Endothelial Nitric Oxide Synthase Gene Polymorphisms and Risk of Preeclampsia

Abstract

Polymorphisms in endothelial nitric oxide synthase (eNOS) gene may affect the risk of preeclampsia. This systematic review aimed to provide an updated review of the literature to better understand the association between the eNOS gene polymorphisms and the risk of preeclampsia. We searched electronic databases of the human literature in PubMed, EMBASE, and the Cochrane Library up to July 2012. A meta-analysis was conducted on the association of eNOS G894T, T786C, and intron 4b/a polymorphisms with preeclampsia using (1) allele contrast, (2) recessive, (3) dominant, and (4) additive models. Thirty-three studies comprising 10,671 participants met the inclusion criteria. There was statistically significant association between the G894T variant and increased risk of preeclampsia (TT versus TG + GG: odds ratio 1.43, 95% confidence interval: 1.13 to 1.82). However, no significant risk of preeclampsia was observed either in the T786C or the intron 4b/a polymorphism. Homozygosity TT in eNOS G894T variant is significantly associated with an increased risk of preeclampsia.

Keywords

preeclampsia - endothelial nitric oxide synthase - polymorphism

• References

• 1 Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010; 376: 631-644
• 2 Pappa KI, Roubelakis M, Vlachos G , et al. Variable effects of maternal and paternal-fetal contribution to the risk for preeclampsia combining GSTP1, eNOS, and LPL gene polymorphisms. J Matern Fetal Neonatal Med 2011; 24: 628-635
• 3 Tempfer CB, Dorman K, Deter RL, O'Brien WE, Gregg AR. An endothelial nitric oxide synthase gene polymorphism is associated with preeclampsia. Hypertens Pregnancy 2001; 20: 107-118
• 4 Sheppard SJ, Khalil RA. Risk factors and mediators of the vascular dysfunction associated with hypertension in pregnancy. Cardiovasc Hematol Disord Drug Targets 2010; 10: 33-52
• 5 Cross JC. The genetics of pre-eclampsia: a feto-placental or maternal problem?. Clin Genet 2003; 64: 96-103
• 6 Founds SA, Conley YP, Lyons-Weiler JF, Jeyabalan A, Hogge WA, Conrad KP. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta 2009; 30: 15-24
• 7 Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep 2003; 5: 19-25
• 8 Piccoli JC, Gottlieb MG, Castro L , et al. Association between 894G > T endothelial nitric oxide synthase gene polymorphisms and metabolic syndrome. Arq Bras Endocrinol Metabol 2008; 52: 1367-1373
• 9 Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-2012
• 10 Arngrímsson R, Hayward C, Nadaud S , et al. Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region. Am J Hum Genet 1997; 61: 354-362
• 11 Metzger IF, Sertório JT, Tanus-Santos JE. Modulation of nitric oxide formation by endothelial nitric oxide synthase gene haplotypes. Free Radic Biol Med 2007; 43: 987-992
• 12 Tanus-Santos JE, Desai M, Flockhart DA. Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 2001; 11: 719-725
• 13 Chen H, Zhao G, Sun M , et al. Endothelial nitric oxide synthase gene polymorphisms (G894T, 4b/a and T-786C) and preeclampsia: meta-analysis of 18 case-control studies. DNA Cell Biol 2012; 31: 1136-1145
• 14 Stroup DF, Berlin JA, Morton SC , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008-2012
• 15 Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330: 565
• 16 Yu CK, Casas JP, Savvidou MD, Sahemey MK, Nicolaides KH, Hingorani AD. Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and development of pre-eclampsia: a case-control study and a meta-analysis. BMC Pregnancy Childbirth 2006; 6: 7
• 17 Fatini C, Sticchi E, Gensini F , et al. Endothelial nitric oxide synthase gene influences the risk of pre-eclampsia, the recurrence of negative pregnancy events, and the maternal-fetal flow. J Hypertens 2006; 24: 1823-1829
