Journal of Reproduction & Infertility

Journal of Reproduction & Infertility

Allele, Genotype and Haplotype Structures of Functional Polymorphic Variants in Endothelial Nitric Oxide Synthase (eNOS), Angiotensinogen (ACE) and Aldosterone Synthase (CYP11B2) Genes in Healthy Pregnant Women of Indian Ethnicity

Authors
Anichavezhi Devendran 1
Sreekala Nampoothiri 2
Deepak Shewade 1
Suvro Chatterjee 3
Balachandar Jayaraman 4
Adithan Chandrasekharan 1
1 Department of Pharmacology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Pondicherry, India
2 Department of Biotechnology and Biochemical Engineering, Sree Buddha College of Engineering, Alappuzha, Kerala, India
3 Vascular Biology Division, AU-KBC Research Centre, Madras Institute of Technology (M.I.T), Anna University, Chrompet, Chennai, India
4 Department of Cardiology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Pondicherry, India
Abstract
Background: Variants in the candidate genes eNOS, CYP11B2 and ACE have been implicated as liable biomarkers that can predict complications like hypertension and preeclampsia. Studies on the impact and distribution of these variants on healthy pregnancy have not been done so far in south Indian or in any of the native Indian population. Examining these variants could lay a strong basis in understanding the genetic aspects of preeclampsia and further offer effective means in early risk assessment in a preeclampsia. Methods: Genotyping for 303 unrelated healthy women of Tamilian origin who underwent uncomplicated term pregnancies was executed by PCR-RFLP for eNOS, CYP11B2 and ACE variants. Haplotype assessment and pairwise linkage disequilibrium (LD) investigation were performed by Haploview software. Results: The prevalence of eNOS variants (-786T>C, Glu298Asp and intron 4 VNTR) was 12%, 21.6% and 21.1%, respectively. The incidence of CYP11B2 (-344C>T) and ACE (287 bp Alu I/D) variants was found to be 43.8% and 42.7%. The observed frequencies of the studied polymorphisms did not diverge from the HWE (p>0.05). Significant LD was observed between 3 eNOS gene polymorphisms. Six different haplotype structures with a frequency of >1% were generated from three eNOS variants. Among the haplotypes generated, the haplotype T-4b-G was the most common with the frequency of 64.4%. There was a statistically significant inconsistency in the study population in comparison to other global races. Conclusion: The outcome of this study could be used for investigating future therapeutic value of the variants in a preeclamptic set-up which could pose a credible diagnostic potential for primary risk assessment of women susceptible to preeclampsia/other pregnancy related complications.
Keywords
CYP11B2
eNOS
haplotypes
Hypertension
preeclampsia
Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2(8670):997-1000.
Freel EM, Connell JM. Mechanisms of hypertension: the expanding role of aldosterone. J Am Soc Nephrol. 2004;15(8):1993-2001.
White PC, Rainey WE. Editorial: polymorphisms in CYP11B genes and 11-hydroxylase activity. J Clin Endocrinol Metab. 2005;90(2):1252-5.
Bassett MH, Zhang Y, Clyne C, White PC, Rainey WE. Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol. 2002;28(2):125-35.
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343-6.
Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359(6396):641-4.
Hohenfellner K, Wingen AM, Nauroth O, Wuhl E, Mehls O, Schaefer F. Impact of ACE I/D gene polymorphism on congenital renal malformations. Pediatr Nephrol. 2001;16(4):356-61.
Schmidt MA, Chakrabarti AK, Kehrer C, Pfeninnger D, Brook RD, Kaciroti N, et al. Interactive effects of the ACE DD polymorphism with the NOS III homozygous G849T (Glu298-->Asp) variant in determining endothelial function in coronary artery disease. Vasc Med. 2003;8(3):177-83.
Cockell AP, Poston L. Flow-mediated vasodilatation is enhanced in normal pregnancy but reduced in preeclampsia. Hypertension. 1997;30(2 Pt 1):247-51.
Dorup I, Skajaa K, Sorensen KE. Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation. Am J Physiol. 1999;276(3 Pt 2):H821-5.
Satyanarayana CR, Devendran A, Sundaram R, Gopal SD, Rajagopal K, Chandrasekaran A. Genetic variations and haplotypes of the 5' regulatory region of CYP2C19 in South Indian population. Drug Metab Pharmacokinet. 2009;24(2):185-93.
Arun Kumar AS, Chakradhara Rao US, Umamaheswaran G, Ramu P, Kesavan R, Shewade DG, et al. Haplotype structures of common variants of CYP2C8, CYP2C9, and ADRB1 genes in a South Indian population. Genet Test Mol Biomarkers. 2011;15(6):407-13.
