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

Background. 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 2 95% confidence interval (CI) and X-2 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.