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A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese

Nature Genetics volume 42, pages 707–710 (2010)Cite this article

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Abstract

Although the pathogenesis of endometriosis is not well understood, genetic factors have been considered to have critical roles in its etiology. Through a genome-wide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, we identified a significant association of endometriosis with rs10965235 (P = 5.57 × 10−12, odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15, p16 and p14. A SNP, rs16826658, in the LD block including WNT4 on chromosome 1p36, which is considered to play an important role in the development of the female genital tract, revealed a possible association with endometriosis (P = 1.66 × 10−6, odds ratio = 1.20). Our findings suggest that these regions are new susceptibility loci for endometriosis.

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Figure 1: P value plots, genomic structures and LD maps of chromosome 9p21.

References

  1. Mori, H., Taketani, Y., Uemura, T., Miyake, A. & Tango, T. Rates of endometriosis recurrence and pregnancy 1 year after treatment with intranasal buserelin acetate (Suprecur) (a prospective study). J. Obstet. Gynaecol. Res. 25, 153–164 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Stern, R.C. et al. Malignancy in endometriosis: frequency and comparison of ovarian and extraovarian types. Int. J. Gynecol. Pathol. 20, 133–139 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Bulun, S.E. Endometriosis. N. Engl. J. Med. 360, 268–279 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Giudice, L.C. & Kao, L.C. Endometriosis. Lancet 364, 1789–1799 (2004).

    Article  PubMed  Google Scholar 

  5. Sampson, J.A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110.43 (1927).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Matalliotakis, I.M. et al. Familial aggregation of endometriosis in the Yale Series. Arch. Gynecol. Obstet. 278, 507–511 (2008).

    Article  PubMed  Google Scholar 

  7. Seracchioli, R. et al. Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptom-recurrence after conservative surgery for endometriosis. Hum. Reprod. 24, 2729–2735 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Juo, S.H. et al. CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Hum. Reprod. 21, 1498–1502 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Vietri, M.T. et al. CYP17 and CYP19 gene polymorphisms in women affected with endometriosis. Fertil. Steril. 92, 1532–1535 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Sato, H. et al. Intron 1 and exon 1 alpha estrogen receptor gene polymorphisms in women with endometriosis. Fertil. Steril. 90, 2086–2090 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Shan, K. et al. The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China. Mol. Hum. Reprod. 11, 423–427 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Han, Y.J. et al. Haplotype analysis of the matrix metalloproteinase-9 gene associated with advanced-stage endometriosis. Fertil. Steril. 91, 2324–2330 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Jarinova, O. et al. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler. Thromb. Vasc. Biol. 29, 1671–1677 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Liu, Y. et al. INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosis. PLoS One 4, e5027 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pasmant, E. et al. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 67, 3963–3969 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Kool, J. et al. Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes. Cancer Res. 70, 520–531 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Okuda, T. et al. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases. Genomics 29, 623–630 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Nakashima, R. et al. Alteration of p16 and p15 genes in human uterine tumours. Br. J. Cancer 80, 458–467 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yanokura, M. et al. Hypermethylation in the p16 promoter region in the carcinogenesis of endometrial cancer in Japanese patients. Anticancer Res. 26, 851–856 (2006).

    CAS  PubMed  Google Scholar 

  20. Ignatov, A. et al. P16 alterations increase the metastatic potential of endometrial carcinoma. Gynecol. Oncol. 111, 365–371 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Martini, M. et al. Possible involvement of hMLH1, p16(INK4a) and PTEN in the malignant transformation of endometriosis. Int. J. Cancer 102, 398–406 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Guida, M. et al. Aberrant DNA hypermethylation of hMLH-1 and CDKN2A/p16 genes in benign, premalignant and malignant endometrial lesions. Eur. J. Gynaecol. Oncol. 30, 267–270 (2009).

    CAS  PubMed  Google Scholar 

  23. Goumenou, A.G., Arvanitis, D.A., Matalliotakis, I.M., Koumantakis, E.E. & Spandidos, D.A. Loss of heterozygosity in adenomyosis on hMSH2, hMLH1, p16Ink4 and GALT loci. Int. J. Mol. Med. 6, 667–671 (2000).

    CAS  PubMed  Google Scholar 

  24. Samani, N.J. et al. Genome-wide association analysis of coronary artery disease. N. Engl. J. Med. 357, 443–453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shen, G.Q. et al. Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population. J. Hum. Genet. 53, 144–150 (2008).

    Article  PubMed  Google Scholar 

  26. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Silander, K. et al. Worldwide patterns of haplotype diversity at 9p21.3, a locus associated with type 2 diabetes and coronary heart disease. Genome Med. 1, 51 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Horikawa, Y. et al. Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan. J. Clin. Endocrinol. Metab. 93, 3136–3141 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Helgadottir, A. et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat. Genet. 40, 217–224 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Yasuno, K. et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat. Genet. 42, 420–425 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bishop, D.T. et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920–925 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stacey, S.N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909–914 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Falchi, M. et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 41, 915–919 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cunnington, M.S., Santibanez Koref, M., Mayosi, B.M., Burn, J. & Keavney, B. Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression. PLoS Genet. 6, e1000899 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Shen, G.Q. et al. Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 28, 360–365 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Omori, S. et al. Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes 57, 791–795 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Gaetje, R. et al. Endometriosis may be generated by mimicking the ontogenetic development of the female genital tract. Fertil. Steril. 87, 651–656 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Vinatier, D., Orazi, G., Cosson, M. & Dufour, P. Theories of endometriosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 96, 21–34 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Vainio, S., Heikkila, M., Kispert, A., Chin, N. & McMahon, A.P. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Parr, B.A. & McMahon, A.P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Stark, K., Vainio, S., Vassileva, G. & McMahon, A.P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Babu, K.A. et al. N-acetyl transferase 2 polymorphism and advanced stages of endometriosis in South Indian women. Reprod. Biomed. Online 9, 533–540 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Nakamura, Y. The BioBank Japan Project. Clin. Adv. Hematol. Oncol. 5, 696–697 (2007).

    PubMed  Google Scholar 

  45. Ohnishi, Y. et al. A high-throughput SNP typing system for genome-wide association studies. J. Hum. Genet. 46, 471–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We also thank the technical staff of the Laboratory for Genotyping Development in RIKEN, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo and Department of Obstetrics and Gynecology, Keio University, School of Medicine. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Satoko Uno, Hitoshi Zembutsu & Yusuke Nakamura

  2. First Department of Surgery, Sapporo Medical University, School of Medicine, Sapporo, Japan

    Satoko Uno & Koichi Hirata

  3. Department of Obstetrics and Gynecology, Keio University, School of Medicine, Tokyo, Japan

    Akira Hirasawa, Tomoko Akahane & Daisuke Aoki

  4. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Atsushi Takahashi & Naoyuki Kamatani

  5. Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Japan

    Michiaki Kubo

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Contributions

Y.N. conceived the study. Y.N., H.Z., S.U., K.H. and M.K. designed the study. S.U., T.A. and M.K. performed genotyping. S.U., A.T., N.K. and M.K. performed the data analyses. Y.N., H.Z., and M.K. managed DNA samples belonging to BioBank Japan. A.H. and D.A. managed DNA samples belonging to Keio University. S.U. summarized the results. S.U., H.Z. and Y.N. wrote the manuscript. Y.N. obtained funding for the study.

Corresponding author

Correspondence to Yusuke Nakamura.

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Uno, S., Zembutsu, H., Hirasawa, A. et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 42, 707–710 (2010). https://doi.org/10.1038/ng.612

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