The genetics of pre-eclampsia and other hypertensive disorders of pregnancy




Hypertension is the most frequent medical complication occurring during pregnancy. In this chapter, we aim to address the genetic contribution to these disorders, with specific focus on pre-eclampsia. The pathogenic mechanisms underlying pre-eclampsia remain to be elucidated; however, immune maladaptation, inadequate placental development and trophoblast invasion, placental ischaemia, oxidative stress and thrombosis are all thought to represent key factors in the development of disease. Furthermore, all of these components have genetic factors that may be involved in the pathogenic changes occurring. The familial nature of pre-eclampsia has been known for many years and, as such, extensive genetic research has been carried out in this area using strategies that include candidate gene studies and linkage analysis. Interactions between fetal and maternal genotypes, the effect of environmental factors, and epistasis will also be considered.


Definition of hypertensive disorders of pregnancy


A wide diversity of terminology and diagnostic criteria have been used over the years to classify the hypertensive disorders of pregnancy and define pre-eclampsia. Several internationally recognised definitions are available, but at present there is no universal classification system or definition of pre-eclampsia. The hypertensive disorders of pregnancy have four defined categories, characterised in Table 1 . These are gestational hypertension; pre-eclampsia and eclampsia; superimposed pre-eclampsia and chronic hypertension. This topic is considered further in this issue of Best Practice and Research Clinical Obstetrics and Gynaecology .



Table 1

Commonly used diagnostic criteria and classification of hypertensive disorders of pregnancy. The pregnancy-specific conditions may also be diagnosed where diastolic pressure exceeds 90 mmHg but systolic pressure is < 140 mmHg. It is usual to exclude the diagnosis if hypertension is recorded only during labour.


























Classification Diagnostic criteria
Gestational hypertension Hypertension: blood pressure ≥ 140/90 mmHg after 20th week of pregnancy in a previously normotensive woman.
Pre-eclampsia Hypertension: blood pressure of ≥ 140/90 mmHg after 20th week of pregnancy in a woman who was previously normotensive.
Proteinuria: urinary excretion ≥ 300 mg/L or 500 mg/24 h in the absence of urinary tract infection.
Eclampsia Occurs in a woman with pre-eclampsia.
Characterised by seizures not attributed to other causes.
Superimposed pre-eclampsia Chronic hypertension with development of proteinuria during pregnancy.
Chronic hypertension Hypertension present before 20th week of pregnancy, persistent for more than 6 weeks postpartum, or both.




Genetic aspects of pre-eclampsia


Clustering of cases of pre-eclampsia within families has been recognised since the 19th century, suggesting a genetic component to the disorder. Deciphering the genetic involvement in pre-eclampsia is challenging, not least because the phenotype is expressed only in parous women. Furthermore, in complex disorders of pregnancy, it is necessary to consider two genotypes, that of the mother and that of the fetus, which includes genes inherited from both mother and father. Maternal and fetal genes may have independent or interactive effects on the risk of pre-eclampsia. Finally, the heterogeneous nature of the disorder, with a sliding scale of severity, has resulted in differences in the definition of pre-eclampsia used within studies (see above), often with overlap of non-proteinuric gestational hypertension.


Twin studies investigating the relative contribution of genetic versus environmental factors to pre-eclampsia risk, initially yielded disappointing results. They showed that discordance for pre-eclampsia between monozygotic twin sisters was common, suggesting that heritability caused by maternal genes was low. These early studies were small. More recent investigations, however, using the large Swedish Twin, Medical Birth and Multigeneration Registries have estimated the heritability of pre-eclampsia to be about 55%, with contributions from both maternal and fetal genes. A further study in monozygotic twins found concordance of pre-eclampsia to be as common as discordance. Evidence from the largest published twin study, which correlated the Swedish Twin Register with the Swedish Medical Register, revealed pre-eclampsia penetrance to be less than 50%, suggesting diversity within models of inheritance.


