J Korean Med Sci.  2004 Apr;19(2):253-257. 10.3346/jkms.2004.19.2.253.

Association of Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms with Preeclampsia

• Choi H
• Kang JY
• Yoon HS
• Han SS
• Whang CS
• Moon IG
• Shin HH
• Park JB

• KMID: 1733485
• DOI: http://doi.org/10.3346/jkms.2004.19.2.253

Abstract

We tested the hypothesis that angiotensin-converting enzyme (ACE) and angiotensinogen gene polymorphism influence the incidence, development and outcome of preeclampsia. Subjects were recruited from 90 Korean patients with preeclampsia during pregnancy and 98 age-matched controls. After isolation of DNA, polymerase chain reactions (PCR) were carried out to detect polymorphism of the ACE and angiotensinogen. M235T and T174M genotypes of angiotensinogen were determined by digestion with restriction enzyme endonuclease Tth 111-I and NCo I, respectively. The frequency of DD genotype was significantly greater in preeclampsia (0.36) than in controls (0.14) (p<0.05). The frequency of D allele was 0.55 in preeclampsia and 0.40 in controls (p<0.05). There were no differences in the onset of preeclampsia and pregnancy outcomes according to the ACE genotypes. There was no difference in the frequency of a allele of angiotensinogen M235T between the groups (0.79:0.78 in preeclampsia : controls). The frequency of T allele of angiotensinogen T174M gene was slightly increased, but not significantly, in preeclampsia (0.11) than in controls (0.07). In a multivariate analysis, only ACE genotype was associated with the development of preeclampsia (beta=0.27, p=0.05). In conclusion, a molecular variant of ACE, but not angiotensinogen, gene is associated with preeclampsia in Korean women.

Keyword

Genetics; Peptidyl-Dipeptidase A; Angiotensin Converting Enzyme; Angiotensinogen Genes; Pre-Eclampsia

MeSH Terms

Adult
Angiotensinogen/*genetics
Female
Gene Frequency
Genotype
Human
Korea
Peptidyl-Dipeptidase A/*genetics
*Polymorphism (Genetics)
Pre-Eclampsia/*genetics
Pregnancy

Reference

1. Roberts JM, Pearson G, Cutler J, Lindheimer M. NHLBI Working Group on Research on Hypertension During Pregnancy. Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy. Hypertension. 2003. 41:437–445.

2. Cooper DW, Hill JA, Chesley LC, Bryans CI. Genetic control of susceptibility to eclampsia and miscarriage. Br J Obstet Gynaecol. 1988. 95:644–653.

3. Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J, Varner MW. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med. 2001. 344:867–872.

4. Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001. 357:53–56.

5. Roberts JM, Lain KY. Recent Insights into the pathogenesis of preeclampsia. Placenta. 2002. 23:359–372.

6. Ward K, Hata A, Jeunemaitre X, Helin C, Nelson L, Namikawa C, Farrington PF, Ogasawara M, Suzumori K, Tomoda S, Berrebi S, Sasaki M, Corvol P, Lifton RP, Lalouel JM. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet. 1993. 4:59–61.

7. Arngrimsson R, Purandare S, Connor M, Walker JJ, Bjornsson S, Soubrier F, Kotelevtsev YV, Geirsson RT, Bjornsson H. Angiotensinogen: a candidate gene involved in preeclampsia? (letter). Nat Genet. 1993. 4:114–115.

8. Shim SS, Shim JY, Lim JH, Park JS, Jun JK, Bai KB, Yoon BH, Syn HC. Molecular biological approach to find out the etiology of hypertensive disorder in pregnancy: analysis of the polymorphism in the promoter of human angiotensinogen gene in Korean population. Korean J Obstet Gynecol. 2003. 46:1486–1492.

9. Guo G, Wilton AN, Fu Y, Qiu H, Brennecke SP, Cooper DW. Angiotensinogen gene variation in a population case-control study of preeclampsia/ eclampsia in Australians and Chinese. Electrophoresis. 1997. 18:1646–1649.

10. Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation. 1994. 90:2199–2202.

11. Tamura T, Johanning GL, Goldenberg RL, Johnston KE, DuBard MB. Effect of angiotensin-converting enzyme gene polymorphism on pregnancy outcome, enzyme activity, and zinc concentration. Obstet Gynecol. 1996. 88:497–502.

