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Yousefian, M., Angaji, A., Siasi, E., Rahmani, S. A., & Abbasalizadeh Khiaban, S. (2022). Role of CYP1A1, CYP2D6, and NOS3 gene polymorphisms in idiopathic recurrent pregnancy loss in the Iranian Azeri population: A case-control study. International Journal of Reproductive BioMedicine (IJRM), 20(8), 671–682. https://doi.org/10.18502/ijrm.v20i8.11756
https://doi.org/10.18502/ijrm.v20i8.11756
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authors
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Mahsa Yousefian
Mahsa Yousefian
Department of Genetics, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
-
Abdolhamid Angaji
Abdolhamid Angaji
Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
-
Elham Siasi
Elham Siasi
Department of Genetics, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
-
Seyed Ali Rahmani
Seyed Ali Rahmani
Department of Medical Genetics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
-
Shamsi Abbasalizadeh Khiaban
Shamsi Abbasalizadeh Khiaban
Department of Obstetrics and Gynecology, Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Published Date
- Sep 6, 2022
Role of CYP1A1, CYP2D6, and NOS3 gene polymorphisms in idiopathic recurrent pregnancy loss in the Iranian Azeri population: A case-control study
Abstract
Background: It is estimated that 1-5% of couples suffer from recurrent pregnancy loss (RPL). Recent studies have shown the effects of gene polymorphisms in RPL.
Objective: The aim of this study was to evaluate 3 gene polymorphisms including rs1048943 of CYP1A1, rs28371725 of CYP2D6, and rs7830 of NOS3 in idiopathic RPL to identify their association with RPL.
Materials and Methods: Blood samples were collected from 136 women with at least 2 consecutive idiopathic miscarriages (case group) and 136 women with no history of miscarriage and at least one successful pregnancy (control group) from the Iranian Azeri population. This study was carried out between April 2018-April 2020. Amplification-refractory mutation system polymerase chain reaction was used for the rs7830, rs1048943 and rs28371725 polymorphisms in order to genotype each extracted genomic DNA sample. After that, Chi-square, Fisher’s exact test and logistic regression were used to investigate whether each of these polymorphisms is associated with RPL.
Results: Among these polymorphisms, only rs1048943 of CYP1A1 showed a statistically significant association with RPL in the Iranian Azeri women studied.
Conclusion: Our results suggest that CYP1A1 gene polymorphisms might be associated with a reduced risk of RPL. Further studies in other populations and in the same population with a larger sample size, as well as functional genomics analyses such as gene expression analyses or epigenetic studies are required to validate our results.
Key words: Recurrent pregnancy loss, Polymorphism, CYP1A1, CYP2D6, NOS3.
References
[1] Diaz-Nunez M, Rabanal A, Exposito A, Ferrando M, Quintana F, Soria JM, et al. Recurrent miscarriage and implantation failure of unknown cause studied by a panel of thrombophilia conditions: Increased frequency of FXIII Val34Leu polymorphism. J Reprod Infertil 2019; 20: 76– 82.
[2] Asgari N, Akbari MT, Zare Sh, Babamohammadi Gh. Positive association of apolipoprotein E4 polymorphism. with recurrent pregnancy loss in Iranian patients. J Assist Reprod Genet 2013; 30: 265–268.
[3] Hashemi M, Mokhtari M, Khazaeian S, Bahari G, Rezaei M, Nakhaee A, et al. Evaluation of HLA-G 14-bp ins/del and +3142G>C polymorphisms with susceptibility to recurrent spontaneous abortion. Taiwan J Obstet Gynecol 2017; 56: 276–280.
[4] Zhang M, Xu J, Bao X, Niu W, Wang L, Du L, et al. Association between genetic polymorphisms in interleukin genes and recurrent pregnancy loss: A systematic review and meta-analysis. PLoS One 2017; 12:e0169891.
[5] Karatas A, Eroz R, Albayrak M, Ozlu T, Cakmak B, Keskin F. Evaluation of chromosomal abnormalities and common trombophilic mutations in cases with recurrent miscarriage. Afr Health Sci 2014; 14: 216–222.
[6] Shi X, Xie X, Jia Y, Li S. Maternal genetic polymorphisms and unexplained recurrent miscarriage: A systematic review and meta-analysis. Clin Genet 2017; 91: 265–284.
[7] Li J, Chen Y, Wu H, Li L. Apolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: A meta-analysis. J Assist Reprod Genet 2014; 31: 139–148.
