Genetische Grundlagen der schwangerschaftsinduzierten Hypertonie

Chesley introduced the notion that preeclampsia is heritable. He performed a study of women with preeclampsia, their sisters, their daughters, and their daughters in law. He clearly showed that genetic variance influences the condition as well as numerous environmental factors. With the advent of molecular techniques, much interest has arisen in the genetics of preeclampsia because of the possibility that genes can be found to explain the mechanisms. Linkage studies have been used to identify relevant gene loci. Association studies have been used to test candidate genes. Both maternal and fetal candidate genes are being considered, as well as immunogenetic variables. In addition to microsatellite and single nucleotide polymorphism analysis, gene expression studies in maternal or placental tissues may give insight into molecular mechanisms. Such insights may permit risk assessment, earlier diagnoses, and improved therapeutic approaches.     

Molecular progress in infertility: polycystic ovary syndrome

OBJECTIVE: To review the evidence that polycystic ovary syndrome is a genetic disease.DESIGN: Review of published literature.RESULTS: The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG.CONCLUSIONS: Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.     

Genetic background of preeclampsia

Population studies have been suggesting genetic predisposition to the appearance of preeclampsia (PE) for a considerable period of time now. In familial occurrence of the disease higher frequency of preeclampsia has been observed in mothers, daughters and sisters of women burned of this poor medical history and higher risk to severe PE development. Although a single gene may contribute to the development of the patomechanizm of PE, most authors focus on the analysis of the common influence of candidate genes which are involved in a series of pathophysiological processes of PE. Thus, PE is often believed to be the final phenotype (increase of blood pressure and multiorgan complications development), being the result of intermediate phenotypes acting at the same time and being modulated by environmental factors. PE belongs to the complex human disease. The results of the findings connected with the contribution of maternal, paternal and fetal genotypes in PE development remain unclear, though a stronger influence of maternal genes, with a weaker influence of those transferred from the father, may be observed. Despite the existing divergences (the findings on the genetic background of PE are in conflict, no doubt due to the population differences and small number of investigated groups), the results obtained so far stress the necessity to discover the genetic risk factors as it may do both: facilitate the identification of groups of women predisposed to preeclampsia and allow for an early prophylactic administration.     

Examination of distinct fetal and maternal molecular pathways suggests a mechanism for the development of preeclampsia

In pregnancy, the maternal spiral arteries must widen to nourish the growing fetus. It is this critical step in placental development that is commonly defective in the pathology of preeclampsia. Other features often observed in the placental pathology of preeclampsia include fewer invasive trophoblasts, shallow trophoblast invasion and placental thrombosis and atherotic-like changes. In this review, we propose that there are two distinct pathways, maternal and fetal, which converge on narrow spiral arteries. The unmodified (along the fetal pathway) or blocked (along the maternal pathway) spiral artery, or a combination of the two, may in turn lead to placental insufficiency and induce the maternal cascade of events leading to preeclampsia. We suggest a paradigm for the molecular developmental events that cause preeclampsia through narrow spiral arteries and focus on early events that may cause failed remodeling or blockage of the arteries, which then lead to placental insufficiency and ultimately the hypoxic placenta associated with preeclampsia. We propose that examination of the molecular mechanisms of maternal and fetal pathways that lead to the development of preeclampsia may aid researchers to focus on new potential factors in this molecular basis and ultimately in treatment of this disease.     

Molecular epidemiology of preeclampsia

Numerous articles have been published that address the possible genetic influences on the development of preeclampsia (PE). However, to our knowledge, a complete review of the results has not yet been completed. We undertook a MEDLINE search to identify English-language articles published after January 1, 1990 that examined the possible role of specific genes in the etiology of PE. After a brief introduction and a concise review of the prevailing etiologic hypotheses, we have categorized the candidate genes into six categories, based on their hypothesized role in PE etiology. The purpose of this paper is to review the literature, comment on its quality, and provide a reference for researchers interested in the molecular epidemiology of preeclampsia. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to list the prevailing etiologic hypotheses of preeclampsia, to outline the published data on possible genetic influence on the development of preeclampsia, and to clearly state the definition of preeclampsia.     

Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia

Preeclampsia is a pregnancy-specific complex disease in which numerous genetic, immunological and environmental factors interact. Characterized by new onset hypertension, proteinuria and edema after 20 weeks of gestation, preeclampsia is often complicated by small-for-gestational-age (SGA) babies and pre-term delivery, and is therefore a significant cause of maternal and fetal morbidity and mortality. The only definitive treatment of preeclampsia is delivery of the placenta. Recent data suggest that the anti-angiogenic state induced by excess circulating anti-angiogenic factors of placental origin may be responsible for the clinical signs and symptoms of preeclampsia. Natural killer (NK) cells at the maternal/fetal interface, which are thought to play an important role in normal placental development, have been noted recently to induce angiogenic factors and vascular remodeling. Moreover, genetic studies suggest that susceptibility to preeclampsia may be influenced by polymorphic HLA-C ligands and killer cell receptors (KIR) present on NK cells. This review summarizes our current understanding of the role of angiogenic factors and NK cells in the pathogenesis of preeclampsia.     

Genetics of erectile dysfunction: a review of the interface between sex and molecular biomarkers

IntroductionIn recent years, new tools for the study of molecular biology and genetics have resulted in significant contributions to the scientific community. The potential use of genetic variations as biomarkers in the management of current and future conditions is generating considerable excitement in health care for disorders such as erectile dysfunction (ED).AimThis review briefly describes the molecular and genetic mechanisms involved in ED and provides an overall view of the literature relevant to possible relationships between genetic factors and ED.MethodsThis is a narrative review of studies on the potential influence of polymorphisms on the risk of developing ED.Main Outcome MeasureWe reviewed genetic association studies involving polymorphisms and the ED phenotype.ResultsThere is growing evidence for the influence of genetic polymorphisms on the risk of ED and on the interindividual variability in sildenafil treatment.ConclusionsAlthough this field is still in its infancy, genetic association studies aimed at defining a molecular basis for ED have provided some important evidence that a patient's genotype may be used in the future to assess risk, as well as to plan treatment and prevention programs in the clinic. Andersen ML, Guindalini C, and Tufik S. Genetics of erectile dysfunction: A review of the interface between sex and molecular biomarkers. J Sex Med 2011;8:3086–3097.     

Association between gamete source,exposure and preeclampsia: A review of literature

Preeclampsia complicates 3%-5% of pregnancies and is one of the major causes of maternal morbidity and mortality. The pathologic mechanisms are well described but despite decades of research, the exact etiology of preeclampsia remains poorly understood. For years it was believed that the etiology of preeclampsia was the result of maternal factors, but recent evidence suggests that preeclampsia may be a couple specific disease where the interplay between both female and male factors plays an important role. Recent studies have suggested a complex etiologic mechanism that includes genetic imprinting, immune maladaptation, placental ischemia and generalized endothelial dysfunction. The immunological hypothesis suggests exaggerated maternal response against fetal antigens. While the role of maternal exposure to new paternal antigens in the development of preeclampsia was the initial focus of research in this area, studies examining pregnancy outcomes in pregnancies from donor oocytes provide intriguingly similar findings. The pregnancies that resulted from male or female donor gametes or donor embryos bring new insight into the role of immune response to new antigens in pathogenesis of preeclampsia. The primary goal of the current review is the role of exposure to new gametes on the development of preeclampsia. The objective was therefore to provide a review of current literature on the role of cohabitation length, semen exposure and gamete source in development of preeclampsia.     

Fetal DNA in maternal plasma in preeclamptic pregnancies

Cell-free fetal DNA present in maternal circulation has revolutionized non-invasive prenatal diagnosis of genetic diseases. In preeclampsia, the quantity of fetal DNA in maternal plasma has been studied and found to be higher in comparison to healthy pregnant women. Whether the quantity of fetal DNA can be used as a reliable predictive biomarker of preeclampsia is currently uncertain. This is a systematic review on studies quantifying fetal DNA in preeclamptic pregnancies. Using a PubMed search 22 studies were identified. In all of them, elevated levels of fetal DNA in maternal plasma in preeclampsia were found. In some of the studies, the higher concentration of fetal DNA was observed before the onset of clinical symptoms. This shows that fetal DNA levels might have a potential informative value as an early diagnostic biomarker of preeclampsia. However, in most of the studies important data are missing and there is an enormous variability in the reported results between the studies. From the available data it is currently not possible to perform a meta-analysis due to the variation between studies. If once fetal DNA should be used as a marker for determining preeclampsia at early stage, it is necessary to reduce these variations via standardized protocols for the quantification of cell-free fetal DNA as well as its reporting in the publications.     

Preeclampsia: Definitions,screening tools and diagnostic criteria in the supersonic era

Preeclampsia is still a major risk factor for maternal-fetal health. Therefore, early identification of pregnant women at risk for preeclampsia is a big priority in obstetrics in order to decrease the mortality and morbidity associated with this disease. On the basis of well known and new pathophysiological mechanisms of preeclampsia, different biochemical and ultrasonographic parameters have been investigated in the literature, without finding an ideal marker for early screening. In this brief review, we present the best studied ultrasonographic markers and the most recent genetic factors and promising emerging biomarkers of preeclampsia, to date. We hope that in the future the combination of these tests will allow us to predict which women are at risk of preeclampsia.     

Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia

Objective: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. Methods: Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002–May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. Results: The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82–0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). Conclusion: Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.     

Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF)

Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.     

Genetic thrombophilias and preeclampsia: a meta-analysis

OBJECTIVE: To assess the relationship between the factor V Leiden (1691 G-A) single nucleotide polymorphism (SNP), the methylene tetrahydrofolate reductase (MTHFR) 677 C-T SNP, and the prothrombin 20210 G-A SNP and the risk of preeclampsia, by conducting a meta-analysis of all case-control studies with data on these polymorphisms and the risk of preeclampsia. DATA SOURCES: MEDLINE (1966 to November 2002), EMBASE (1980 to November 2002). Search terms included "preeclampsia," "thrombophilia," "factor V Leiden," "protein C," "MTHFR," "methylenetetrahydrofolate reductase," "homocysteine," and "prothrombin gene 20210."METHODS OF STUDY SELECTION: Case-control studies of genetic thrombophilias and preeclampsia were included. TABULATION, INTEGRATION, AND RESULTS: We identified 349 titles and reviewed 47 articles for inclusion and exclusion criteria. Thirty-one studies with 7,522 patients were included in the meta-analysis. Data from patients characterized as having severe preeclampsia were extracted and analyzed separately. The pooled odds ratio (OR) for the association of factor V Leiden and all cases of preeclampsia was 1.81 (95% confidence interval [CI] 1.14-2.87) and 2.24 (95% CI 1.28-3.94) for cases of severe preeclampsia. The pooled OR for the MTHFR 677 TT genotype and all preeclampsia was 1.01 (95% CI 0.79-1.29) and 1.38 (95% CI 0.93-2.06) for severe preeclampsia. The OR for the prothrombin 20210 polymorphism and all preeclampsia was 1.37 (95% CI 0.72-2.57) and 1.98 (.94-4.17) for severe preeclampsia. CONCLUSION: This meta-analysis suggests that the factor V Leiden SNP is associated with an increased risk of preeclampsia. Further studies are warranted to determine whether subgroups of high-risk women should be screened for this mutation.     

Immunogenetic determinants of preeclampsia and related pregnancy disorders: a systematic review

OBJECTIVE: We sought to systematically review the impact of immunogenetic factors, specifically human leukocyte antigen (HLA) allele frequencies, maternal homozygosity, couple sharing, and maternal-fetal sharing, on the risk of preeclampsia and intrauterine growth restriction. DATA SOURCES: A computerized search of PubMed databases from 1975 to 2003 was performed with the terms "preeclampsia," "eclampsia," "intrauterine growth restriction," and "human leukocyte antigens" and limited to studies of human subjects in English. No restrictions were placed on study design. All bibliographies were cross-referenced to identify additional pertinent studies. METHODS OF STUDY SELECTION: Titles and abstracts were reviewed carefully. Observational and basic science research studies were selected if their main objective was to assess the relationship of any aspect of HLA genotypes with preeclampsia and related disorders of pregnancy. TABULATION, INTEGRATION, AND RESULTS: Data were abstracted and tabulated from 22 original research studies. Meta-analytic techniques were not performed owing to variations in disease and exposure definitions as well as research methodologies. Studies that examined maternal, paternal, and fetal HLA allele frequencies, maternal homozygosity, and couple sharing yielded inconsistent results. Although the cumulative evidence points to the HLA-DR locus (particularly DR4) as a correlate of preeclampsia, it remains unclear whether any specific HLA allele, haplotype, or susceptibility gene in linkage disequilibrium with the HLA region is responsible. Although genetic evidence is suggestive of gene-gene interaction between mother and fetus, few studies have evaluated the influence of maternal-fetal HLA sharing. CONCLUSION: In the early 1990s, HLA genotypes were dismissed as possible etiologic factors for preeclampsia, based on studies that are heterogeneous with respect to study design, outcome, and exposure assessment. Many of these studies did not take into account the interactions between maternal, paternal, and infant genotypes. Thus, adequately powered studies designed specifically to assess the effect of maternal-fetal HLA sharing on risk of preeclampsia are needed.     

