Abstract
Increased expression and activity of inducible nitric oxide synthase (iNOS) may contribute to the pathogenesis of pre-eclampsia (PE) and gestational hypertension (GH). However, no previous study has examined whether genetic polymorphisms in the iNOS gene are associated with PE or GH. We examined whether two functional, clinically relevant iNOS genetic polymorphisms (the C−1026A polymorphism, rs2779249, in the promoter region, and the G2087A polymorphism, rs2297518, in exon 16) are associated with GH or with PE. We studied 565 pregnant women: 212 healthy pregnant (HP), 166 pregnant with GH and 187 pregnant with PE. Genotypes were determined by real-time PCR, using the Taqman allele discrimination assay. The PHASE 2.1 program was used to estimate haplotype distributions in the three study groups. We found no significant association between the C−1026A polymorphism and PE or GH (P>0.05). However, we found the GA genotype and the A allele for the G2087A polymorphism at higher frequency in PE, but not in GH, compared with HP (P<0.05). The haplotype analysis showed no significant intergroup differences (P>0.05). These findings suggest that iNOS genetic variants may affect the susceptibility to PE, but not to GH.
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References
Walker JJ . Pre-eclampsia. Lancet 2000; 356 (9237): 1260–1265.
Redman CW, Sargent IL . Latest advances in understanding preeclampsia. Science 2005; 308 (5728): 1592–1594.
Lam C, Lim KH, Karumanchi SA . Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia. Hypertension 2005; 46 (5): 1077–1085.
Sandrim VC, Palei AC, Metzger IF, Gomes VA, Cavalli RC, Tanus-Santos JE . Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endogline in preeclampsia. Hypertension 2008; 52 (2): 402–407.
Palei AC, Sandrim VC, Cavalli RC, Tanus-Santos JE . Comparative assessment of matrix metalloproteinase (MMP)-2 and MMP-9, and their inhibitors, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in preeclampsia and gestational hypertension. Clin Biochem 2008; 41 (10–11): 875–880.
McCarthy AL, Woolfson RG, Raju SK, Poston L . Abnormal endothelial cell function of resistance arteries from women with preeclampsia. Am J Obstet Gynecol 1993; 168 (4): 1323–1330.
Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK . Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161 (5): 1200–1204.
Zhou Y, Damsky CH, Fisher SJ . Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997; 99 (9): 2152–2164.
Sandrim VC, Montenegro MF, Palei AC, Metzger IF, Sertorio JT, Cavalli RC et al. Increased circulating cell-free hemoglobin levels reduce nitric oxide bioavailability in preeclampsia. Free Radic Biol Med 2010; 49 (3): 493–500.
Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G et al. eNOS haplotypes associated with gestational hypertension or preeclampsia. Pharmacogenomics 2008; 9 (10): 1467–1473.
Sandrim VC, Palei AC, Luizon MR, Izidoro-Toledo TC, Cavalli RC, Tanus-Santos JE . eNOS haplotypes affect the responsiveness to antihypertensive therapy in preeclampsia but not in gestational hypertension. Pharmacogenomics J 2010; 10 (1): 40–45.
Sandrim VC, Palei AC, Metzger IF, Cavalli RC, Duarte G, Tanus-Santos JE . Interethnic differences in ADMA concentrations and negative association with nitric oxide formation in preeclampsia. Clin Chim Acta 2010; 411 (19–20): 1457–1460.
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 (7): 506–510.
Moncada S, Higgs A . The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329 (27): 2002–2012.
Matsubara K, Matsubara Y, Hyodo S, Katayama T, Ito M . Role of nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res 2010; 36 (2): 239–247.
Sankaralingam S, Arenas IA, Lalu MM, Davidge ST . Preeclampsia: current understanding of the molecular basis of vascular dysfunction. Expert Rev Mol Med 2006; 8 (3): 1–20.
Bhatnagar S, Bhattacharjee J, Vaid M, Madan T, Trivedi SS, Sarma PU . Inducible nitric oxide synthase (iNOS) gene polymorphism in pre-eclampsia: a pilot study in North India. Aust N Z J Obstet Gynaecol 2007; 47 (6): 477–482.
Hong HJ, Loh SH, Yen MH . Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase. Br J Pharmacol 2000; 131 (3): 631–637.
Li W, Liu H, Fu L, Li D, Zhao Y . Identification of Yin Yang 1-interacting partners at -1026C/A in the human iNOS promoter. Arch Biochem Biophys 2010; 498 (2): 119–126.
Fu L, Zhao Y, Lu J, Shi J, Li C, Liu H et al. Functional single nucleotide polymorphism-1026C/A of inducible nitric oxide synthase gene with increased YY1-binding affinity is associated with hypertension in a Chinese Han population. J Hypertens 2009; 27 (5): 991–1000.
Wang SS, Davis S, Cerhan JR, Hartge P, Severson RK, Cozen W et al. Polymorphisms in oxidative stress genes and risk for non-Hodgkin lymphoma. Carcinogenesis 2006; 27 (9): 1828–1834.
Lee KM, Kang D, Park SK, Berndt SI, Reding D, Chatterjee N et al. Nitric oxide synthase gene polymorphisms and prostate cancer risk. Carcinogenesis 2009; 30 (4): 621–625.
Report of the National High Blood Pressure Education Program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000; 183: S1–S22.
Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68 (4): 978–989.
Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73 (5): 1162–1169.
Sandrim VC, Palei AC, Cavalli RC, Araujo FM, Ramos ES, Duarte G et al. Vascular endothelial growth factor genotypes and haplotypes are associated with pre-eclampsia but not with gestational hypertension. Mol Hum Reprod 2009; 15 (2): 115–120.
de Vasconcelos D, Izidoro-Toledo TC, Sandrim VC, Tanus-Santos JE, Palei AC, Cavalli RC . Aldosterone synthase gene polymorphism is not associated with gestational hypertension or preeclampsia. Clin Chim Acta 2009; 400 (1–2): 139–141.
Johannesen J, Pie A, Pociot F, Kristiansen OP, Karlsen AE, Nerup J . Linkage of the human inducible nitric oxide synthase gene to type 1 diabetes. J Clin Endocrinol Metab 2001; 86 (6): 2792–2796.
Baker PN, Davidge ST, Roberts JM . Plasma from women with preeclampsia increases endothelial cell nitric oxide production. Hypertension 1995; 26 (2): 244–248.
Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H . Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem 2001; 276 (31): 29596–29602.
McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ . Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008; 156 (5): 918–930.
Rutherford S, Johnson MP, Curtain RP, Griffiths LR . Chromosome 17 and the inducible nitric oxide synthase gene in human essential hypertension. Hum Genet 2001; 109 (4): 408–415.
Clark AG . The role of haplotypes in candidate gene studies. Genet Epidemiol 2004; 27 (4): 321–333.
Palei AC, Sandrim VC, Duarte G, Cavalli RC, Gerlach RF, Tanus-Santos JE . Matrix metalloproteinase (MMP)-9 genotypes and haplotypes in preeclampsia and gestational hypertension. Clin Chim Acta 2010; 411 (11–12): 874–877.
Acknowledgements
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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Amaral, L., Palei, A., Sandrim, V. et al. Maternal iNOS genetic polymorphisms and hypertensive disorders of pregnancy. J Hum Hypertens 26, 547–552 (2012). https://doi.org/10.1038/jhh.2011.65
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DOI: https://doi.org/10.1038/jhh.2011.65
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