March 22, 2004 Access past issues

Reviewed by: Jenny Clayton Rollins School of Public Health Emory University

The Health Outcome

This study addresses two main health outcomes: preeclampsia and chronic essential hypertension in pregnancy. The health outcomes were chosen because they are both hypertensive complications associated with pregnancy. The etiologies of both preeclampsia and chronic essential hypertension are not understood. The authors of this study examined the possibility of a shared, underlying genetic cause of these two disorders. Preeclampsia is a pregnancy-related hypertensive disorder that occurs in approximately 6% of pregnant women (1). It is characterized by the presence of proteinuria and an increase in blood pressure. The etiology of preeclampsia is unknown. Several factors suggest that susceptibility to preeclampsia is partly inherited. For example, a study of Swedish twins reported an estimated heritability of 54%. Several candidate genes have been suggested in previously published studies, including the genes examined in this study: angiotensinogen (AGT), factor 5 (F5), glutathione-S transferase pi (GSTP1), 5-10 methylenetetrahydrofolate reductase (MTHFR), and tumor necrosis factor- (TNF) .

Essential hypertension is characterized as high blood pressure with no known identifiable cause. The disease has many hypothesized explanations, including alterations in nitric oxide metabolism, oxidative stress in relation to endothelial dysfunction, and changes in the renin-angiotensin-aldosterone system. Genetic susceptibility has been investigated mainly in men >40 years old, and heritability has been estimated as 30-50%. Several candidate genes have been suggested by previous work, including the genes examined in this study: angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type I receptor (AGTR1), and transforming growth factor ß-1 (TGFB1).

The Finding

This study addressed two main purposes. The first was to validate previously published associations related to preeclampsia and chronic essential hypertension by examining ten different polymorphisms in nine genes, from nine different studies. The second was to determine whether polymorphisms previously found to be associated with preeclampsia are associated with essential hypertension and vice versa.

The study used a population-based, prospective sample of 3391 nulliparous French Canadian pregnant women, of whom 98% were white (11). In this group there were 180 cases of preeclampsia and 203 cases of essential hypertension. Controls were matched with cases at an attempted 2:1 ratio from the same population-based prospective sample; in all, 310 controls were matched with preeclampsia cases and 357 controls were matched with essential hypertension cases. Details of matching factors can be found in Table 1 under Part 2 of the abstraction template. DNA samples from all case and control subjects were examined by genotyping polymorphisms using allele-specific PCR.

None of the five selected published associations with preeclampsia were replicated in the preeclamptic sample, and none of the five selected published associations with essential hypertension were replicated in the chronic hypertensive sample. One significant association was revealed when analyzing published associations for chronic essential hypertension in the preeclamptic study group: the Thr174Met (Met allele) of the AGT gene (odds ratio 1.9; 95%CI, 1.2-2.9; P=0.0033). A 2.1-fold increased risk of preeclampsia was found in association with the A-Met-Thr (G1035A-Thr174Met-Met235Thr) haplotype of the AGT gene (95% CI, 1.4 to 3.4; P=0.0008) (11). These results support a role for this AGT haplotype in genetic susceptibility to preeclampsia.

Public Health Implications

This study was unable to replicate the results of any of the ten previously published associations with preeclampsia and essential hypertension, a finding that further emphasizes the need for reported associations to be confirmed by replication. In particular, the association of AGT Met235Thr with preeclampsia failed to reach statistical significance in this study (OR 1.2, 95% CI 0.9-1.6). However, preeclampsia was significantly associated with AGT Thr174Met, a polymorphism previously reported in association with essential hypertension. Haplotype analysis found the AGTThr174Met allele on a single haplotype (A-Met-Thr), while the Met235Thr allele was found on two additional haplotypes. The authors concluded that Thr174Met is the causative allele. This finding is relevant to future studies of AGT in preeclampsia, but must be replicated before attempting to assess its public health implications.

References

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