[8] Pereza N, Ostojic S, Kapovic M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017; 107: 150–159.
[9] Du B, Shi X, Yin C, Feng X. Polymorphisms of methalenetetrahydrofolate reductase in recurrent pregnancy loss: An overview of systematic reviews and meta-analyses. J Assist Reprod Genet 2019; 36: 1315–1328.
[10] Poursadegh Zonouzi A, Chaparzadeh N, Ghorbian S, Sadaghiani MM, Farzadi L, Ghasemzadeh A, et al. The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 2013; 30: 1353–1359
[11] Tur-Torres MH, Garrido-Gimenez C, Alijotas-Reig J. Genetics of recurrent miscarriage and fetal loss. Best Pract Res Clin Obstet Gynaecol 2017; 42: 11–25.
[12] Zong Ch, Sha Y, Xiang H, Wang J, Chen D, Liu J, etal. Glutathione S-transferase A1 polymorphism and the risk of recurrent spontaneous abortion in Chinese Han population. J Assist Reprod Genet 2014; 31: 379–382.
[13] Li J, Chen Y, Mo S, Nai D. Potential positive association between cytochrome P450 1A1 gene polymorphisms and recurrent pregnancy loss: A meta-analysis. Ann Hum Genet 2017; 81: 161–173.
[14] Nofziger Ch, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agundez JAG, Black JL, et al. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther 2020; 107: 154–170.
[15] Yang Y, Botton MR, Scott ER, Scott SA. Sequencing the CYP2D6 gene: From variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics 2017; 18: 673–685.
[16] Skadric I, Stojkovic O. Defining screening panel of functional variants of CYP1A1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 genes in Serbian population. Int J Legal Med 2020; 134: 433–439.
[17] Monostory K, Dvorak Z. Steroid regulation of drug metabolizing cytochromes P450. Curr Drug Metab 2011; 12: 154–172.
[18] Pereza N, Peterlin B, Volk M, Kapovic M, Ostojic S. A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: Genetic association study, systematic review and meta-analyses. Mol Hum Reprod 2015; 21: 466–478.
[19] Parveen F, Faridi RM, Alam S, Agrawal S. Genetic analysis of eNOS gene polymorphisms in association with recurrent miscarriage among North Indian women. Reprod Biomed Online 2011; 23: 124–131.
[20] Trifonova EA, Swarovskaya MG, Ganzha OA, Voronkova OV, Gabidulina TV, Stepanov VA. The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss. J Assist Reprod Genet 2019; 36: 717– 726.
[21] Azani A, Hosseinzadeh A, Azadkhah R, Zonouzi AAP, Zonouzi AP, Aftabi Y, et al. Association of endothelial nitric oxide synthase gene variants (-786 T>C, intron 4 b/a VNTR and 894 G>T) with idiopathic recurrent pregnancy loss: A case-control study with haplotype and in silico analysis. Eur J Obstet Gynecol Reprod Biol 2017; 215: 93–100.
[22] dbSNP. Available at: https://www.ncbi.nlm.nih.gov/snp.
[23] Wu H, Ouyang Q, Tian C, Xie N, Cao M, Shui ZR. Cytochrome P450 1A1 (CYP1A1) Gene polymorphisms and susceptibility to breast cancer: A meta-analysis in the Chinese Population. Clin Lab 2017; 63: 67–72.
[24] Akhtar S, Mahjabeen I, Akram Z, Kayani MA. CYP1A1 and GSTP1 gene variations in breast cancer: A systematic review and case-control study. Fam Cancer 2016; 15: 201–214.
[25] Mrozikiewicz PM, Grześkowiak E, Seremak-Mrozikiewicz A, Bogacz A, Barlik M, Semczuk A, et al. Importance of CYP1A1 polymorphism and its transcriptional regulation in ovarian and endometrial cancer. Ginekol Pol 2011; 82: 925–932.
[26] Wu Y, Chen X, Chang X, Huang YJ, Bao S, He Q, et al.Potential involvement of placental AhR in unexplained recurrent spontaneous abortion. Reprod Toxicol 2016; 59: 45–52.
[27] de Oliveira CBM, Cardoso-Filho C, Bossi LS, Lourenço. GJ, Costa-Gurgel MS, Lima CS. Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. Clinics 2015; 70: 680–685.