Valenzuela FJ, Perez-Sepulveda A, Torres MJ, Correa P, Repetto GM, Illanes SE. Pathogenesis of preeclampsia: the genetic component. J Pregnancy. 2012;2012:632732.
Umamaheswaran G, Praveen RG, Arunkumar AS, Das AK, Shewade DG, Adithan C. Genetic analysis of OCT1 gene polymorphisms in an Indian population. Indian J Hum Genet. 2011;17(3):164-8.
Wang Y, Kikuchi S, Suzuki H, Nagase S, Koyama A. Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal diseases. Nephrol Dial Transplant. 1999;14(12):2898-902.
Rajan S, Ramu P, Umamaheswaran G, Adithan C. Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population. Indian J Med Res. 2010;132:379-85.
Krex D, Fortun S, Kuhlisch E, Schackert HK, Schackert G. The role of endothelial nitric oxide synthase (eNOS) genetic variants in European patients with intracranial aneurysms. J Cereb Blood Flow Metab. 2006;26(10):1250-5.
Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993;3(2):120-1.
Antoniades C, Tousoulis D, Vasiliadou C, Pitsavos C, Chrysochoou C, Panagiotakos D, et al. Genetic polymorphism on endothelial nitric oxide synthase affects endothelial activation and inflammatory response during the acute phase of myocardial infarction. J Am Coll Cardiol. 2005;46(6):1101-9.
Kumar RG, Spurthi MK, Kumar KG, Sahu SK, Rani SH. Endothelial nitric oxide synthase polymorphism G298T in association with oxidative DNA damage in coronary atherosclerosis. J Genet. 2012;91(3):349-52.
Sharma D, Hussain SA, Akhter N, Singh A, Trivedi SS, Bhatttacharjee J. Endothelial nitric oxide synthase (eNOS) gene Glu298Asp polymorphism and expression in North Indian preeclamptic women. Pregnancy Hypertens. 2014;4(1):65-9.
Zhao Q, Su SY, Chen SF, Li B, Gu DF. Association study of the endothelial nitric oxide synthase gene polymorphisms with essential hypertension in northern Han Chinese. Chin Med J (Engl). 2006;119(13):1065-71.
Krischek B, Kasuya H, Akagawa H, Tajima A, Narita A, Onda H, et al. Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients. J Neurosurg. 2006;105(5):717-22.
Serrano NC, Diaz LA, Casas JP, Hingorani AD, Moreno de Lucca D, Paez MC. Frequency of eNOS polymorphisms in the Colombian general population. BMC Genet. 2010;11:54.
Akagawa H, Kasuya H, Onda H, Yoneyama T, Sasahara A, Kim CJ, et al. Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size. J Neurosurg. 2005;102(1):68-71.
Angeline T, Isabel W, Tsongalis GJ. Endothelial nitric oxide gene polymorphisms, nitric oxide production and coronary artery disease risk in a South Indian population. Exp Mol Pathol. 2010;89(3): 205-8.
Shimizu T, Onuma T, Kawamori R, Makita Y, Tomino Y. Endothelial nitric oxide synthase gene and the development of diabetic nephropathy. Diabetes Res Clin Pract. 2002;58(3):179-85.
NCBI: dbSNP Short Genetic Variations [Internet]. HapMap -786T>C [cited 2014 Sept 20]. Available from: http://www.ncbi.nlm.nih.gov/ projects/SNP/snp_ref.cgi?rs=2070744.
Lin S, Qu H, Qiu M. Allele A in intron 4 of ecNOS gene will not increase the risk of diabetic nephropathy in type 2 diabetes of Chinese population. Nephron. 2002;91(4):768.
Ezzidi I, Mtiraoui N, Mohamed MB, Mahjoub T, Kacem M, Almawi WY. Association of endothelial nitric oxide synthase Glu298Asp, 4b/a, and -786T>C gene variants with diabetic nephropathy. J Diabetes Complications. 2008;22(5):331-8.
Mollsten A, Lajer M, Jorsal A, Tarnow L. The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes. Mol Genet Metab. 2009;97(1):80-4.
Rippin JD, Patel A, Belyaev ND, Gill GV, Barnett AH, Bain SC. Nitric oxide synthase gene polymorphisms and diabetic nephropathy. Diabetologia. 2003;46(12):1706.
Srivastava S, Bhagi S, Kumari B, Chandra K, Sarkar S, Ashraf MZ. Association of polymorphisms in angiotensin and aldosterone synthase genes of the rennin-angiotensin-aldosterone system with high-altitude pulmonary edema. J Renin Angiotensin Aldosterone Syst. 2012;13(1):155-60.
