Abstract
We set up to analyze polymorphisms in hyaluronan-binding protein 2 (HABP2) gene in healthy fertile women (n = 158) and in women with unexplained infertility (n = 116) and to investigate the potential role of HABP2 in receptive endometrium. Minor rs1157916 A and the major rs2240879 A alleles together with AA genotypes were significantly less frequent in infertile women than in controls. Immunohistochemistry analysis of endometrial HABP2 expression at the time of implantation identified significantly lower HABP2 protein level in infertile women in stroma and vessels than in fertile women. Migration assay analysis of cultured trophoblast and endothelial cells toward HABP2 protein referred to the function of HABP2 in endometrial endothelial cells. In conclusion, our results indicate that polymorphisms in the regulatory region of HABP2 gene could influence gene expression levels in the receptive endometrium and could thereby be one reason for infertility complications in women with unexplained infertility. Additionally, HABP2 protein involvement in endometrial angiogenesis is proposed.
Similar content being viewed by others
References
Choi-Miura NH, Tobe T, Sumiya J, et al. Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. J Biochem. 1996;119(6):1157–1165.
Romisch J, Vermohlen S, Feussner A, Stohr H. The FVII activating protease cleaves single-chain plasminogen activators. Haemostasis. 1999;29(5):292–299.
Etscheid M, Beer N, Dodt J. The hyaluronan-binding protease upregulates ERK1/2 and PI3K/Akt signalling pathways in fibroblasts and stimulates cell proliferation and migration. Cell Signal. 2005;17(12):1486–1494.
Kannemeier C, Al-Fakhri N, Preissner KT, Kanse SM. Factor VII-activating protease (FSAP) inhibits growth factor-mediated cell proliferation and migration of vascular smooth muscle cells. FASEB J. 2004;18(6):728–730.
Mambetsariev N, Mirzapoiazova T, Mambetsariev B, et al. Hyaluronic acid binding protein 2 is a novel regulator of vascular integrity. Arterioscler Thromb Vasc Biol. 2010;30(3):483–490.
Sedding D, Daniel JM, Muhl L, et al. The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation. J Exp Med. 2006;203(13):2801–2807.
Horcajadas JA, Pellicer A, Simon C. Wide genomic analysis of human endometrial receptivity: new times, new opportunities. Hum Reprod Update. 2007;13(1):77–86.
Riesewijk A, Martin J, van Os R, et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol Hum Reprod. 2003;9(5):253–264.
Horcajadas JA, Riesewijk A, Polman J, et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol Hum Reprod. 2005;11(3):195–205.
Horcajadas JA, Sharkey AM, Catalano RD, et al. Effect of an intrauterine device on the gene expression profile of the endometrium. J Clin Endocrinol Metab. 2006;91(8):3199–3207.
Altmäe S, Martinez-Conejero JA, Salumets A, Simon C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod. 2010;16(3):178–187.
Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA, et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2010; July 7 (e-pub ahead of print).
Sumiya J, Asakawa S, Tobe T, et al. Isolation and characterization of the plasma hyaluronan-binding protein (PHBP) gene (HABP2). J Biochem. 1997;122(5):983–990.
Roemisch J, Feussner A, Nerlich C, Stoehr HA, Weimer T. The frequent Marburg I polymorphism impairs the pro-urokinase activating potency of the factor VII activating protease (FSAP). Blood Coagul Fibrinolysis. 2002;13(5):433–441.
Altmäe S, Stavreus-Evers A, Ruiz JR, et al. Variations in folate pathway genes are associated with unexplained female infertility. Fertil Steril. 2010;94(1):130–137.
WHO. In: Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge: Cambridge University Press; 1999.
Helmestam M, Stavreus-Evers A, Olovsson M. Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro. Reprod Toxicol. 2010;Nov;30(3):370–6.
Auerbach R, Auerbach W, Polakowski I. Assays for angiogenesis: a review. Pharmacol Ther. 1991;51(1):1–11.