Pre-eclampsia: a complex genetic disorder


For a small number of families, pre-eclampsia seems to follow Mendelian patterns of disease inheritance, consistent with a rare deleterious monogenic variant or mutation with high penetrance. For most of the population, however, pre-eclampsia seems to represent a complex genetic disorder, and occurs as the result of numerous common variants at different loci which, individually, have small effects but collectively contribute to an individual’s susceptibility to disease. Environmental exposures, including age and weight, also determine whether these low penetrant variants result in phenotypic manifestation of the disease. It is likely that no single cause or genetic variant will account for all cases of pre-eclampsia, although it is possible that different variants are associated with various subsets of disease (e.g. pre-eclampsia combined with intrauterine growth restriction). Complex genetic disorders affect a high proportion of the population, representing a large burden to public health. New approaches to susceptibility gene discovery have emerged to address this challenge. Unfortunately, early diagnosis would only permit closer focus on routine antenatal care, as at present no intervention other than delivery has been shown to alter the course of pre-eclampsia.


Determining susceptibility to pre-eclampsia


The need to assess both the maternal and the fetal genotype is clear. The role of the placenta in the primary pathogenesis of the disorder indisputably indicates a fetal contribution to susceptibility to the disorder. Reports of severe, very early-onset pre-eclampsia in cases of fetal chromosomal abnormalities such as diandric hydatifidiform moles of entirely paternal genetic origin are consistent with a role for paternally inherited fetal genes in the determination of clinical phenotype. This is supported by epidemiological studies reporting a higher rate of pre-eclampsia in pregnancies fathered by men who were themselves born of pre-eclamptic pregnancies. The occurrence of pre-eclampsia in daughters-in-law of index women further supports a genetic contribution from both parents. The genetic conflict hypothesis states that fetal (paternal) genes will be selected to increase the transfer of nutrients to the fetus, whereas maternal genes will be selected to limit transfer in excess of a specific maternal optimum. Fetal genes are predicted to raise maternal blood pressure in order to enhance the uteroplacental blood flow, whereas maternal genes act the opposite way. Endothelial dysfunction in mothers with pre-eclampsia could, therefore, be interpreted as a fetal attempt to compensate for an inadequate uteroplacental nutrient supply.


As the phenotype is apparently only expressed during pregnancy, identification of ‘susceptible’ men is impossible. Most genetic studies of pre-eclampsia have focused on maternal genotypes only. The Genetics of Pre-eclampsia consortium highlighted the need to include analysis of all contributing genotypes, and carried out transmission disequilibrium testing in maternal and fetal triads. Understanding the contribution of the fetal genotype will require large sample sizes, with the development of algorithms to determine the relative contribution from mother and fetus. Furthermore, the decreased incidence of pre-eclampsia in second and subsequent pregnancies hampers analysis of the contribution of the fetal genotype.


Candidate gene approach


The candidate gene approach has been widely used in pre-eclampsia, and largely focuses on the maternal genotype. In this method, a single gene is chosen as the candidate for investigation based on prior biological knowledge of the pathophysiology of pre-eclampsia. The choice is strengthened if the gene lies within a region identified by linkage studies. A case-control design is usually used, comparing the frequencies of allelic variants in women with pre-eclampsia and normotensive pregnancies. Such studies need careful definition of inclusion criteria for cases and controls, and subtle ethnic stratification of groups must be avoided. Such performance characteristics of the genotyping assays as the rate of mis-genotyping, and the quality assurance methods used, should be clearly stated, but this is rarely done. Over 70 biological candidate genes have been examined, representing pathways involved in various pathophysiological processes, including vasoactive proteins, thrombophilia and hypofibrinolysis, oxidative stress and lipid metabolism, endothelial injury and immunogenetics. In common with the experience in other genetically complex disorders, results from candidate gene studies have been inconsistent, and no universally accepted susceptibility gene has been identified. Although this may, in part, be attributed to variation within populations, a more important factor is the small size of most of the candidate studies, which have been underpowered to detect variants with small effects. As there are more than 20,000 genes and 10 million single nucleotide polymorphisms (SNP) available, multiple testing will inevitably result in numerous results that achieve P values of less than 0.05. The development of robust statistical techniques for the minimisation of both false positive and false negative results is an important area. Only in recent years, as susceptibility genes for other complex disorders have been reported, has the small effect size of individual genetic variants become apparent, the majority increasing the risk of disease by less than 50%. A further limitation of the candidate gene approach is its reliance on the generation of an a-priori hypothesis based on our current incomplete knowledge of the pathophysiology of the disorder. The candidate genes studied belong to different groups according to their functional properties and plausible role in the pathophysiology ( Table 2 ).