• 18 Hocher B, Chen YP, Hügle S , et al. Impact of maternal endothelial nitric oxide synthase gene polymorphisms on blood pressure, protein excretion and fetal outcome in pregnancy. J Hum Hypertens 2008; 22: 641-647
• 19 Hillermann R, Carelse K, Gebhardt GS. The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia. J Hum Genet 2005; 50: 415-419
• 20 Sandrim VC, Palei AC, Cavalli RC , et al. eNOS haplotypes associated with gestational hypertension or preeclampsia. Pharmacogenomics 2008; 9: 1467-1473
• 21 Sandrim VC, Palei AC, Sertorio JT, Cavalli RC, Duarte G, Tanus-Santos JE. Effects of eNOS polymorphisms on nitric oxide formation in healthy pregnancy and in pre-eclampsia. Mol Hum Reprod 2010; 16: 506-510
• 22 Serrano NC, Casas JP, Díaz LA , et al. Endothelial NO synthase genotype and risk of preeclampsia: a multicenter case-control study. Hypertension 2004; 44: 702-707
• 23 Häkli T, Romppanen EL, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S. Endothelial nitric oxide synthase polymorphism in preeclampsia. J Soc Gynecol Investig 2003; 10: 154-157
• 24 Landau R, Xie HG, Dishy V, Wood AJ, Stein CM, Smiley RM. No association of the Asp298 variant of the endothelial nitric oxide synthase gene with preeclampsia. Am J Hypertens 2004; 17 (5 Pt 1) 391-394
• 25 Aggarwal PK, Jain V, Jha V. Endothelial nitric oxide synthase, angiotensin-converting enzyme and angiotensinogen gene polymorphisms in hypertensive disorders of pregnancy. Hypertens Res 2010; 33: 473-477
• 26 Kim YJ, Park BH, Park H , et al. No association of the genetic polymorphisms of endothelial nitric oxide synthase, dimethylarginine dimethylaminohydrolase, and vascular endothelial growth factor with preeclampsia in Korean populations. Twin Res Hum Genet 2008; 11: 77-83
• 27 Ozturk E, Balat O, Pehlivan S , et al. Endothelial nitric oxide synthase gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population. J Obstet Gynaecol Res 2011; 37: 1778-1783
• 28 Sharma D, Trivedi SS, Bhattacharjee J. Oxidative stress and eNOS (Glu298Asp) gene polymorphism in preeclampsia in Indian population. Mol Cell Biochem 2011; 353: 189-193
• 29 Turan F, Ilhan N, Kaman D, Ateş K, Kafkasli A. Glu298Asp polymorphism of the endothelial nitric oxide synthase gene and plasma concentrations of asymmetric dimethylarginine in Turkish pre-eclamptic women without fetal growth retardation. J Obstet Gynaecol Res 2010; 36: 495-501
• 30 Yoshimura T, Yoshimura M, Tabata A , et al. Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with severe preeclampsia. J Soc Gynecol Investig 2000; 7: 238-241
• 31 Díaz-Olguín L, Coral-Vázquez RM, Canto-Cetina T , et al. Endothelial nitric oxide synthase haplotypes are associated with preeclampsia in Maya mestizo women. Dis Markers 2011; 31: 83-89
• 32 Bashford MT, Hefler LA, Vertrees TW, Roa BB, Gregg AR. Angiotensinogen and endothelial nitric oxide synthase gene polymorphisms among Hispanic patients with preeclampsia. Am J Obstet Gynecol 2001; 184: 1345-1350 ; discussion 1350–1351
• 33 Benedetto C, Marozio L, Ciccone G , et al. Synergistic effect of renin-angiotensin system and nitric oxide synthase genes polymorphisms in pre-eclampsia. Acta Obstet Gynecol Scand 2007; 86: 678-682
• 34 Grandone E, Colaizzo D, Martinelli P , et al. Does endothelial nitric oxide synthase gene variation play a role in the occurrence of hypertension in pregnancy?. Hypertens Pregnancy 2003; 22: 149-155
• 35 Seremak-Mrozikiewicz A, Drews K, Mrozikiewicz PM. The -786T/C polymorphism of the endothelial nitric oxide synthase gene in preeclampsia. Eur J Obstet Gynecol Reprod Biol 2008; 138: 118-119