Westberg L, Melke J, Landen M, et al. Association between a dinucleotide repeat polymorphism of the estrogen receptor alpha gene and personality traits in women. Mol Psychiatry. 2003;8(1):118–122.
Salustri A, Camaioni A, Di Giacomo M, Fulop C, Hascall VC. Hyaluronan and proteoglycans in ovarian follicles. Hum Reprod Update. 1999;5(4):293–301.
Salamonsen LA, Shuster S, Stern R. Distribution of hyaluronan in human endometrium across the menstrual cycle. Implications for implantation and menstruation. Cell Tissue Res. 2001;306(2):335–340.
Hambiliki F, Ljunger E, Karlstrom PO, Stavreus-Evers A. Hyaluronan-enriched transfer medium in cleavage-stage frozen-thawed embryo transfers increases implantation rate without improvement of delivery rate. Fertil Steril. 2010;94(5):1669–1673.
Jeon JW, Song HS, Moon EJ, et al. Anti-angiogenic action of plasma hyaluronan binding protein in human umbilical vein endothelial cells. Int J Oncol. 2006;29(1):209–215.
Lockwood CJ, Krikun G, Papp C, et al. The role of progestationally regulated stromal cell tissue factor and type-1 plasminogen activator inhibitor (PAI-1) in endometrial hemostasis and menstruation. Ann N Y Acad Sci. 1994;734:57–79.
Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online. 2006;12(3):322–327.
Azem F, Many A, Ben Ami I, et al. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod. 2004;19(2):368–370.
Kanse SM, Parahuleva M, Muhl L, Kemkes-Matthes B, Sedding D, Preissner KT. Factor VII-activating protease (FSAP): vascular functions and role in atherosclerosis. Thromb Haemost. 2008;99(2):286–289.
Kao LC, Tulac S, Lobo S, et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology. 2002;143(6):2119–2138.
Osteen KG, Keller NR, Feltus FA, Melner MH. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest. 1999;48(suppl 1):2–13.
Qiao J, Wang L, Li R, Zhang X. Microarray evaluation of endometrial receptivity in Chinese women with polycystic ovary syndrome. Reprod Biomed Online. 2008;17(3):425–435.
Meseguer M, Aplin JD, Caballero-Campo P, et al. Human endometrial mucin MUC1 is up-regulated by progesterone and down-regulated in vitro by the human blastocyst. Biol Reprod. 2001;64(2):590–601.
Staton CA, Reed MW, Brown NJ. A critical analysis of current in vitro and in vivo angiogenesis assays. Int J Exp Pathol. 2009;90(3):195–221.
Li XF, Gregory J, Ahmed A. Immunolocalisation of vascular endothelial growth factor in human endometrium. Growth Factors. 1994;11(4):277–282.
Kawano Y, Matsui N, Kamihigashi S, Narahara H, Miyakawa I. Effects of interferon-gamma on secretion of vascular endothelial growth factor by endometrial stromal cells. Am J Reprod Immunol. 2000;43(1):47–52.
Gleicher N, Barad D. Unexplained infertility: does it really exist? Hum Reprod. 2006;21(8):1951–1955.
Olive DL, Schwartz LB. Endometriosis. N Engl J Med. 1993;328(24):1759–1769.
Author information
Authors and Affiliations
Corresponding author
Additional information
Author’s Note
S.A. was involved in the study design, analysis and interpretation of the data, and drafting of the manuscript. T.K.K. contributed to the study design, analysis and interpretation of the data, and drafting of the manuscript. B.F. was involved in the sample collection and manuscript preparation. A.S-E. was involved in the study design, interpretation of the data and manuscript preparation.
Rights and permissions
About this article
Cite this article
Altmäe, S., Kallak, T.K., Fridén, B. et al. Variation in Hyaluronan-Binding Protein 2 (HABP2) Promoter Region is Associated With Unexplained Female Infertility. Reprod. Sci. 18, 485–492 (2011). https://doi.org/10.1177/1933719110388849
Published:
Issue Date:
DOI: https://doi.org/10.1177/1933719110388849