Abstract
The multifactorial basis of preeclampsia (PE) implies that there are several genes and risk factors that are important in the development of the disease. Therefore, the exact etiology and pathogenesis of preeclampsia remains unclear. It is suggested that inappropriate regulation of the renin–angiotensin system (RAS) is a risk factor for hypertension during pregnancy. The angiotensin I-converting enzyme (ACE) serum level, a key component of the RAS, affects the blood pressure. It is hypothesized that the ACE gene polymorphisms contribute to preeclampsia development. In a case–control study containing 296 subjects (165 PE patients and 131 normotensive controls), we aimed to examine the association of the ACE gene I/D and rs4343 polymorphisms with preeclampsia in Iranian women. Genotyping for rs4343 and ACE I/D polymorphisms was performed by using TP-ARMS-PCR and conventional PCR, respectively. The rs4343 G allele frequency was higher in the case group (OR = 1.90, 95% CI, 1.37–2.65; P = 0.0001). Besides, a significant difference was detected for the genotype frequencies between the studied groups under dominant (OR = 3.94, 95% CI, 2.05–7.56; P < 0.0001) and recessive (OR = 2.21, 95% CI, 1.22–4.01; P = 0.009) inheritance models. For the I/D polymorphism, no significant differences were detected in the genotype and allele frequencies or any of the inheritance models between PE patients and controls. To verify the current results and validate the significance of the studied genetic variations, additional studies in diverse ethnic populations are required.
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References
Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365:785–99.
Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–94.
Obstetricians ACo, Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002;99:159–67.
Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet. 2005;366:1797–803.
Salonen Ros H, Lichtenstein P, Lipworth L, Cnattingius S. Genetic effects on the liability of developing pre‐eclampsia and gestational hypertension. Am J Med Genet A. 2000;91:256–60.
Krotz S, Fajardo J, Ghandi S, Patel A, Keith LG. Hypertensive disease in twin pregnancies: a review. Twin Res Hum Genet. 2002;5:8–14.
Lachmeijer AM, Arngrímsson R, Bastiaans EJ, Pals G, Leo P, de Vries JI, et al. Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia. Am J Obstet Gynecol. 2001;184:394–402.
Christina K, 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.
Kosmas IP, Tatsioni A, Ioannidis JP. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens. 2003;21:1221–28.
Gholami M, Mirfakhraie R, Pirjani R, Taheripanah R, Bayat S, Daryabari SA et al. Association study of FOXP3 gene and the risk of 0020 pre-eclampsia. Clin Exp Hypertens. 2017;5:1–4.
Colhoun HM, McKeigue PM, Smith GD. Problems of reporting genetic associations with complex outcomes. Lancet. 2003;361:865–72.
Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin–angiotensin–aldosterone system. Nat Rev Drug Discov. 2002;1:621.
Shah DM. The role of RAS in the pathogenesis of preeclampsia. Curr HypertensRrep. 2006;8:144–52.
Eisenmann JC, Sarzynski MA, Glenn K, Rothschild M, Heelan KA. ACE I/D genotype, adiposity, and blood pressure in children. Cardiovasc Diabetol. 2009;8:14.
Chung C, Wang R, Chen J, Fann C, Leu H, Ho H, et al. genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharm J. 2010;10:537.
Firouzabadi N, Shafiei M, Bahramali E, Ebrahimi SA, Bakhshandeh H, Tajik N. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population. Psychiat Res. 2012;200:336–42.
Hühne K, Leis S, Schmelz M, Rautenstrauss B, Birklein F. A polymorphic locus in the intron 16 of the human angiotensin‐converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I). Eur J Pain. 2004;8:221–25.
Abedin-Do A, Pouriamanesh S, Kamaliyan Z, Mirfakhraie R. Angiotensin-converting enzyme gene rs4343 polymorphism increases susceptibility to migraine. CNS Neurosci Ther. 2017;23:698–99.
Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–29.
Choi H, Kang JY, Yoon HS, Han SS, Whang CS, Moon IG, et al. Association of angiotensin-converting enzyme and angiotensinogen gene polymorphisms with preeclampsia. J Korean Med Sci. 2004;19:253–57.