Table 2

Predominant functional candidate genes studied in pre-eclampsia.










































































Pathophysiological mechanism group Gene name Gene symbol Predominant polymorphism investigated
Thrombophilia Factor V Leiden F5 506Gln>Arg
Methylenetetrahydrofolate MTHFR C667T
Prothrombin F2 G20210A
Plasminogen activator factor-1 SERPINE1 I/D promoter
Integrin glycoprotein IIIa GPIIIA C98T
Endothelial function Endothelial nitric oxide synthase 3 eNOS3 298Glu>Asp
Vascular endothelial growth factor receptor 1 VEGFR1 TG repeat
Vascular endothelial growth factor VEGF C936T
Vasoactive proteins Angiotensinogen AGT 235Met>Thr
Angiotensin converting enzyme ACE I/D intron 16
Oxidative stress and lipid metabolism Apolipoprotein E APOE C866T
Microsomal epoxide hydrolase EPHX 113Tyr>His
Glutathione S-transferase GST A313G
Immunogenetics Tumor necrosis factor α TNF G-308A
Interleukin 10 IL10 G1082A

I/D, insertion/dilution.


Thrombophilia


A successful pregnancy requires the development of adequate placental circulation. It is hypothesised that thrombophilias may increase the risk of placental insufficiency because of placental micro-vascular thrombosis, macro-vascular thrombosis, or both, as well as effects on trophoblast growth and differentiation. Abnormalities of the clotting cascade are well documented in women with pre-eclampsia. The endothelial damage of pre-eclampsia is associated with an altered phenotype from anticoagulant to procoagulant and decreased endothelially mediated vasorelaxation. It is possible that this phenotype is present before pre-eclampsia in pregnancy, or it may develop as a consequence of damage initiated during placentation. Furthermore, a subset of women develop frank thrombocytopaenia, often in association with haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Association of the three most widely studied thrombophilic factors, factor V Leiden ( F5 ), methylenetetrahydrofolate ( MTHFR ) and prothrombin ( F2 ), with pre-eclampsia has been shown; however, several studies have also shown contradictory results. A recent meta-analysis indicated a two-fold increase in risk for pre-eclampsia associated with 1691G>A mutation in F5 , but no associations were found for MTHFR or F2. To date, the number of studies showing no association with pre-eclampsia for these three genes is much higher than the number confirming association. Association with the inhibitor of fibrinolysis plasminogen activator factor-1 gene has also been reported; however, replication attempts have failed.


Haemodynamics and endothelial function


The renin-angiotensin system (RAS) is important for regulating the cardiovascular and renal changes that occur in pregnancy. Several studies have implicated the RAS in the pathophysiology of pre-eclampsia. As such, genes in the RAS have been considered as plausible candidates for pre-eclampsia. Angiotensin-converting enzyme ( ACE ), angiotensin II type 1 and type 2 receptor ( AGTR1, AGTR2 ), and angiotensinogen ( AGT ) have all been studied extensively in pre-eclampsia. Recent meta-analyses have identified the T allele of AGT M235T as increasing the risk of developing pre-eclampsia by 1.62 times and similar increases in disease risk have been found in AGT and the angiotensin-converting enzyme I/D polymorphism. A rare functional polymorphism in AGT , which results in replacement of leucine by phenylalanine at the site of renin cleavage, has been reported in association with severe pre-eclampsia.


Endothelial nitric oxide synthase 3 ( eNOS3 ), which is involved in vascular remodelling and vasodilation, has been shown to have reduced activity in pre-eclampsia Association studies in different ethnic populations, however, have yielded both positive and negative findings. A meta-analysis investigating the E298D polymorphism, which had initially been associated with pre-eclampsia in Colombian women, failed to find increased risk. Vascular endothelial growth factor ( VEGF ) is important for endothelial cell proliferation, migration, survival and regulation of vascular permeability. The number of studies that have investigated SNP in the genes involved in the VEGF system is small. Two polymorphisms in VEGF , 405G>C and 936C>T, were found to be associated with the severe form of pre-eclampsia in two small studies, but cannot at present be considered as major risk factors.


