Značaj genotipizacije polimorfizma angiotenzin I-konvertirajućeg enzima kao molekularnog biljega trudnoćom potaknute hipertenzije [ The significance of angiotensin I-converting enzyme gene polymorphism as a molecular marker of pregnancy-induced hypertension ]

Stipoljev, Feodora (2006) Značaj genotipizacije polimorfizma angiotenzin I-konvertirajućeg enzima kao molekularnog biljega trudnoćom potaknute hipertenzije [ The significance of angiotensin I-converting enzyme gene polymorphism as a molecular marker of pregnancy-induced hypertension ]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Introduction. Abnormal process of formation and remodeling of uteroplacental blood vessels contribute to the development of preeclampsia. Deficient placentation can be caused by polymorphism-induced altered expression in renin-angiotensin system genes, which are the main factors regulating blood pressure and fluid and electrolyte balance. Insertional/deletional polymorphism of angiotensin I-converting enzyme has an important role in pathogenesis of wide variety of diseases that exhibit endothelian function and several forms of experimental and human hypertension. Aim of this study was determine the significance of insertion/deletion polymorphism of angiotensin I-converting enzyme as a contributing factor in the development of preeclampsia, the D and I allele frequencies in preeclamptic and control group, and to compare them according to the pregnancy outcome, duration of pregnancy, parity, maternal age, body mass index, gestational age at delivery and birth weight. Methods. Genomic DNA was extracted from whole blood of 60 preeclamptic and 50 normotensive pregnant women. Preeclampsia was defined as the development of blood pressure exceeding 140/90 mmHg in a previously normotensive women with proteinuria >300mg/l in a 24-hour collection after 20 weeks of pregnancy. Gene polymorphism was studied by the polymerase chain reaction followed by the agarose electrophoresis. Genotype and allele frequencies were compared by Mantel-Haenszel χ2 testing. Results. The D and I allele frequency between preeclamptic and control group was not statistically significant. The rate of DD genotype was slightly increased but not significantly in preeclampsia (43.3%) compared with 28% in controls (p=0.096). The D allele frequency was 0.735 in preeclamptic patients who required delivery before 34 weeks of pregnancy, which was statisticaly significant compared to the women in whom obstetric complications took place after 34 weeks of pregnancy (p=0.036). The D allele prevalence was 0.83 in women who had both in the previous and successive pregnancy preeclampsia (p=0.01). There was no significant difference between genotype distribution and observed fetal growth retardation in preeclamptic group. Conclusions. Deletion polymorphism is unlikely to play a major role in the development of preeclampsia, although moderate positive associations cannot be rule out. This study found a significantly positive correlation between D allele frequency and risk of recurrent preeclampsia and required delivery before 34 weeks of pregnancy in preeclamptic women. In such cases, the deletion genotype could be an additional risk factor, acting synergistically with other gene polymorphisms to increase the risk of preeclampsia.

Abstract in Croatian

Uvod. Abnormalni procesi nastajanja i modeliranja krvnih žila vode razvoju preeklampsije. Moduliranje genske ekspresije mogu uzrokovati polimorfizmi kandidatnih gena koji sudjeluju u reguliranju krvnog tlaka, kao što su geni reninsko-angiotenzinskog sustava. Insercijsko/delecijski polimorfizam angiotenzin I-konvertirajućeg enzima, ima značajnu ulogu u patogenezi velikog broja poremećaja funkcije endotelnih žila i patogenezi nekoliko oblika eksperimentalne i humane hipertenzije. Cilj istraživanja bio je utvrditi probirni značaj insercijsko/delecijskog polimorfizma angiotenzin I-konvertirajućeg enzima kao mogućeg čimbenika rizika razvoja hipertenzije u trudnoći; odrediti pojavnost I i D alela u preeklamptičnoj i usporednoj skupini trudnica i usporediti ove dvije skupine prema ishodu, trajanju trudnoće, paritetu, dobi, indeksu tjelesne težine, porodnoj gestacijskoj dobi i porodnoj težini djeteta. Metode. Genomska DNA izolirana je iz pune krvi 60 preeklamptičnih trudnica i 50 normotenzivnih trudnica. Preeklampsija se definira kao krvni tlak viši od 140/90 mmHg u odnosu na vrijednosti prije trudnoće i proteinurija >300mg/l tijekom 24 sata nakon 20 tjedana trudnoće. Genotipizacija insercijsko/delecijskog polimorfizma unutar introna 16 ACE gena provela se metodom lančane reakcije polimeraze i vizualizacijom elektroforezom u gelu agaroze. Usporedba genotipova i pojavnosti alela provela se Mantel-Haenszelovim χ2 testom. Rezultati. Raspodjela I i D alela ACE polimorfizma izmedu usporedne i preeklamptične skupine nije se statistički razlikovala. Zastupljenost trudnica s DD genotipom u preeklamptičnoj skupini je veća, ali ne statistički značajna, i iznosi 43.3%, dok 28% normotenzivnih trudnica ima isti genotip (p=0.096). Kod preeklamptičnih trudnica koje su rodile prije 34. tjedna trudnoće, raspodjela D alela bila je statistički značajno viša i iznosila je 0.735 u odnosu na ostale (p=0.036). U preeklamptičnoj skupini trudnica koje su i u prethodnoj trudnoći imale preeklampsiju udio D alela iznosio je 0.83 (p=0.01). Nismo našli statistički značajnu razliku između pojavnosti određenog genotipa i intrauterinog zastoja rasta ploda u preeklamptičnoj skupini. Zaključci. Delecijski polimorfizam nema direktnu ulogu u razvoju preeklampsije, međutim određene pozitivne sveze se ne mogu u potpunosti isključiti. Naše istraživanje je pokazalo statistički značajnu pozitivnu svezu izmedu pojavnosti D alela I rizika razvoja preeklampsije u sljedećoj trudnoći kod trudnica koje su u prethodnoj trudnoći imale preeklampsiju i poroda prije 34. tjedna trudnoće kod preeklamptičnih trudnica. U ovakvim slučajevima delecijski genotip mogao bi biti dodatni čimbenik rizika, koji djeluje sinergistički s drugim genskim polimorfizimima, povećavajuci rizik razvoja preeklampsije.

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