[28] Mao Y, Zhang K, Ma L, Yun X, Ou F, Liu G, et al. Interaction between CYP1A1/CYP17A1 polymorphisms and parental risk factors in the risk of hypospadias in a Chinese population. Sci Rep 2019; 9: 4123.
[29] Mohammed AM, Huuskonen P, Juvonen R, Sahlman H, Repo J, Myöhänen K, et al. Activities of metabolizing enzymes in human placenta. Toxicol Lett 2020; 326: 70– 77.
[30] Abbas M, Srivastava K, Imran M, Banerjee M. Association of CYP1A1 gene variants rs4646903 (T>C) and rs1048943 (A>G) with cervical cancer in a North Indian population. Eur J Obstet Gynecol Reprod Biol 2014; 176: 68–74.
[31] Jain V, Ratre YK, Amle D, Mishra PK, Patra PK. Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation to the incidence of cervical cancer in Chhattisgarh. Environ Toxicol Pharmacol 2017; 52: 188– 192.
[32] Peng DD, Xie W, Yu ZX. Impact of interaction between CYP1A1 genetic polymorphisms and smoking on coronary artery disease in the Han of China. Clin Exp Hypertens 2017; 39: 339–343.
[33] Khadzhieva MB, Lutcenko NN, Volodin IV, Morozova KV, Salnikova LE. Association of oxidative stress-related genes with idiopathic recurrent miscarriage. Free Radic Res 2014; 48: 534–541.
[34] Sun ChJ, Li L, Li XY, Zhang WY, Liu XW. Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy. Arch Gynecol Obstet 2018; 298: 125–132.
[35] Suryanarayana V, Deenadayal M, Singh L. Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population. Hum Reprod 2004; 19: 2648–2652.
[36] Najafi T, Ghaffari Novin M, Ghazi R, Khorram O. Altered endometrial expression of endothelial nitric oxide synthase in women with unexplained recurrent miscarriage and infertility. Reprod Biomed Online 2012; 25: 408–414.
[37] Barbitoff YA, Tsarev AA, Vashukova ES, Maksiutenko EM, Kovalenko LV, Belotserkovtseva LD, et al. A data-driven review of the genetic factors of pregnancy complications. Int J Mol Sci 2020; 21: 3384.
[38] Chakraborty P, Khamit A, Hermesz E. Fetal oxygen supply can be improved by an effective cross-talk between fetal erythrocytes and vascular endothelium. Biochim Biophys Acta Mol Basis Dis 2021; 1867: 166243.
[39] Al Sallout RJ, Sharif FA. Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the Gaza Strip. Med Princ Pract 2010; 19: 99–104.
[40] Jimenez-Sousa MA, Lopez E, Fernandez-Rodriguez A, Tamayo E, Fernandez-Navarro P, Segura-Roda L, et al. Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: A preliminary study. BMC Med Genet 2012; 13: 58.
[41] Popov AF, Hinz J, Schulz EG, Schmitto JD, Wiese CH, Quintel M, et al. The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction. Eur J Cardiothorac Surg 2009; 36: 651–656.
[42] Kullo IJ, Greene MT, Boerwinkle E, Chu J, Turner ST, Kardia SL. Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. Atherosclerosis 2008; 196: 905–912.
[43] Wang ChH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, et al. A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Proc Natl Acad Sci U S A 2011; 108: 2070–2075.
[44] Luo L, Li DH, Wei SG, Zhang HB, Li SB, Zhao J. Polymorphisms in the endothelial nitric oxide synthase gene associated with recurrent miscarriage. Genet Mol. Res 2013; 12: 3879–3886.
[2] Asgari N, Akbari MT, Zare Sh, Babamohammadi Gh. Positive association of apolipoprotein E4 polymorphism. with recurrent pregnancy loss in Iranian patients. J Assist Reprod Genet 2013; 30: 265–268.
[3] Hashemi M, Mokhtari M, Khazaeian S, Bahari G, Rezaei M, Nakhaee A, et al. Evaluation of HLA-G 14-bp ins/del and +3142G>C polymorphisms with susceptibility to recurrent spontaneous abortion. Taiwan J Obstet Gynecol 2017; 56: 276–280.
[4] Zhang M, Xu J, Bao X, Niu W, Wang L, Du L, et al. Association between genetic polymorphisms in interleukin genes and recurrent pregnancy loss: A systematic review and meta-analysis. PLoS One 2017; 12:e0169891.