12. Kim DK, Kim JW, Kim S, Gwon HC, Ryu JC, Huh JE, Choo JA, Choi Y, Rhee CH, Lee WR. Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 1997. 17:3242–3247.

13. Johanning GL, Johnston KE, Tamura T, Goldenberg RL. Ethnic differences in angiotensin converting enzyme gene polymorphism. J Hypertens. 1995. 13:710–711.

14. 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.

15. 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. 86:1343–1346.

16. Marre M, Jeunemaitre X, Gallois Y, Rodier M, Chatellier G, Sert C, Dusselier L, Kahal Z, Chaillous L, Halimi S, Muller A, Sackmann H, Bauduceau B, Bled F, Passa P, Alhenc-Gelas F. 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. 99:1585–1595.

17. Morise T, Takeuchi Y, Takeda R. Rapid detection and prevalence of the variants of the angiotensinogen gene in patients with essential hypertension. J Intern Med. 1995. 237:175–180.

18. Bennett CL, Schrader AP, Morris BJ. Cross-sectional analysis of Met235-->Thr variant of angiotensinogen gene in severe, familial hypertension. Biochem Biophys Res Commun. 1993. 197:833–839.

19. Cugini P, Letizia C, Di Palma L, Battisti P, Caserta D, Moscarini M, Scavo D. Serum angiotensin-converting enzyme activity in pre-eclamptic pregnancy: evidence for a relative hypermesorACEemia. Enzyme. 1990. 43:113–121.

20. Dux S, Yaron A, Carmel A, Rosenfeld JB. Renin, aldosterone, and serum-converting enzyme activity during normal and hypertensive pregnancy. Gynecol Obstet Invest. 1984. 17:252–257.

21. 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. 111:562–564.

22. Langer B, Grima M, Coquard C, Bader AM, Schlaeder G, Imbs JL. Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia. Obstet Gynecol. 1998. 91:196–202.

23. Morgan L, Foster F, Hayman R, Crawshaw S, Baker PN, Pipkin FB, Kalsheker N. Angiotensin converting enzyme insertion-deletion polymorphism in normotensive and preeclamptic pregnancies. J Hypertens. 1999. 17:765–768.

24. Heiskanen JTM, Pirskanen MM, Hiltunen MJ, Mannermaa AJ, Punnonem KRA, Heinonen ST. Insertion-deletion polymorphism in the gene for angiotensin-converting enzyme is associated with obstetric cholestasis but not with preeclampsia. Am J Obstet Gynecol. 2001. 185:600–603.

25. Rasmussen AB, Pedersen EB, Romer FK, Johannesen P, Kristensen S, Lauritsen JG, Wohlert M. The influence of normotensive pregnancy and pre-eclampsia on angiotensin-converting enzyme. Acta Obstet Gynecol Scand. 1983. 62:341–344.

26. Jacob HJ, Lindpaintner K, Lincoln SE, Kusumi K, Bunker RK, Mao YP, Ganten D, Dzau VJ, Lander ES. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991. 67:213–224.

27. Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Soubrier F, Dubay C, Cartwright P, De Gouyon B, Julier C, Takahasi S, Vincent M, Ganten D, Georges M, Lathrop GM. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991. 353:521–529.

28. Mello G, Parretti E, Gensini F, Sticchi E, Mecacci F, Scarselli G, Genuardi M, Abbate R, Fatini C. Maternal-fetal flow, negative events, and preeclampsia: role of ACE I/D polymorphism. Hypertension. 2003. 41:932–937.

29. Fatini C, Gensini F, Battaglini B, Prisco D, Cellai AP, Fedi S, Marcucci R, Brunelli T, Mello G, Parretti E, Pepe G, Abbate R. Angiotensin converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetalloss susceptibility. Blood Coagul Fibrinolysis. 2000. 11:657–662.

30. Roh CR, Kim DK, Yoon BK, Yang SH, Chung JH, Bae DS, Lee JH. A common genetic variant of the angiotensin converting enzyme (ACE) gene and pregnancy induced hypertensive disorders. Korean J Obstet Gynecol. 1997. 40:1189–1199.

31. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, Corvol P. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992. 71:169–180.

32. August P, Sealey JE. Lahagh JH, Brenner BM, editors. The renin-angiotensin system in normal and hypertensive pregnancy and in ovarian function. Hypertension: Pathophysiology, Diagnosis, and Management. 1990. New York: Raven Press;1761–1778.