Association of angiotensin-converting enzyme intron 16 insertion/deletion polymorphism with history of foetal loss

Abstract

Introduction. The angiotensin-converting enzyme (ACE) intron 16 insertion/deletion (I/D) polymorphism is associated with ACE activity and has been discussed as a risk factor for pre-eclampsia. Disturbances of uteroplacental circulation are involved in the pathogenesis of pre-eclampsia. In this study, we tested whether the ACE I/D genotype is associated with history of foetal loss (FL) or uteroplacental dysfunction (UPD).

Patients and methods. ACE I/D genotype was determined in 312 women presenting with a history of FL and 112 women admitted because of UPD. The association of the ACE I/D genotype with FL or UPD was assessed in a case-control study using 527 patients with diagnoses other than FL or UPD. To exclude potential biases due to associations of this genotype with other diagnoses, we additionally performed a case-control study using 553 healthy controls. Results. ACE I/D genotype was significantly associated with history of FL in both case-control studies (patient controls: odds ratio 1.52, p<0.02; healthy controls: odds ratio 1.48, p=0.02). There was no evidence for allele-dose dependency. No association of the ACE I/D genotype with UPD could be detected.

Conclusions. The ACE I/D genotype exhibits a statistically significant association with a history of FL. These results corroborate an involvement of the renin-angiotensin system in pregnancy complications.

Keywords

ACE foetal loss genotype pregnancy uteroplacental dysfunction

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References

Belo L. , Santos-Silva A. , Quintanilha A. , Rebelo I.

Similarities between pre-eclampsia and atherosclerosis: a protective effect of physical exercise?

Curr Med Chem 2008;15:2223-9.

Redman CW , Sacks GP , Sargent IL Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999;180:499-506.

Ndumele CE , Pradhan AD , Ridker PM Interrelationships between inflammation, C-reactive protein, and insulin resistance . J Cardiometab Syndr 2006;1:190-6.

Irani RA , Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia . Placenta 2008;29:763-71.

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;86:1343-6.

Tiret L. , Rigat B. , Visvikis S. et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992;51:197-205.

Reyes-Engel A. , Morcillo L. , Aranda FJ et al. Influence of gender and genetic variability on plasma angiotensin peptides. J Renin Angiotensin Aldosterone Syst 2006;7:92-7.

van Essen GG , Rensma PL , de Zeeuw D. et al. Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. Lancet 1996;347:94-5.

Jimenez PM , Conde C. , Casanegra A. , Romero C. , Tabares AH , Orias M. Association of ACE genotype and predominantly diastolic hypertension: a preliminary study. J Renin Angiotensin Aldosterone Syst 2007;8:42-4.

10.

Gurdol F. , Isbilen E. , Yilmaz H. , Isbir T. , Dirican A. The association between preeclampsia and angiotensin-converting enzyme insertion/deletion polymorphism. Clin Chim Acta 2004;341:127-31.

11.

Serrano NC , Diaz LA , Paez MC et al. Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias. PLoS Med 2006;3:e520.

12.

Buchholz T. , Lohse P. , Rogenhofer N. , Kosian E. , Pihusch R. , Thaler CJ Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod 2003;18:2473-7.

13.

Fatini C. , Gensini F. , Battaglini B. et al. Angiotensin-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetal-loss susceptibility. Blood Coagul Fibrinolysis 2000;11:657-62.

14.

Hoppe B. , Tolou F. , Dorner T. , Kiesewetter H. , Salama A. Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population . Thromb Haemost 2006;96:465-70.

15.

Hoppe B. , Heymann GA , Koscielny J. , Hellstern P. , Kiesewetter H. , Salama A. Screening for multiple hereditary hypercoagulability factors using the amplification refractory mutation system. Thromb Res 2003 ;111:115-20.

16.

Valdez-Velazquez LL , Quintero-Ramos A. , Perez SA et al. Genetic polymorphisms of the renin-angiotensin system in preterm delivery and premature rupture of membranes. J Renin Angiotensin Aldosterone Syst 2007;8:160-8.

17.

The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-78.

18.

von Depka M. , Czwalinna A. , Wermes C. et al. The deletion polymorphism in the angiotensin-converting enzyme gene is a moderate risk factor for venous thromboembolism. Thromb Haemost 2003;89:847-52.

19.

Koppel H. , Renner W. , Gugl A. et al. The angiotensin-converting-enzyme insertion/deletion polymorphism is not related to venous thrombosis. Thromb Haemost 2004;91:76-9.