[5] Karatas A, Eroz R, Albayrak M, Ozlu T, Cakmak B, Keskin F. Evaluation of chromosomal abnormalities and common trombophilic mutations in cases with recurrent miscarriage. Afr Health Sci 2014; 14: 216–222.
[6] Shi X, Xie X, Jia Y, Li S. Maternal genetic polymorphisms and unexplained recurrent miscarriage: A systematic review and meta-analysis. Clin Genet 2017; 91: 265–284.
[7] Li J, Chen Y, Wu H, Li L. Apolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: A meta-analysis. J Assist Reprod Genet 2014; 31: 139–148.
[8] Pereza N, Ostojic S, Kapovic M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017; 107: 150–159.
[9] Du B, Shi X, Yin C, Feng X. Polymorphisms of methalenetetrahydrofolate reductase in recurrent pregnancy loss: An overview of systematic reviews and meta-analyses. J Assist Reprod Genet 2019; 36: 1315–1328.
[10] Poursadegh Zonouzi A, Chaparzadeh N, Ghorbian S, Sadaghiani MM, Farzadi L, Ghasemzadeh A, et al. The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 2013; 30: 1353–1359
[11] Tur-Torres MH, Garrido-Gimenez C, Alijotas-Reig J. Genetics of recurrent miscarriage and fetal loss. Best Pract Res Clin Obstet Gynaecol 2017; 42: 11–25.
[12] Zong Ch, Sha Y, Xiang H, Wang J, Chen D, Liu J, etal. Glutathione S-transferase A1 polymorphism and the risk of recurrent spontaneous abortion in Chinese Han population. J Assist Reprod Genet 2014; 31: 379–382.
[13] Li J, Chen Y, Mo S, Nai D. Potential positive association between cytochrome P450 1A1 gene polymorphisms and recurrent pregnancy loss: A meta-analysis. Ann Hum Genet 2017; 81: 161–173.
[14] Nofziger Ch, Turner AJ, Sangkuhl K, Whirl-Carrillo M, Agundez JAG, Black JL, et al. PharmVar GeneFocus: CYP2D6. Clin Pharmacol Ther 2020; 107: 154–170.
[15] Yang Y, Botton MR, Scott ER, Scott SA. Sequencing the CYP2D6 gene: From variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics 2017; 18: 673–685.
[16] Skadric I, Stojkovic O. Defining screening panel of functional variants of CYP1A1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 genes in Serbian population. Int J Legal Med 2020; 134: 433–439.
[17] Monostory K, Dvorak Z. Steroid regulation of drug metabolizing cytochromes P450. Curr Drug Metab 2011; 12: 154–172.
[18] Pereza N, Peterlin B, Volk M, Kapovic M, Ostojic S. A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: Genetic association study, systematic review and meta-analyses. Mol Hum Reprod 2015; 21: 466–478.
[19] Parveen F, Faridi RM, Alam S, Agrawal S. Genetic analysis of eNOS gene polymorphisms in association with recurrent miscarriage among North Indian women. Reprod Biomed Online 2011; 23: 124–131.
[20] Trifonova EA, Swarovskaya MG, Ganzha OA, Voronkova OV, Gabidulina TV, Stepanov VA. The interaction effect of angiogenesis and endothelial dysfunction-related gene variants increases the susceptibility of recurrent pregnancy loss. J Assist Reprod Genet 2019; 36: 717– 726.
[21] Azani A, Hosseinzadeh A, Azadkhah R, Zonouzi AAP, Zonouzi AP, Aftabi Y, et al. Association of endothelial nitric oxide synthase gene variants (-786 T>C, intron 4 b/a VNTR and 894 G>T) with idiopathic recurrent pregnancy loss: A case-control study with haplotype and in silico analysis. Eur J Obstet Gynecol Reprod Biol 2017; 215: 93–100.
[22] dbSNP. Available at: https://www.ncbi.nlm.nih.gov/snp.
[23] Wu H, Ouyang Q, Tian C, Xie N, Cao M, Shui ZR. Cytochrome P450 1A1 (CYP1A1) Gene polymorphisms and susceptibility to breast cancer: A meta-analysis in the Chinese Population. Clin Lab 2017; 63: 67–72.
[24] Akhtar S, Mahjabeen I, Akram Z, Kayani MA. CYP1A1 and GSTP1 gene variations in breast cancer: A systematic review and case-control study. Fam Cancer 2016; 15: 201–214.
