A microRNA-520 mirSNP at the MMP2 gene influences susceptibility to endometriosis in Chinese women

The MMP2 gene has been implicated in the pathogenesis of endometriosis. We investigated the role and function of single-nucleotide polymorphisms (SNP) of MMP2 in relation to endometriosis. First a case–control study was conducted and 17 SNPs were examined in 211 patients and 344 controls. Regression analysis was used to evaluate the genetic effect. We used reporter assay to validate the functional consequences of the significant SNP. Two SNPs (rs243832 and rs7201) had P-values <0.05 and they are in strong linkage disequilibrium (D′=0.96 and r2=0.47). Further analysis showed that rs7201 but not rs246832 was an independent risk factor and the risk C allele of rs7201 had an odds ratio (OR) of 1.88 (P=0.004). SNP rs7201 is located at the 3′-untranslated region and is predicted to be within the microRNA-520g binding site. The reporter assay for rs7201 showed that the risk C allele had a higher expression level than the A allele (P=0.027). Using microRNA-520g mimic and inhibitor, the results indicated that the A allele but not the risk C allele can be regulated by microRNA-520g. The C allele of SNP rs7201 increases a risk for endometriosis because of out of regulation by microRNA-520g. Similar content being viewed by others Log in or create a free account to read this content Gain free access to this article, as well as selected content from this journal and more on nature.com or