Genes and the preeclampsia syndrome

Preeclampsia is specific to pregnancy and is still a leading cause of maternal and perinatal mortality and morbidity, affecting about 3% of women, but the underlying pathogenetic mechanisms still remain unclear. Immune maladaptation, placental ischemia and increased oxidative stress represent the main components discussed to be of etiologic importance, and they all may have genetic implications. Since the familial nature of preeclampsia is known for many years, extensive research on the genetic contribution to the pathogenesis of this severe pregnancy disorder has been performed. In this review, we will overview the linkage and candidate gene studies carried out so far as well as summarize important historical notes on the genetic hypotheses generated in preeclampsia research. Moreover, the influence of maternal and fetal genes and their interaction as well as the role of genomic imprinting in preeclampsia will be discussed.     

Mapping the theories of preeclampsia: the role of homocysteine

OBJECTIVE: We conducted a systematic review to examine the hypothesized mechanism through which homocysteine could lead to preeclampsia. DATA SOURCES: We searched MEDLINE, EMBASE, BIOSIS, SciSearch, and bibliographies of primary and review articles, and we contacted experts. METHODS OF STUDY SELECTION: Of the 25 relevant primary articles, 8 studies measured total serum homocysteine concentrations before the clinical onset of preeclampsia (1,876 women), whereas 17 measured it afterward (1,773 women). Meta-analytic techniques were used to examine consistency, strength, temporality, dose-response, and plausibility of the disease mechanisms implicating folate, vitamin B(6), vitamin B(12), genetic polymorphisms, oxidative stress, and endothelial dysfunction in the pathway linking hyperhomocysteinemia to preeclampsia. TABULATION, INTEGRATION, AND RESULTS: Overall, there were higher serum homocysteine concentrations among pregnant women with preeclampsia than among those with uncomplicated pregnancies, but the results were heterogeneous (P = .12; I(2) = 38.8%). Among studies with temporality, the size of association was smaller than that among those without (weighted mean difference 0.68 mumol/L versus 3.36 mumol/L; P < .006). There was no dose-response relationship between homocysteine concentration and severity of preeclampsia. The mechanisms underlying hyperhomocysteinemia (folate and vitamin B(12) deficiency and genetic polymorphisms) were not found to be plausible, but markers of oxidative stress and endothelial dysfunction were higher in hyperhomocysteinemia. CONCLUSION: Homocysteine concentrations are slightly increased in normotensive pregnancies that later develop preeclampsia and are considerably increased once preeclampsia is established. However, because of a lack of consistency in data, dose-response relationship, and biologic plausibility, the observed association cannot be considered causal from the current literature.     

Bridging global gene expression candidates in first trimester placentas with susceptibility loci from linkage studies of preeclampsia

Preeclampsia is as a leading cause of maternal and perinatal morbidity and mortality. Prevention, early identification, and individualized treatments may become feasible if reliable early biomarkers can be developed. Towards a systems biology framework, this review synthesizes prior linkage studies and genome scans of preeclampsia with candidates identified in a global gene expression microarray analysis of chorionic villus sampling (CVS) specimens from women who subsequently developed preeclampsia. Nearly 40% of these CVS candidate genes occurred in previously identified susceptibility loci for preeclampsia. Integration of genetic epidemiologic and functional gene expression data could help to elucidate preeclampsia as a complex disease resulting from multiple maternal and fetal/placental factors that each contributes a greater or lesser effect. These loci and related candidate genes are set to substantially improve insights into the first trimester pathogenesis of this pregnancy disorder.     

Pathophysiology of preeclampsia.

Preeclampsia is a complex clinical syndrome, with hypertension representing but one manifestation. Pathogenetically important events in the development of preeclampsia include incomplete trophoblastic invasion of the maternal spiral arteries, poor trophoblastic perfusion, elaboration of a putative endothelial cell toxin, and endothelial cell injury with resulting activation of coagulation, impairment of vasodepressor function, and altered endothelial permeability. These changes lead to the clinical signs and symptoms, which occur relatively late in the course of preeclampsia. The primary immunologic, genetic, and biochemical basis of preeclampsia remains speculative.     

Effect of the blood pressure on the perinatal fetal outcome in patients with preeclampsia

No matter the fact that the changes in the blood pressure are quite often the first clinical feature of preeclampsia, is known that they are not early, but are quite late preeclampsia symptom. Close follow-up of the blood pressure trough whole pregnancy and in preeclamptic patients plays an important role in the improvement of the perinatal outcome. Five hundred forty four singleton pregnant women were enrolled in the study. Of them 334 were with mild preeclampsia and 210 were with severe form of the disease. The analysis of correlations shows a correlation between the blood pressure at admititon and before delivery of the women with mild and severe form of preeclampsia and the perinatal fetal outcome. The fifth minute Apgar score is significantly lower in the patients with severe preeclampsia in comparison with women with mild disease. The represented data confirm the hypothesis about the influence of the maternal blood pressure on the perinatal fetal outcome.