[25] Mrozikiewicz PM, Grześkowiak E, Seremak-Mrozikiewicz A, Bogacz A, Barlik M, Semczuk A, et al. Importance of CYP1A1 polymorphism and its transcriptional regulation in ovarian and endometrial cancer. Ginekol Pol 2011; 82: 925–932.
[26] Wu Y, Chen X, Chang X, Huang YJ, Bao S, He Q, et al.Potential involvement of placental AhR in unexplained recurrent spontaneous abortion. Reprod Toxicol 2016; 59: 45–52.
[27] de Oliveira CBM, Cardoso-Filho C, Bossi LS, Lourenço. GJ, Costa-Gurgel MS, Lima CS. Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. Clinics 2015; 70: 680–685.
[28] Mao Y, Zhang K, Ma L, Yun X, Ou F, Liu G, et al. Interaction between CYP1A1/CYP17A1 polymorphisms and parental risk factors in the risk of hypospadias in a Chinese population. Sci Rep 2019; 9: 4123.
[29] Mohammed AM, Huuskonen P, Juvonen R, Sahlman H, Repo J, Myöhänen K, et al. Activities of metabolizing enzymes in human placenta. Toxicol Lett 2020; 326: 70– 77.
[30] Abbas M, Srivastava K, Imran M, Banerjee M. Association of CYP1A1 gene variants rs4646903 (T>C) and rs1048943 (A>G) with cervical cancer in a North Indian population. Eur J Obstet Gynecol Reprod Biol 2014; 176: 68–74.
[31] Jain V, Ratre YK, Amle D, Mishra PK, Patra PK. Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation to the incidence of cervical cancer in Chhattisgarh. Environ Toxicol Pharmacol 2017; 52: 188– 192.
[32] Peng DD, Xie W, Yu ZX. Impact of interaction between CYP1A1 genetic polymorphisms and smoking on coronary artery disease in the Han of China. Clin Exp Hypertens 2017; 39: 339–343.
[33] Khadzhieva MB, Lutcenko NN, Volodin IV, Morozova KV, Salnikova LE. Association of oxidative stress-related genes with idiopathic recurrent miscarriage. Free Radic Res 2014; 48: 534–541.
[34] Sun ChJ, Li L, Li XY, Zhang WY, Liu XW. Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy. Arch Gynecol Obstet 2018; 298: 125–132.
[35] Suryanarayana V, Deenadayal M, Singh L. Association of CYP1A1 gene polymorphism with recurrent pregnancy loss in the South Indian population. Hum Reprod 2004; 19: 2648–2652.
[36] Najafi T, Ghaffari Novin M, Ghazi R, Khorram O. Altered endometrial expression of endothelial nitric oxide synthase in women with unexplained recurrent miscarriage and infertility. Reprod Biomed Online 2012; 25: 408–414.
[37] Barbitoff YA, Tsarev AA, Vashukova ES, Maksiutenko EM, Kovalenko LV, Belotserkovtseva LD, et al. A data-driven review of the genetic factors of pregnancy complications. Int J Mol Sci 2020; 21: 3384.
[38] Chakraborty P, Khamit A, Hermesz E. Fetal oxygen supply can be improved by an effective cross-talk between fetal erythrocytes and vascular endothelium. Biochim Biophys Acta Mol Basis Dis 2021; 1867: 166243.
[39] Al Sallout RJ, Sharif FA. Polymorphisms in NOS3, ACE and PAI-1 genes and risk of spontaneous recurrent miscarriage in the Gaza Strip. Med Princ Pract 2010; 19: 99–104.
[40] Jimenez-Sousa MA, Lopez E, Fernandez-Rodriguez A, Tamayo E, Fernandez-Navarro P, Segura-Roda L, et al. Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: A preliminary study. BMC Med Genet 2012; 13: 58.
[41] Popov AF, Hinz J, Schulz EG, Schmitto JD, Wiese CH, Quintel M, et al. The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction. Eur J Cardiothorac Surg 2009; 36: 651–656.
[42] Kullo IJ, Greene MT, Boerwinkle E, Chu J, Turner ST, Kardia SL. Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. Atherosclerosis 2008; 196: 905–912.
[43] Wang ChH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, et al. A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Proc Natl Acad Sci U S A 2011; 108: 2070–2075.
[44] Luo L, Li DH, Wei SG, Zhang HB, Li SB, Zhao J. Polymorphisms in the endothelial nitric oxide synthase gene associated with recurrent miscarriage. Genet Mol. Res 2013; 12: 3879–3886.