Oxidative stress and lipid metabolism


Oxidative stress plays a central role in the pathogenesis of pre-eclampsia. Maternal perfusion of the placenta does not occur until towards the end of the first trimester, when a rapid increase in local oxygen tension takes place, and the probable occurrence of a period of hypoxia–reperfusion until stability is reached. This is accompanied by increased expression and activity of such antioxidants as glutathione peroxidase, catalase and the various forms of superoxide dismutase. If this antioxidant response were reduced, then the cascade of events leading to impaired placentation could be initiated. Evidence for reduced antioxidant activity in pre-eclampsia has recently been reviewed. Genes involved in the generation or inactivation of reactive oxygen species, if defective, could increase endothelial dysfunction via lipid peroxidation, which has been a candidate causative agent for the endothelial damage of pre-eclampsia for more than 20 years. Despite the strong correlation between oxidative stress and pre-eclampsia, only a small handful of genes have been investigated. Functional polymorphisms in the gene for microsomal epoxide hydrolase ( EPHX ) that catalyses the hydrolysis of certain oxides and may produce toxic intermediates that could be involved in pre-eclampsia, and glutathione S-transferase ( GST ), an antioxidant capable of inactivating reactive oxygen species, have shown associations. Conflicting results, however, have also been reported.


Abnormal lipid profiles associated with the lipid peroxidation caused by oxidative stress are also characteristic of pre-eclampsia. Lipoprotein lipase ( LPL ) and apolipoprotein E ( ApoE ) are the two major regulators of lipid metabolism, abundantly expressed in placenta, and have therefore been proposed as possible candidate genes. A recent study using bioinformatic analysis identified altered glycosylation of circulating ApoE isoforms in pre-eclampsia. A deglycosylated basic ApoE isoform was increased in pre-eclampsia, and an acidic ApoE sialyated isoform was decreased. Functionally, this might increase the risk of developing placental atherotic changes. The most promising genetic variant in this context is a mis-sense mutation, Asn291Ser, in LPL which correlates with lowered LPL activity and increased dyslipidaemia in two separate studies. Again, others have failed to replicate these findings. The fetal genotype of these two genes has also been reported to contribute to the metabolism of the maternal lipoproteins.


Immune system


The maternal immune response to pregnancy is crucial in determining pregnancy outcome and success. The increased incidence of pre-eclampsia in primiparous women, especially those at either end of the childbearing age range, indicates a strong association between immune factors and pre-eclampsia. However, the protective effect of multiparity is lost with change of partner. Advances in assisted reproductive technology are also posing new challenges to the maternal immune system. The use of donated sperm or eggs increases the risk of pre-eclampsia three-fold.


Human leucocyte antigen


Trophoblast cells express an unusual repertoire of histocompatibility antigens, comprising human leucocyte C, E and G class antigens (HLA-C, HLA-E, HLA-E), of which only HLA-C displays marked polymorphism. The expression of HLA on the invading cytotrophoblast is important, as these interact with killer immunoglobulin, such as receptors (KIR) expressed on maternal uNKs and cytotoxic T-lymphocytes, down-regulating their cytolytic activity and stimulating the production of cytokines needed for successful placentation. Multiple highly homologous KIR genes map to chromosome 19q, probably arising from ancestral gene duplications, and the two main resulting gene clusters have been classified as haplotypes A and B. The A group codes mainly for KIR, which inhibit natural killer cells, whereas the B group has additional stimulatory genes. Pre-eclampsia is more frequent in women who are homozygous for the inhibitory A haplotypes (AA) than in women homozygous for the stimulatory B haplotypes (BB). The effect is strongest if the fetus is homozygous for the HLA-C2 haplotype. Alteration in KIR interaction on uNK cells with HLA-C on interstitial trophoblast alters the decidual immune response, resulting in impaired extravillous trophoblast invasion and deficient spiral artery remodelling, associated with pre-eclampsia.


An association of HLA-G, which displays limited polymorphism, with pre-eclampsia, has also been reported. A possible association between the presence of the HLA-G allele G*0106 in the placenta and an increased risk of pre-eclampsia has been identified in two small studies. these were underpowered, however, and further studies using larger cohorts of mothers and babies are needed to replicate these results. HLA-G variants foreign to the mother may lead to histo-incompatibility between mother and child. A maternal rejection response to the semi-allogeneic fetus may represent one of the pathways involved in the development of pre-eclampsia.


