Skip to main content

Advertisement

SpringerLink
Log in

Genetic association studies of endothelial nitric oxide synthase gene polymorphisms in women with unexplained recurrent pregnancy loss: a systematic and meta-analysis

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Recurrent pregnancy loss (RPL) is a multifactorial disorder, both genetic and environmental factors contribute to the development of RPL. Recently, the association between endothelial nitric oxide synthase (eNOS) gene polymorphisms and unexplained recurrent pregnancy loss (URPL) has been reported, and the results were inconsistent. Hence, we performed the meta-analysis to drive a more precise estimation of association between eNOS polymorphisms and URPL. Odds ratio (OR) and its 95 % confidence interval were calculated under co-dominant (AA vs. BB, TT vs. GG) and additive (A vs. B, T vs. G) genetic models. Studies of eNOS intron 4 VNTR and Glu298Asp were separated by ethnicities. 13 studies included 1,769 URPL cases and 1,376 healthy controls on eNOS intron 4 VNTR polymorphism, and 11 studies were involved in Glu298Asp polymorphism with 1,498 URPL cases and 1,123 healthy controls. The integrated results showed that eNOS Glu298Asp polymorphism was associated with URPL [ORs were 1.91 (1.42–2.56), P < 0.001; 1.67 (1.36–2.04), P < 0.001, respectively]. When analyses were separated by ethnic subgroups, the association between eNOS Glu298Asp polymorphism and URPL was only observed in East Asians [OR = 1.88 (1.52–2.33), P < 0.001 under additive model], and there was no association between eNOS intron 4 VNTR polymorphism and URPL in Caucasians and East Asians. The results indicated a significant association between eNOS Glu298Asp polymorphism and URPL in East Asians. No association was observed between eNOS intron 4 VNTR polymorphism and URPL in Caucasians and East Asians.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Li TC, Makris M, Tomsu M, Tuckerman E, Laird S (2002) Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update 8(5):463–481

    Article  CAS  PubMed  Google Scholar 

  2. Younis JS, Ohel G, Brenner B, Ben Ami M (1997) Familial thrombophilia–the scientific rationale for thrombophylaxis in recurrent pregnancy loss. Hum Reprod 12(7):1389–1390

    Article  CAS  PubMed  Google Scholar 

  3. Wilcox AJ, Baird DD, Weinberg CR (1999) Time of implantation of the conceptus and loss of pregnancy. New Engl J Med 340(23):1796–1799

    Article  CAS  PubMed  Google Scholar 

  4. Regan L, Braude PR, Trembath PL (1989) Influence of past reproductive performance on risk of spontaneous abortion. BMJ 299(6698):541–545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Kutteh WH (1999) Recurrent pregnancy loss: an update. Curr Opin Obstet Gynecol 11(5):435–439

    Article  CAS  PubMed  Google Scholar 

  6. Okon MA, Laird SM, Tuckerman EM, Li TC (1998) Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. Fertil Steril 69(4):682–690

    Article  CAS  PubMed  Google Scholar 

  7. Yamada H, Sata F, Saijo Y, Kishi R, Minakami H (2005) Genetic factors in fetal growth restriction and miscarriage. Semin Thromb Hemost 31(3):34–345

    Article  Google Scholar 

  8. Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N.Engl. J. Med. 329(27):2002–2012

    Article  CAS  PubMed  Google Scholar 

  9. Rossmanith WG et al (1999) Expression and functional analysis of endothelial nitric oxide synthase (eNOS) in human placenta. Mol Hum Reprod 5(5):487–494

    Article  CAS  PubMed  Google Scholar 

  10. Lefer AM (1997) Nitric oxide: nature’s naturally occurring leukocyte inhibitor. Circulation 95(3):553–554

    Article  CAS  PubMed  Google Scholar 

  11. Radomski MW, Palmer RM, Moncada S (1987) Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2(8567):1057–1058

    Article  CAS  PubMed  Google Scholar 

  12. Garg UC, Hassid A (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83(5):1774–1777

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hogg N, Kalyanaraman B, Joseph J, Struck A, Parthasarathy S (1993) Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis. FEBS Lett 334(2):170–174

    Article  CAS  PubMed  Google Scholar 

  14. Lind L, Granstam SO, Millgard J (2000) Endothelium-dependent vasodilation in hypertension: a review. Blood Press 9(1):4–15

    Article  CAS  PubMed  Google Scholar 

  15. Nakayama M et al (1999) T-786–>C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99(22):2864–2870

    Article  CAS  PubMed  Google Scholar 

  16. Tempfer C, Unfried G, Zeillinger R, Hefler L, Nagele F, Huber JC (2001) Endothelial nitric oxide synthase gene polymorphism in women with idiopathic recurrent miscarriage. Hum Reprod 16(8):1644–1647

    Article  CAS  PubMed  Google Scholar 

  17. Buchholz T, Lohse P, Kosian E, Thaler CJ (2004) Vasoconstrictively acting AT1R A1166C and NOS3 4/5 polymorphisms in recurrent spontaneous abortions (RSA). Am J Reprod Immunol 51(5):323–328

    Article  PubMed  Google Scholar 

  18. Suryanarayana V, Rao L, Kanakavalli M, Padmalatha V, Deenadayal M, Singh L (2006) Recurrent early pregnancy loss and endothelial nitric oxide synthase gene polymorphisms. Arch Gynecol Obstet 274(2):119–124