• 36 Seremak-Mrozikiewicz A, Drews K, Barlik M, Sieroszewski P, Grześkowiak E, Mrozikiewicz P. The significance of -786T > C polymorphism of endothelial NO synthase (eNOS) gene in severe preeclampsia. J Matern Fetal Neonatal Med 2011; 24: 432-436
• 37 Yoshimura T, Chowdhury FA, Yoshimura M, Okamura H. Genetic and environmental contributions to severe preeclampsia: lack of association with the endothelial nitric oxide synthase Glu298Asp variant in a developing country. Gynecol Obstet Invest 2003; 56: 10-13
• 38 Tempfer CB, Jirecek S, Riener EK , et al. Polymorphisms of thrombophilic and vasoactive genes and severe preeclampsia: a pilot study. J Soc Gynecol Investig 2004; 11: 227-231
• 39 Zdoukopoulos N, Doxani C, Messinis IE, Stefanidis I, Zintzaras E. Polymorphisms of the endothelial nitric oxide synthase (NOS3) gene in preeclampsia: a candidate-gene association study. BMC Pregnancy Childbirth 2011; 11: 89
• 40 Singh A, Sharma D, Raghunandan C, Bhattacharjee J. Role of inflammatory cytokines and eNOS gene polymorphism in pathophysiology of pre-eclampsia. Am J Reprod Immunol 2010; 63: 244-251
• 41 Salimi S, Naghavi A, Mokhtari M, Noora M, Yaghmaei M. Lack of relationship between endothelial nitric oxide synthase gene 4b/a and T-786C polymorphisms with preeclampsia in southeast of Iran. Arch Gynecol Obstet 2012; 285: 405-409
• 42 Kim YJ, Park HS, Lee HY , et al. Reduced L-arginine level and decreased placental eNOS activity in preeclampsia. Placenta 2006; 27: 438-444
• 43 Kobashi G, Yamada H, Ohta K, Kato E, Ebina Y, Fujimoto S. Endothelial nitric oxide synthase gene (NOS3) variant and hypertension in pregnancy. Am J Med Genet 2001; 103: 241-244
• 44 Ohta K, Kobashi G, Hata A , et al. Association between a variant of the glutathione S-transferase P1 gene (GSTP1) and hypertension in pregnancy in Japanese: interaction with parity, age, and genetic factors. Semin Thromb Hemost 2003; 29: 653-659
• 45 Nishizawa H, Pryor-Koishi K, Suzuki M , et al. Analysis of nitric oxide metabolism as a placental or maternal factor underlying the etiology of pre-eclampsia. Gynecol Obstet Invest 2009; 68: 239-247
• 46 Chen LK, Huang CH, Yeh HM , et al. Polymorphisms in the endothelial nitric oxide synthase gene may be protective against preeclampsia in a Chinese population. Reprod Sci 2007; 14: 175-181
• 47 Medica I, Kastrin A, Peterlin B. Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2007; 131: 115-126
• 48 Shaik AP, Sultana A, Bammidi VK, Sampathirao K, Jamil KJ. A meta-analysis of eNOS and ACE gene polymorphisms and risk of pre-eclampsia in women. J Obstet Gynaecol 2011; 31: 603-607
• 49 Vadillo-Ortega F, Perichart-Perera O, Espino S , et al. Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. BMJ 2011; 342: d2901
• 50 Salvarani C, Boiardi L, Casali B , et al. Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease. J Rheumatol 2002; 29: 535-540
• 51 Tesauro M, Thompson WC, Rogliani P, Qi L, Chaudhary PP, Moss J. Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci U S A 2000; 97: 2832-2835
• 52 Rankinen T, Rice T, Pérusse L , et al. NOS3 Glu298Asp genotype and blood pressure response to endurance training: the HERITAGE family study. Hypertension 2000; 36: 885-889
• 53 Nakayama M, Yasue H, Yoshimura M , et al. T-786—> C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999; 99: 2864-2870
• 54 Miyamoto Y, Saito Y, Nakayama M , et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T—> C mutation associated with coronary spastic angina. Hum Mol Genet 2000; 9: 2629-2637
• 55 Rossi GP, Taddei S, Virdis A , et al. The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients. J Am Coll Cardiol 2003; 41: 938-945
• 56 Casas JP, Bautista LE, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation 2004; 109: 1359-1365