Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Preeclampsia in Japanese Patients

ABSTRACT

To clarify whether the homozygous deletion (DD) genotype of angiotensin-converting enzyme gene (ACE) is a genetic risk factor for preeclampsia in Japanese women, we performed ACE genotyping in patients with preeclampsia and healthy pregnant women, and analyzed the relationship between preeclampsia and ACE genotype, taking into account some well-known contributing factors for preeclampsia, such as primiparity, positive family history of hypertension, prepregnancy body mass index < 24, and heterozygosity and homozygosity of T235 (MT+TT) genotypes of the angiotensinogen (AGT) gene. Among all of the subjects, the frequency of the DD genotype was not different between patients with preeclampsia and controls (16% and 12%, respectively). Regarding primiparity, prepregnancy body mass index < 24, and MT+TT genotypes of AGT, no significant differences in the frequency of the DD genotype of ACE were found between patients with preeclampsia and controls, although in a subgroup positive for family history of hypertension, the frequency of the DD genotype tended to be higher in patients with preeclampsia (25%) than in controls (8%; p = 0.061). Carrying the DD genotype may have some influence on the pathogenesis of preeclampsia, perhaps through effects on placental hypoxia or the interaction of hypertensive disease and atherosclerosis, although this influence may not be strong. Additional studies using a larger number of patients and analyses that include other genetic and environmental factors will be necessary to confirm these results.

KEYWORDS

Preeclampsia - pregnancy - angiotensin-converting enzyme - polymorphism

REFERENCES

• 1 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
• 2 Tiret L, Rigat B, Visvikis S et al.. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-convertin enzyme (ACE) gene controls plasma ACE levels.  Am J Hum Genet. 1992;  51 197-205
• 3 Cambien F, Poirier O, Lecerf L et al.. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction.  Nature. 1992;  359 641-644
• 4 Oike Y, Hata A, Ogata Y, Numata Y, Shido K, Kondo K. Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.  J Clin Invest. 1995;  96 2975-2979
• 5 Uemura K, Nakura J, Kohara K, Miki T. Association of ACE I/D polymorphism with cardiovascular risk factors.  Hum Genet. 2000;  107 239-242
• 6 Abbud Z A, Wilson A C, Cosgrove N M, Kostis J B. Angiotensin-converting enzyme gene polymorphism in systemic hypertension.  Am J Cardiol. 1998;  81 244-246
• 7 Higashimori K, Zhao Y, Higaki J et al.. Association analysis of the angiotensin coverting enzyme gene with essential hypertension in the Japanese population.  Biochem Biophys Res Commun. 1993;  191 399-404
• 8 Ishigami T, Iwamoto T, Tamura K et al.. Angiotensin I converting enzyme (ACE) gene polymorphism and essential hypertension in Japan. Ethnic difference of ACE genotype.  Am J Hypertens. 1995;  8 95-97
• 9 Tamaki S, Nakamura Y, Tsujita Y et al.. Polymorphism of the angiotensinogen converting enzyme gene and blood pressure in Japanese general population (the Shigaraki Study).  Hypertens Res. 2002;  25 843-848
• 10 Parente J V, Franco Jr J G, Greene L J, Meirelles R S, Martinez A R. Angiotensin-converting enzyme: serum levels during normal pregnancy.  Am J Obstet Gynecol. 1979;  135 586-589
• 11 Oats J N, Pipkin F B, Symonds E M. Angiotensin-converting enzyme and the renin-angiotensin system in normotensive primigravid pregnancy.  Clin Exp Hypertens Res. 1982;  1 73-91
• 12 Goldkrand J W, Fuentes A M. The relation of angiotensin-converting enzyme to the pregnancy-induced hypertension-preeclampsia syndrome.  Am J Obstet Gynecol. 1986;  154 792-800
• 13 Rasmussen A B, Pedersen E B, Romer F K et al.. The influence of normotensive pregnancy and pre-eclampsia on angiotensin-converting enzyme.  Acta Obstet Gynecol Scand. 1983;  62 341-344
• 14 Li J, Hu H Y, Zhao Y N. Serum angiotensin-converting enzyme activity in pregnancy-induced hypertension.  Gynecol Obstet Invest. 1992;  33 138-141
• 15 Zhou N, Yu P, Chen J, Huang H, Jiang S. Detection of insertion/deletion polymorphism of angiotensin converting enzyme gene in preeclampsia.  Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 1999;  16 29-31
• 16 Ward K, Hata A, Jeunemaitre X et al.. A molecular variant of angiotensinogen associated with preeclampsia.  Nat Genet. 1993;  4 59-61
• 17 Kobashi G, Hata A, Shido K et al.. Association of a variant of the angiotensinogen gene with pure type of hypertension in pregnancy in the Japanese: implication of a racial difference and significance of an age factor.  Am J Med Genet. 1999;  86 232-236
• 18 Inoue I, Nakajima T, Williams C S et al.. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.  J Clin Invest. 1997;  99 1786-1797
• 19 Morgan T, Craven C, Lalouel J M, Ward K. Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spinal arteries in first-trimester decidua.  Am J Obstet Gynecol. 1999;  180 95-102
• 20 National High Blood Pressure Education Program Working Group . report on high blood pressure in pregnancy.  Am J Obstet Gynecol. 1990;  163 1689-1712
• 21 Tamakoshi A, Ishikawa S, Ojima T et al.. The guideline of informed consent in epidemiological studies, Ver. 1.0 Tokyo; Nihonijishinposya 2000: 1-27
• 22 Odawara M, Matsunuma A, Yamashita K. Mistyping frequency of the angiotensin-converting enzyme gene polymorphism and an improved method for its avoidance.  Hum Genet. 1997;  100 163-166
• 23 Russ A P, Maerz W, Ruzicka V, Stein U, Gross W. Rapid detection of the hypertension-associated Met235→Thr allele of the human angiotensinogen gene.  Hum Mol Genet. 1993;  2 609-610
• 24 Tamura T, Johanning G L, Goldenberg R L, Johnston K E, DuBard M B. Effect of angiotensin-converting enzyme gene polymorphism on pregnancy outcome, enzyme activity, and zinc concentration.  Obstet Gynecol. 1996;  88 497-502
• 25 Morgan L, Foster F, Hayman R et al.. Angiotensin-converting enzyme insertion-deletion polymorphism in normotensive and preeclamptic pregnancies.  J Hypertens. 1999;  17 765-768
• 26 Nalogowska-Glosnicka K, Lacka B, Zychma M et al.. Lack of relationship between angiotensinogen gene m235t polymorphism and gene insertion/deletion (I/D-intron 16) and Pst I RFLP (P/M-intron 7) polymorphisms of the angiotensin I converting enzyme (ACE) gene and the development of H-gestosis. Preliminary results.  Pol Arch Med Wewn. 1998;  100 19-26
• 27 Kobashi G, Shido K, Hata A et al.. Multivariate analysis of genetic and acquired factors: T235 variant of angiotensinogen gene as a potent independent risk factor for preeclampsia.  Semin Thromb Hemost. 2001;  27 143-147
• 28 Kawamoto R, Kohara K, Tabara Y, Miki T. An interaction between systolic blood pressure and angiotensin-converting enzyme gene polymorphism on carotid atherosclerosis.  Hypertens Res. 2002;  25 875-880