Gu D, Ge D, He J, Li B, Chen J, Liu D, et al. Haplotypic analyses of the aldosterone synthase gene CYP11B2 associated with stage-2 hypertension in northern Han Chinese. Clin Genet. 2004;66(5): 409-16.
Tsukada K, Ishimitsu T, Teranishi M, Saitoh M, Yoshii M, Inada H, et al. Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. J Hum Hypertens. 2002;16(11):789-93.
Yan G, Wang Y. Association of CYP11B2 gene polymorphism with ischemic stroke in the north Chinese Han population. Neurol India. 2012;60(5):504-9.
NCBI: dbSNP Short Genetic Variations [Internet]. HapMap CYP11B2 [cited 2014 Sept 20]. Available from: http://www.ncbi.nlm.nih.gov /projects/SNP/snp_ref.cgi?rs=1799998.
Davies E, Holloway CD, Ingram MC, Inglis GC, Friel EC, Morrison C, et al. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension. 1999;33(2):703-7.
Jaganmohan P, Narayana Rao SVL, Sambasiva Rao KRS. Studies on the evaluation of angiotensin-I converting enzyme polymorphism under fluorosis mediated renal failures in Nellore District Andhra Pradesh, India P. Global J Mol Sci. 2010;5(2):74-9.
Ramu P, Umamaheswaran G, Shewade DG, Swaminathan RP, Dutta TK, Balachander J, et al. Candidate gene polymorphisms of renin angiotensin system and essential hypertension in a South Indian Tamilian population. Int J Hum Genet. 2011;11(1):31-40.
Yang K, Zhang F, Li F, Su J, Wen S, Liu Y, et al. Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to psoriasis in a Chinese population. J Renin Angiotensin Aldosterone Syst. 2014;15(1):39-43.
Ali T, Mohammed OH, Mehmet S, Hameeda AB, Riad B. Genotypes and allele frequencies of angiotensin converting enzyme (ACE) insertion/deletion polymorphism among Omanis. J Sci Res Med Sci. 2002;4(1-2):25-7.
Marre M, Jeunemaitre X, Gallois Y, Rodier M, Chatellier G, Sert C, et al. Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group. J Clin Invest. 1997;99(7):1585-95.
Rigoli L, Chimenz R, di Bella C, Cavallaro E, Caruso R, Briuglia S, et al. Angiotensin-converting enzyme and angiotensin type 2 receptor gene genotype distributions in Italian children with congenital uropathies. Pediatr Res. 2004;56(6):988-93.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, 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(22):2864-70.
Akhter MS, Arijit B, Renu S. Role of endothelial nitric oxide synthase gene in vascular diseases. East J Med. 2009;14(2):46-50.
Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, et al. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun. 1998;245(1):190-3.
Tu Y, Cui G, Xu Y, Bao X, Wang X, Wang DW. Genetic polymorphism of CYP11B2 gene and stroke in the Han Chinese population and a meta-analysis. Pharmacogenet Genomics. 2011;21(3): 115-20.
White PC, Hautanen A, Kupari M. Aldosterone synthase (CYP11B2) polymorphisms and cardiovascular function. J Steroid Biochem Mol Biol. 1999;69(1-6):409-12.
Re RN, Frohlich ED. Controversies in the genetic analysis of hypertensive diseases. Hypertension. 1996;28(5):880.
Staessen JA, Wang JG, Ginocchio G, Petrov V, Saavedra AP, Soubrier F, et al. The deletion/insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. J Hypertens. 1997;15(12 Pt 2):1579-92.
Ashavaid TF, Shalia KK, Nair KG, Dalal JJ. ACE and AT1R gene polymorphisms and hypertension in Indian population. J Clin Lab Anal. 2000;14(5): 230-7.
Rai TS, Dhandapany PS, Ahluwalia TS, Bhardwaj M, Bahl A, Talwar KK, et al. ACE I/D polymorphism in Indian patients with hypertrophic cardiomyopathy and dilated cardiomyopathy. Mol Cell Biochem. 2008;311(1-2):67-72.
Gui-yan W, Yan-hua W, Qun X, Wei-jun T, Ming-ling G, Jian W, et al. Associations between RAS Gene polymorphisms, environmental factors and hypertension in Mongolian people. Eur J Epidemiol. 2006;21(4):287-92.
Ethnicity and power in the contemporary world; 1996. Ethnic conflict, federalism and democracy in India; 1996, Chapter 10. Available from: http://archive.unu.edu/unupress/unupbooks/uu12ee/uu12ee00.htm.
Journal of Reproduction & Infertility
Volume 16, Issue 4
Autumn 2015
Pages 180-192