A number of pro-inflammatory cytokines have also been investigated for possible associations with pre-eclampsia. Excessive release of tumour necrosis factor alpha (TNFα) has been implicated owing to its contribution to endothelial activation, which in turn could contribute to maternal symptoms. Interestingly, in pregnant rats, TNF induces hypertension, a response not seen in non-pregnant rats. Furthermore, plasma levels of TNFα are significantly higher in women with pre-eclampsia than matched controls. TNFα is also involved in the production of reactive oxygen species and subsequently oxidant mediated endothelial damage. The most frequently studied variant in pre-eclampsia is the –308G>A transition in the promoter region, which is associated with increased levels of TNFα production and an increased risk for pre-eclampsia linked disorders, including type 2 diabetes, coronary artery disease and dyslipidaemia. However, a meta-analysis from 2008 combined 16 studies investigating this promoter SNP, but failed to detect a significant association to pre-eclampsia.


Interleukin-10 ( IL-10 ) has also been implicated in the pathogenesis of pre-eclampsia by enhancing the inflammatory response towards trophoblast cells resulting in reduced invasion and remodelling of the spiral arteries. Expression of IL-10 is reduced in pre-eclamptic placentae. Studies investigating associations of variants of the gene and pre-eclampsia, however, have yielded conflicting results. Associations have also been detected for two additional inflammatory genes, interleukin-1α ( IL-1α ) and the interleukin 1 receptor anatagonist ( IL1Ra ) in relatively small studies, but few studies have addressed the role of polymorphisms in these genes so far.


Antioxidant enzymes


A large family of cytosolic glutathione-s-transferases (GST) exists, and the P class is highly expressed in the human placenta. Several relatively small case-control studies of polymorphisms in this family in relation to pre-eclampsia have failed to identify any significant effect of several GST polymorphisms studied individually. However, a cumulative effect of the number of polymorphisms in various biotransformation enzymes, including GST, which would result in decreased antioxidant capacity, has been reported. Intriguingly, the use of semi-quantitative polymerase chain reaction on a small data set identified using serial analysis of gene expression profiles, seems to identify a specific molecular signature for HELLP, which includes decreased expression of GST P1.


Remarkably, few studies of possible functional polymorphisms in antioxidant enzyme systems have been reported. The 242C>T polymorphism in exon 4 of the gene for the p22phox subunit of NADPH/NADH oxidase ( CYBA ), which is part of the cascade of superoxide generation, has been reported as showing no evidence of an association with either pre-eclampsia or HELLP and pre-eclampsa. A small preliminary study of the Ala40Thr polymorphism of the superoxide dismutase 3 gene ( SOD3 ), which has been associated with insulin resistance, reported a significant excess of the mutant allele in women with severe intrauterine growth restriction.




Genetic aspects of pre-eclampsia


Clustering of cases of pre-eclampsia within families has been recognised since the 19th century, suggesting a genetic component to the disorder. Deciphering the genetic involvement in pre-eclampsia is challenging, not least because the phenotype is expressed only in parous women. Furthermore, in complex disorders of pregnancy, it is necessary to consider two genotypes, that of the mother and that of the fetus, which includes genes inherited from both mother and father. Maternal and fetal genes may have independent or interactive effects on the risk of pre-eclampsia. Finally, the heterogeneous nature of the disorder, with a sliding scale of severity, has resulted in differences in the definition of pre-eclampsia used within studies (see above), often with overlap of non-proteinuric gestational hypertension.


Twin studies investigating the relative contribution of genetic versus environmental factors to pre-eclampsia risk, initially yielded disappointing results. They showed that discordance for pre-eclampsia between monozygotic twin sisters was common, suggesting that heritability caused by maternal genes was low. These early studies were small. More recent investigations, however, using the large Swedish Twin, Medical Birth and Multigeneration Registries have estimated the heritability of pre-eclampsia to be about 55%, with contributions from both maternal and fetal genes. A further study in monozygotic twins found concordance of pre-eclampsia to be as common as discordance. Evidence from the largest published twin study, which correlated the Swedish Twin Register with the Swedish Medical Register, revealed pre-eclampsia penetrance to be less than 50%, suggesting diversity within models of inheritance.