Hadfield, R. M., Mardon, H. J., Barlow, D. H. & Kennedy, S. H. Endometriosis in monozygotic twins. Fertil. Steril. 68, 941–942 (1997). Simpson, J. L. & Bischoff, F. Z. Heritability and molecular genetic studies of endometriosis. Ann. NY Acad. Sci. 955, 239–251 (2002). Tempfer, C. B., Simoni, M., Destenaves, B. & Fauser, B. C. Functional genetic polymorphisms and female reproductive disorders: part II—endometriosis. Hum. Reprod. Update 15, 97–118 (2009). Giudice, L. C. & Kao, L. C. Endometriosis. Lancet 364, 1789–1799 (2004). Curry, T. E. & Osteen, K. G. The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr. Rev. 24, 428–465 (2003). Chung, H. W., Lee, J. Y., Moon, H. S., Hur, S. E., Park, M. H., Wen, Y. et al. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil. Steril. 78, 787–795 (2002). Rawdanowicz, T. J., Hampton, A. L., Nagase, H., Woolley, D. E. & Salamonsen, L. A. Matrix metalloproteinase production by cultured human endometrial stromal cells: identification of interstitial collagenase, gelatinase-A, gelatinase-B, and stromelysin-1 and their differential regulation by interleukin-1 alpha and tumor necrosis factor-alpha. J. Clin. Endocrinol. Metab. 79, 530–536 (1994). Huang, H. F., Hong, L. H., Tan, Y. & Sheng, J. Z. Matrix metalloproteinase 2 is associated with changes in steroid hormones in the sera and peritoneal fluid of patients with endometriosis. Fertil. Steril. 81, 1235–1239 (2004). Inagaki, N., Ung, L., Otani, T., Wilkinson, D. & Lopata, A. Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp. Eur. J. Obstet. Gynecol. Reprod. Biol. 111, 197–203 (2003). Uzan, C., Cortez, A., Dufournet, C., Fauvet, R., Siffroi, J. P. & Darai, E. Eutopic endometrium and peritoneal, ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, -3 and -11, and of tissue inhibitor metalloproteinases-1 and -2. Virchows Arch. 445, 603–609 (2004). Juo, S. H., Wang, T. N., Lee, J. N., Wu, M. T., Long, C. Y. & Tsai, E. M. CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Hum. Reprod. 21, 1498–1502 (2006). Tsai, H. T., Wu, C. H., Lai, H. L., Li, R. N., Tung, Y. C., Chuang, H. Y. et al. Association between quantitative high-risk human papillomavirus DNA load and cervical intraepithelial neoplasm risk. Cancer Epidemiol. Biomarkers Prev. 14, 1–6 (2005). Wu, M. T., Lee, L. H., Ho, C. K., Liu, C. L., Wu, T. N., Wu, S. C. et al. Lifetime exposure to environmental tobacco smoke and cervical intraepithelial neoplasms among nonsmoking Taiwanese women. Arch. Environ. Health 58, 353–359 (2003). Juo, S. H., Wu, R., Lin, C. S., Wu, M. T., Lee, J. N. & Tsai, E. M. A functional promoter polymorphism in interleukin-10 gene influences susceptibility to endometriosis. Fertil. Steril. 92, 1228–1233 (2009). Price, S. J., Greaves, D. R. & Watkins, H. Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J. Biol. Chem. 276, 7549–7558 (2001). Wang, L. F., Chien, C. Y., Kuo, W. R., Tai, C. F. & Juo, S. H. Matrix metalloproteinase-2 gene polymorphisms in nasal polyps. Arch. Otolaryngol. Head Neck Surg. 134, 852–856 (2008). Tzeng, J. Y., Wang, C. H., Kao, J. T. & Hsiao, C. K. Regression-based association analysis with clustered haplotypes through use of genotypes. Am. J. Hum. Genet. 78, 231–242 (2006). Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K. et al. Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis. Gynecol. Endocrinol. 16, 391–402 (2002). Lin, S. C., Lo, S. S., Liu, C. J., Chung, M. Y., Huang, J. W. & Chang, K. W. Functional genotype in matrix metalloproteinases-2 promoter is a risk factor for oral carcinogenesis. J. Oral Pathol. Med. 33, 405–409 (2004). Ye, S. Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome. Cardiovasc. Res. 69, 636–645 (2006). Saare, M., Lamp, M., Kaart, T., Karro, H., Kadastik, U., Metspalu, A. et al. Polymorphisms in MMP-2 and MMP-9 promoter regions are associated with endometriosis. Fertil. Steril. 94, 1560–1563 (2010). Kang, S., Zhao, X. W., Wang, N., Chen, S. C., Zhou, R. M. & Li, Y. Association of polymorphisms of the MMP-2 and TIMP-2 genes with the risk of endometriosis in North Chinese women. Fertil. Steril. 90, 2023–2029 (2008). Zhao, X. W., Li, Y., Wang, N., Zhao, J., Li, X. L., Liu, Q. et al. Study on the association of SNPs of MMP-2 and TIMP-2 genes with the risk of endometriosis and adenomyosis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 25, 280–283 (2008). Fatar, M., Stroick, M., Steffens, M., Senn, E., Reuter, B., Bukow, S. et al. Single-nucleotide polymorphisms of MMP-2 gene in stroke subtypes. Cerebrovasc. Dis. 26, 113–119 (2008). Pan, Q., Luo, X., Toloubeydokhti, T. & Chegini, N. The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol. Hum. Reprod. 13, 797–806 (2007). Ohlsson Teague, E. M., Van der Hoek, K. H., Van der Hoek, M. B., Perry, N., Wagaarachchi, P., Robertson, S. A. et al. MicroRNA-regulated pathways associated with endometriosis. Mol. Endocrinol. 23, 265–275 (2009). Filigheddu, N., Gregnanin, I., Porporato, P. E., Surico, D., Perego, B., Galli, L. et al. Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J. Biomed. Biotechnol. 2010, 369549 (2010). Hawkins, S. M., Creighton, C. J., Han, D. Y., Zariff, A., Anderson, M. L., Gunaratne, P. H. et al. Functional microRNA involved in endometriosis. Mol. Endocrinol. 25, 821–832 (2011). Melichar, V. O., Behr-Roussel, D., Zabel, U., Uttenthal, L. O., Rodrigo, J., Rupin, A. et al. Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis. Proc. Natl Acad. Sci. USA 101, 16671–16676 (2004). Mishra, P. J., Humeniuk, R., Longo-Sorbello, G. S., Banerjee, D. & Bertino, J. R. A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc. Natl Acad. Sci. USA 104, 13513–13518 (2007). Mishra, P. J., Banerjee, D. & Bertino, J. R. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: introducing microRNA pharmacogenomics. Cell Cycle 7, 853–858 (2008). Zhao, Z. Z., Croft, L., Nyholt, D. R., Chapman, B., Treloar, S. A., Hull, M. L. et al. Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis. Mol. Hum. Reprod. 17, 92–103 (2011). Grechukhina, O., Petracco, R., Popkhadze, S., Massasa, E., Paranjape, T., Chan, E. et al. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol. Med. 4, 206–217 (2012). Yu, C., Pan, K., Xing, D., Liang, G., Tan, W., Zhang, L. et al. Correlation between a single nucleotide polymorphism in the matrix metalloproteinase-2 promoter and risk of lung cancer. Cancer Res. 62, 6430–6433 (2002).

This work was supported by the National Science Council, Taiwan (Grant numbers NSC 97-2314-B-037-010-MY3, 99-2628-B-037-009-MY3); Kaohsiung Medical University Research Foundation (KMUER-004) and the Kaohsiung Medical University Hospital Research Fund (Grant Numbers KMUH98-8I11, KMUH 99-9I04 and KMUH 99-9R30). Author information Authors and Affiliations Corresponding author Ethics declarations Competing interests The authors declare no conflict of interest. Additional information Supplementary Information accompanies the paper on Journal of Human Genetics website Supplementary information Rights and permissions About this article Cite this article Tsai, EM., Wang, YS., Lin, CS. et al. A microRNA-520 mirSNP at the MMP2 gene influences susceptibility to endometriosis in Chinese women. J Hum Genet 58, 202–209 (2013). https://doi.org/10.1038/jhg.2013.1 Received: Revised: Accepted: Published: Issue date: DOI: https://doi.org/10.1038/jhg.2013.1

This article is cited by - The effect of MicroRNAs variants on idiopathic recurrent pregnancy loss Journal of Assisted Reproduction and Genetics (2023) - Circulating non-coding RNAs as non-invasive diagnostic markers of endometriosis: a comprehensive meta-analysis Archives of Gynecology and Obstetrics (2019)