Renate Hillermann

The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia

AbstractAttempts to define a pre-eclampsia susceptibility profile have been hampered by the wide clinical spectrum of the condition and the complex genetics underlying it. Genes that modulate blood pressure, fluid homeostasis and placental vascular development have been considered plausible candidates. Among these are the angiotensinogen (AGT) gene variant Met235Threo, which has been associated with pre-eclampsia and the endothelial nitric oxide synthase (eNOS) polymorphism Glu298Asp, which has been associated with both pre-eclampsia and abruptio placentae, a condition that often co-exists with pre-eclampsia. The aim of this study was to investigate a potential association between these gene variants and pre-eclampsia with and without abruptio placentae in a South African patient group. Fifty primigravidas with early onset, severe pre-eclampsia, 50 women presenting primarily with abruptio placentae (whether associated with pre-eclampsia or not) and a control panel of 50 healthy pregnant women constituted the study groups. The Met235Threo and Glu298Asp variants were characterised by polymerase chain reaction and restriction enzyme analysis. No association was demonstrated between the M235T variant of the AGT gene and pre-eclampsia or abruptio placentae. In contrast, the combined frequency of the eNOS variant genotypes (GT and TT) was significantly higher in the abruptio placentae group (49%) than the control group (21%) (p = 0.006). Furthermore, in the pre-eclampsia patients who subsequently developed abruptio placentae, the eNOS GT genotype emerged as a major risk factor for the development of abruptio placentae (p < 0.0001). These data suggest that the presence of a Glu298Asp eNOS variant may pre-dispose a pre-eclamptic woman to develop abruptio placentae or that it is a marker for predisposition.

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction

OBJECTIVE This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). STUDY DESIGN DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by the polymerase chain reaction (PCR). The resulting fragments were subjected to restriction enzyme analysis and resolved by gel electrophoresis. RESULTS A significant association could be demonstrated between mutation A1298C and both abruptio placentae and IUGR. Combined heterozygosity for mutations C677T and A1298C was detected in 22.2% of abruptio placentae cases. CONCLUSIONS Combined heterozygosity for MTHFR mutations C677T and A1298C may represent a genetic marker for abruptio placentae.

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation‐based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B‐100 (FDB) and seven low‐density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder‐type ‘South African mutations’ were responsible for FH in ∼20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B‐100 mutation R3500Q. The detection of multiple founder‐type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Minimal alteration in the ratio of circulatory fetal DNA to fetal corticotropin-releasing hormone mRNA level in preeclampsia

Objectives: We have recently observed that fetal DNA and fetal corticotropin-releasing hormone (CRH) mRNA are associated with in vitro generated syncytiotrophoblast-derived microparticles, and that the ratio of fetal DNA to mRNA (CRH) varied according to whether the particles were derived by predominantly apoptotic, apo-necrotic or necrotic pathways. Hence, we examined whether these ratios varied in maternal plasma samples taken from normotensive and preeclamptic pregnancies in vivo. Methods: Maternal plasma samples were collected from 18 cases with preeclampsia and 29 normotensive term controls. Circulatory fetal CRH mRNA and DNA levels were quantified by real-time PCR and RT-PCR. Results: Circulatory fetal mRNA and fetal DNA levels were significantly elevated in the preeclampsia study group when compared to normotensive controls. Alterations in the fetal mRNA to DNA ratio between the study and control groups were minimal, even when stratified into early (<34 weeks of gestation) and late (>34 weeks of gestation) onset preeclampsia. Conclusions: Our data suggest that although circulatory fetal DNA and mRNA levels are significantly elevated in preeclampsia, the ratios in maternal plasma are not dramatically altered.

Third trimester plasma neurokinin B levels in women with and without preeclampsia

Objective. This study was undertaken to measure neurokinin B (NKB) levels in pregnant women with and without preeclampsia (PE) in the third trimester. The study focused on the Black (sub-Saharan ancestry) and ‘mixed ancestry’ (synonymous with ‘colored’ and denotes an established race group of Khoisan, European, Malay, Malagascan, African, and South Indian ancestry) populations, constituting the majority of inhabitants of the Western Cape Province of South Africa. Methods. Questionnaires were used to obtain clinical data from pregnant ‘mixed ancestry’ and Black women. Third trimester plasma NKB levels were determined by enzyme-linked immunosorbent assay technique (EIA) in 72 pregnant women with PE and in 94 healthy women. The EIA results were then correlated with clinical data. Results. The mean NKB concentration in the PE groups (23.5 ng/L for ‘mixed ancestry’ and 15.0 ng/L for Black women) was significantly higher than in the control groups (3.8 ng/L and 4.4 ng/L, respectively; p ≤ 0.001). No significant differences in maternal clinical data were found between the diseased groups. Conclusions. Using the EIA technique, this study confirms previous reports of elevated NKB levels in the plasma of PE women in the third trimester. Whether increased NKB levels are causative or merely associated with PE remains unknown, as do the causative molecular mechanisms. Future longitudinal studies are certainly needed to further elucidate the predictive value of NKB in PE.