Pre-eclampsia: a complex genetic disorder


For a small number of families, pre-eclampsia seems to follow Mendelian patterns of disease inheritance, consistent with a rare deleterious monogenic variant or mutation with high penetrance. For most of the population, however, pre-eclampsia seems to represent a complex genetic disorder, and occurs as the result of numerous common variants at different loci which, individually, have small effects but collectively contribute to an individual’s susceptibility to disease. Environmental exposures, including age and weight, also determine whether these low penetrant variants result in phenotypic manifestation of the disease. It is likely that no single cause or genetic variant will account for all cases of pre-eclampsia, although it is possible that different variants are associated with various subsets of disease (e.g. pre-eclampsia combined with intrauterine growth restriction). Complex genetic disorders affect a high proportion of the population, representing a large burden to public health. New approaches to susceptibility gene discovery have emerged to address this challenge. Unfortunately, early diagnosis would only permit closer focus on routine antenatal care, as at present no intervention other than delivery has been shown to alter the course of pre-eclampsia.


Determining susceptibility to pre-eclampsia


The need to assess both the maternal and the fetal genotype is clear. The role of the placenta in the primary pathogenesis of the disorder indisputably indicates a fetal contribution to susceptibility to the disorder. Reports of severe, very early-onset pre-eclampsia in cases of fetal chromosomal abnormalities such as diandric hydatifidiform moles of entirely paternal genetic origin are consistent with a role for paternally inherited fetal genes in the determination of clinical phenotype. This is supported by epidemiological studies reporting a higher rate of pre-eclampsia in pregnancies fathered by men who were themselves born of pre-eclamptic pregnancies. The occurrence of pre-eclampsia in daughters-in-law of index women further supports a genetic contribution from both parents. The genetic conflict hypothesis states that fetal (paternal) genes will be selected to increase the transfer of nutrients to the fetus, whereas maternal genes will be selected to limit transfer in excess of a specific maternal optimum. Fetal genes are predicted to raise maternal blood pressure in order to enhance the uteroplacental blood flow, whereas maternal genes act the opposite way. Endothelial dysfunction in mothers with pre-eclampsia could, therefore, be interpreted as a fetal attempt to compensate for an inadequate uteroplacental nutrient supply.


As the phenotype is apparently only expressed during pregnancy, identification of ‘susceptible’ men is impossible. Most genetic studies of pre-eclampsia have focused on maternal genotypes only. The Genetics of Pre-eclampsia consortium highlighted the need to include analysis of all contributing genotypes, and carried out transmission disequilibrium testing in maternal and fetal triads. Understanding the contribution of the fetal genotype will require large sample sizes, with the development of algorithms to determine the relative contribution from mother and fetus. Furthermore, the decreased incidence of pre-eclampsia in second and subsequent pregnancies hampers analysis of the contribution of the fetal genotype.


Candidate gene approach


The candidate gene approach has been widely used in pre-eclampsia, and largely focuses on the maternal genotype. In this method, a single gene is chosen as the candidate for investigation based on prior biological knowledge of the pathophysiology of pre-eclampsia. The choice is strengthened if the gene lies within a region identified by linkage studies. A case-control design is usually used, comparing the frequencies of allelic variants in women with pre-eclampsia and normotensive pregnancies. Such studies need careful definition of inclusion criteria for cases and controls, and subtle ethnic stratification of groups must be avoided. Such performance characteristics of the genotyping assays as the rate of mis-genotyping, and the quality assurance methods used, should be clearly stated, but this is rarely done. Over 70 biological candidate genes have been examined, representing pathways involved in various pathophysiological processes, including vasoactive proteins, thrombophilia and hypofibrinolysis, oxidative stress and lipid metabolism, endothelial injury and immunogenetics. In common with the experience in other genetically complex disorders, results from candidate gene studies have been inconsistent, and no universally accepted susceptibility gene has been identified. Although this may, in part, be attributed to variation within populations, a more important factor is the small size of most of the candidate studies, which have been underpowered to detect variants with small effects. As there are more than 20,000 genes and 10 million single nucleotide polymorphisms (SNP) available, multiple testing will inevitably result in numerous results that achieve P values of less than 0.05. The development of robust statistical techniques for the minimisation of both false positive and false negative results is an important area. Only in recent years, as susceptibility genes for other complex disorders have been reported, has the small effect size of individual genetic variants become apparent, the majority increasing the risk of disease by less than 50%. A further limitation of the candidate gene approach is its reliance on the generation of an a-priori hypothesis based on our current incomplete knowledge of the pathophysiology of the disorder. The candidate genes studied belong to different groups according to their functional properties and plausible role in the pathophysiology ( Table 2 ).


Nov 9, 2017 | Posted by in OBSTETRICS | Comments Off on The genetics of pre-eclampsia and other hypertensive disorders of pregnancy

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