Synergistic effect of renin-angiotensin system and nitric oxide synthase genes polymorphisms in pre-eclampsia.

INTRODUCTION. Components of the renin-angiotensin system and endothelial nitric oxide synthase may co-operate in spiral artery remodelling during placentation, and thus reduce the uteroplacental resistance typical of normal pregnancy. Since lack of such remodelling and abnormal placentation are specific features of pre-eclampsia, it has been suggested that abnormal function of both components of the renin-angiotensin system and endothelial nitric oxide synthase may be involved in its pathogenesis. However, previous studies of the association between pre-eclampsia and polymorphisms of single genes encoding renin-angiotensin system components and endothelial nitric oxide synthase have yielded conflicting results. The aim of this study was to assess if interactions among different polymorphisms of the renin-angiotensin system and nitric oxide synthase are involved in the pathogenesis of pre-eclampsia. METHODS. Some 359 pregnant women were enrolled: 103 normotensive, 50 with chronic hypertension, 86 with gestational hypertension, and 120 with pre-eclampsia. DNA analysis was performed to evaluate angiotensin-converting enzyme I/D, angiotensin-II receptor 1 1166A/C, angiotensinogen M235T and endothelial constitutive nitric oxide synthase 4b/a polymorphisms. Odds ratios (OR) with 95% confidence interval (CI) and chi2 tests were calculated. RESULTS. The frequency of single gene polymorphisms was similar in each group. The frequency of pairs including the DD genotype of the angiotensin-converting enzyme I/D polymorphism plus other homozygous genotypes was significantly higher in pre-eclamptic patients than in controls (OR=3.04, 95% CI=1.16-7.93). CONCLUSIONS. Synergism of angiotensin-converting enzyme I/D and other polymorphisms of renin-angiotensin system components and nitric oxide synthase may be a risk factor for pre-eclampsia.