    Article  CAS  PubMed  Google Scholar 

  19. Zammiti W, Mtiraoui N, Mahjoub T (2008) Lack of consistent association between endothelial nitric oxide synthase gene polymorphisms, homocysteine levels and recurrent pregnancy loss in tunisian women. Am J Reprod Immunol 59(2):139–145

    Article  CAS  PubMed  Google Scholar 

  20. Shin SJ et al (2010) Endothelial nitric oxide synthase gene polymorphisms (−786T>C, 4a4b, 894G>T) and haplotypes in Korean patients with recurrent spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 152(1):64–67

    Article  CAS  PubMed  Google Scholar 

  21. Hefler LA et al (2002) Polymorphisms of the angiotensinogen gene, the endothelial nitric oxide synthase gene, and the interleukin-1beta gene promoter in women with idiopathic recurrent miscarriage. Mol Hum Reprod 8(1):95–100

    Article  CAS  PubMed  Google Scholar 

  22. Kitsios GD, Zintzaras E (2010) Synopsis and data synthesis of genetic association studies in hypertension for the adrenergic receptor family genes: the CUMAGAS-HYPERT database. Am J Hypertens 23(3):305–313

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127(9):820–826

    Article  CAS  PubMed  Google Scholar 

  24. Slatkin M (1991) Inbreeding coefficients and coalescence times. Genet Res 58(2):167–175

    Article  CAS  PubMed  Google Scholar 

  25. Zeng Z et al (2010) A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy. Hum Genet 127(4):373–381

    Article  CAS  PubMed  Google Scholar 

  26. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  27. Fan W, Li SW, Wang Y (2007) Association of genetic polymorphisms in endothelial nitric oxide synthase 3 gene with recurrent early spontaneous abortion. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 24:23–26

    CAS  PubMed  Google Scholar 

  28. Gao L, YuWX Guan LX, Li HB, Liu ZC (2009) The G894T polymorphism of eNOS gene and repeated spontaneous abortion. Shi Yong Yi Xue Za Zhi 25:376–377

    CAS  Google Scholar 

  29. Su MT, Lin SH, Chen YC (2011) Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod Update 17(6):803–812

    Article  CAS  PubMed  Google Scholar 

  30. Parveen F, Faridi RM, Alam S, Agrawal S (2011) Genetic analysis of eNOS gene polymorphisms in association with recurrent miscarriage among North Indian women. Reprod Biomed Online 23(1):124–131

    Article  CAS  PubMed  Google Scholar 

  31. Cavalli-Sforza LL, Menozzi P, Piazza A (1993) Demic expansions and human evolution. Science 259(5095):639–646

    Article  CAS  PubMed  Google Scholar 

  32. Ignarro LJ (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30:535–560

    Article  CAS  PubMed  Google Scholar 

  33. Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J (2000) Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate versus glutamate at position 298. Proc Natl Acad Sci USA 97(6):2832–2835

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Huber A et al (2005) Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death. Eur J Obstet Gynecol Reprod Biol 122(2):151–155

    Article  CAS  PubMed  Google Scholar 

  35. Almawi WY et al (2013) Endothelial nitric oxide synthase gene variants and haplotypes associated with an increased risk of idiopathic recurrent miscarriage. Hum Fertil 16(3):200–206

    Article  CAS  Google Scholar 

  36. Yoshimura T et al (2000) Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with severe preeclampsia. J Soc Gynecol Investig 7(4):238–241

    Article  CAS  PubMed  Google Scholar 

  37. Karvela M et al (2008) Endothelial nitric oxide synthase gene polymorphisms in recurrent spontaneous abortions. Arch Gynecol Obstet 278(4):349–352

    Article  CAS  PubMed  Google Scholar 

  38. Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR (2001) Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. J Biol Chem 276(29):27296–27303

    Article  CAS  PubMed  Google Scholar 

  39. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK (2000) Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol 95(4):519–524

    Article  CAS  PubMed  Google Scholar 

  40. Obwegeser R, Hohlagschwandtner M, Sinzinger H (1999) Homocysteine—a pathophysiological cornerstone in obstetrical and gynaecological disorders. Hum Reprod Update 5(1):64–72

    Article  CAS  PubMed  Google Scholar 

  41. Di Simone N et al (2004) Effect of folic acid on homocysteine-induced trophoblast apoptosis. Mol Hum Reprod 10(9):665–669

    Article  PubMed  Google Scholar 

  42. Di Simone N et al (2003) Homocysteine induces trophoblast cell death with apoptotic features. Biol Reprod 69(4):1129–1134

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by The Knowledge Innovation Program in Chinese Academy of Sciences (No. KSCX2-EW-R-06) to YLW and Shanghai Committee of Science and Technology, China (No. 11ZR1431100).

Author information

Authors and Affiliations

  1. Fudan University, 130 Dong’an Road, Shanghai, 200032, China

    Yunlei Cao

  2. NPFPC Laboratory of Contraception and Devices, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai, 200032, China

    Yunlei Cao, Zhaofeng Zhang, Jianhua Xu, Jian Wang, Wei Yuan & Jing Du

  3. Department of Biostatistics and Epidemiology,Public Health School, Soochow University, Suzhou, 215123, China

    Yueping Shen

Authors
  1. Yunlei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhaofeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianhua Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yueping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing Du.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 41 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cao, Y., Zhang, Z., Xu, J. et al. Genetic association studies of endothelial nitric oxide synthase gene polymorphisms in women with unexplained recurrent pregnancy loss: a systematic and meta-analysis. Mol Biol Rep 41, 3981–3989 (2014). https://doi.org/10.1007/s11033-014-3266-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-014-3266-7

Keywords

Search

Navigation