0.42, P=0.749 and 0.811). The frequencies of the 5A and 6A allele among endometriosis patients and healthy controls were 14%, 86% and 20.3%, 79.7%, respectively. No significant difference in the MMP3 allele distribution was shown between the case and controls (2=3.29, P=0.07; Table I). There was no significant difference in genotype distribution between endometriosis patients and healthy women (2=3.58, P=0.167). Compared with the 6A/6A genotype, neither the 5A/5A nor combination with the 5A/6A genotype significantly modified the risk of developing endometriosis. The adjusted OR was 2.51 (95%CI=0.25–25) and 1.63 (95%CI=0.92–2.98), respectively (Table II).
In healthy subjects, the frequencies of MMP1 2G/2G, 2G/1G and 1G/1G genotypes were 50.7, 32.7 and 16.7% and the frequencies of MMP3 6A/6A, 6A/5A and 5A/5A genotypes were 62, 35.3 and 2.7%, respectively. Haplotype analysis showed that 2G/6A was the commonest haplotype in healthy controls (57.7%), followed by the 1G/6A (22.3%), 1G/5A (11%) and 2G/5A (9%) haplotypes (Table III). In addition, the MMP1 and MMP3 SNPs were imperfect in linkage disequilibrium (D'=0.47, 2=61.94, P=0.00) in the study population, i.e. the MMP1 2G allele tended to be linked to the MMP3 6A allele.
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Furthermore, the combined effects of the MMP1 and MMP3 SNP on the risk of endometriosis was analysed by using the EH programme. The overall distribution of the MMP haplotypes in EMs patients and healthy controls showed significant difference (
2=23.38, P=0.00). Compared with the 1G/6A haplotype, the 2G/6A haplotype significantly modified the risk of developing endometriosis, the adjusted OR was 3.12 (95% CI=1.83–5.33), but the risk for the 1G/5A and 1G/6A haplotypes were not significant (Table III). |
Discussion |
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Recently, MMP have been reported to be associated with endometriosis by playing an important role in its development, but most studies are largely focused on the association of MMPs expression with endometriosis. To the best of our knowledge, the relationship between the MMPs SNP and risk of the development of endometriosis has not been documented. This is the first study on the relationship between the MMP1 and MMP3 SNPs and women's susceptibility to endometriosis.
Our data suggest an association of the MMP1 SNP with the development of endometriosis. There is a significant difference in the distribution of the MMP1 genotype between the patients and the healthy controls. The frequency of the 2G allele in endometriosis was significantly higher in patients than in controls. Compared with the 1G homozygotes, neither the 2G homozygotes nor the 2G heterozygotes had a significantly modified risk of developing endometriosis, the adjusted OR being 3.65 and 3.25, respectively. The 2G allele of MMP1 is associated with a higher promoter activity in vitro (Rutter et al., 1998; Tower et al., 2002), which leads to the production of increased amounts of the MMP1 protein (Fujimoto et al., 2002). It has also been reported that ovarian tumour and endometrial cancer tissues from patients carrying the 2G allele contain higher levels of MMP1 transcripts compared with those from patients not carrying this allele (Kanamori et al., 1999; Nishioka et al., 2000). In addition, the proportion of 2G allele was significantly higher in patients than the control subjects, suggesting that individuals carrying the 2G allele are genetically predisposed to the development of cancer (Nishioka et al., 2000; Zhu et al., 2001). In our study, we found that heterozygosity for the 2G allele, not only homozygosity, seemed to increase susceptibility to endometriosis.
Our study failed to detect any association of the MMP3 polymorphism with the susceptibility to endometriosis. MMP3 genotype frequency did not differ between patients and the control. The 6A allele showed a high, but not significant, correlation (P=0.07) with endometriosis. MMP3 is a key member of the MMP family, with broad substrate specificity. It can degrade types II, IV and IX collagen, proteoglycans, laminin, fibronectin, gelatins and elastin. In addition, MMP3 can also activate other MMPs, such as collagenase, matrilysin and gelatinase B, rendering MMP3 crucial to the connective tissue remodelling process (Matrisian, 1990; Birkedal-Hansen et al., 1993). A single adenine insertion/deletion polymorphism (5A/6A) at the –1171 position of the MMP3 promoter region elevates the transcriptional level and local expression of MMP3 (Ye et al., 1995, 1996). The influence of this single nucleotide polymorphism in the MMP3 promoter on the development of disease was not consistent (Ghilardi et al., 2002; Humphries et al., 2002). A few studies of the MMP3 expression and endometriosis have been performed suggesting that ectopic endometrial tissue has high levels of MMP3 expression (Koks et al., 2000). This may play a role in the process of invasion and remodelling of endometrial tissue (Kathryn et al., 2001). In vitro assays of promoter activity revealed that the 5A allele had a 2-fold higher promoter activity than the 6A allele (Ye et al., 1996). It is possible that endometriosis patients should have relatively high rates of the 5A allele. However, this was not observed in our study. On the contrary, this study found a significant association between the 2G/6A haplotype and susceptibility to endometriosis. Compared with the 1G/6A haplotype, the 2G/6A haplotype significantly modified the risk of developing endometriosis, the adjusted OR being 3.12.
Our study shows significant linkage disequilibrium between the 1G/2G MMP1 and the 5A/6A MMP3 polymorphism, i.e. the MMP1 2G allele tended to be linked to the MMP3 6A allele. This phenomenon can be attributed to the proximity of the MMP1 and MMP3 genes. Both genes have been mapped to the long arm of chromosome 11 in the region 11q22.3 (Spurr et al., 1988), with a distance between them of 37.64 kb. The biological function of this phenomenon is still unknown, although the phenomenon had been confirmed in other studies (Hinoda et al., 2002; Zinzindohoue et al., 2004).
In conclusion, our results confirm the role of the 2G allele in the pathogenesis of endometriosis. Although no uniform results were observed for MMP3 gene promoter polymorphism, the presence of 2G/6A haplotype in the same subject shows a strong association with endometriosis.
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Acknowledgements |
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We would like to thank Dr Charles Hocart, Australian National University, for critical reading of the manuscript.
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Submitted on December 11, 2004; resubmitted on April 8, 2005; accepted on April 10, 2005.
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