González-Garrido JA, García-Sánchez JR, Tovar-Rodríguez JM, Olivares-Corichi IM. Preeclampsia is associated with ACE I/D polymorphism, obesity and oxidative damage in Mexican women. Pregnancy Hypertens. 2017;10:22–27.
Yang Y-L, Mo Y-P, He Y-S, Yang F, Xu Y, Li C-C, et al. Correlation between renin-angiotensin system gene polymorphisms and essential hypertension in the Chinese Yi ethnic group. J Renin Angiotensin Aldosterone Syst. 2015;16:975–81.
Freitas AI, Mendonca I, Brion M, et al. RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population. BMC Cardiovasc Disord. 2008;8:15.
Zhang H, Li YX, Peng WJ, Li ZW, Zhang CH, Di HH, et al. The gene variants of maternal/fetal renina-angiotensin system in preeclampsia: a hybrid case-parent/mother-control study. Sci Rep. 2017;7:5087.
Procopciuc LM, Caracostea G, Zaharie G, Puscas M, Iordache G, Popa M, et al. Maternal/newborn genotype contribution of the renin-angiotensin system (Met235Thr, Thr174Met, I/D-ACE, A2350G-ACE, A1166C-AT2R1, C3123A- AT2R2, 83A/G-REN) to the risk of pre-eclampsia: a Romanian study. J Renin Angiotensin Aldosterone Syst. 2011;12:539–48.
Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12:683–91.
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–8.
Fernandez-Calero T, Cabrera-Cabrera F, Ehrlich R, Marin M. Silent polymorphisms: can the tRNA population explain changes in protein properties? Life. 2016;6:9.
Sabarinathan R, Tafer H, Seemann SE, Hofacker IL, Stadler PF, Gorodkin J. RNAsnp: efficient detection of local RNA secondary structure changes induced by SNPs. Hum Mutat. 2013;34:546–56.
Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, et al. Linkage and association analysis of angiotensin I–converting enzyme (ACE)–gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet. 2001;68:1139–48.
Salimi S, Mokhtari M, Yaghmaei M, Jamshidi M, Naghavi A. Association of angiotensin-converting enzyme intron 16 insertion/deletion and angiotensin II type 1 receptor A1166C gene polymorphisms with preeclampsia in South East of Iran. Biomed Res Int. 2011; 2011:941515. https://doi.org/10.1155/2011/941515.
Rahimi Z, Rahimi Z, Mozafari H, Parsian A. Preeclampsia and angiotensin converting enzyme (ACE) I/D and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms: association with ACE I/D polymorphism. J Renin Angiotensin Aldosterone Syst. 2013;14:174–80.
Li H, Ma Y, Fu Q, Wang L. Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women. Hypertens Pregnancy. 2007;26:293–301.
Bereketoglu C, Kasap M, Pazarbasi A. Studies on angiotensin-converting enzyme insertion/deletion polymorphism and genotype distributions in Turkish preeclampsia patients. J Pregnancy. 2012;2012:108–206.
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;86:1343–46.
Uemura K, Nakura J, Kohara K, Miki T. Association of ACE I/D polymorphism with cardiovascular risk factors. Human Genet. 2000;107:239–42.
Rice T, Rankinen T, Province MA, Chagnon YC, Pérusse L, Borecki IB, et al. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec Family Study. Circulation. 2000;102:1956–63.
Jackson A, Brown K, Langdown J, Luddington R, Baglin T. Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism. Br J Haematol. 2000;111:562–64.
Serrano NC, Diaz LA, Paez MC, Mesa CM, Cifuentes R, Monterrosa A, et al. Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias. PLoS Med. 2006;3:e520.
Alvi FM, Hasnain S. ACE I/D and G2350A polymorphisms in Pakistani hypertensive population of Punjab. Clin Exp Hypertens. 2009;31:471–80.
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We are grateful to Arash Women Hospital and all participants for their kind collaboration.
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Abedin Do, A., Esmaeilzadeh, E., Amin-Beidokhti, M. et al. ACE gene rs4343 polymorphism elevates the risk of preeclampsia in pregnant women. J Hum Hypertens 32, 825–830 (2018). https://doi.org/10.1038/s41371-018-0096-4
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DOI: https://doi.org/10.1038/s41371-018-0096-4
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