TOXEMIA OF PREGNANCY HYPERTENSION, PREGNANCY-INDUCED, INCLUDED
HEMOLYSIS, ELEVATED LIVER ENZYMES, AND LOW PLATELET COUNT, INCLUDED
HELLP, INCLUDED
PEE1
PEE
PREG1
Preeclampsia, which along with chronic hypertension and gestational hypertension comprise the hypertensive disorders of pregnancy, is characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks' gestation with clinically relevant proteinuria. Preeclampsia is 1 of ... Preeclampsia, which along with chronic hypertension and gestational hypertension comprise the hypertensive disorders of pregnancy, is characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks' gestation with clinically relevant proteinuria. Preeclampsia is 1 of the top 4 causes of maternal mortality and morbidity worldwide (summary by Payne et al., 2011). Preeclampsia is otherwise known as gestational proteinuric hypertension (Davey and MacGillivray, 1988). A high proportion of patients with preeclampsia have glomerular endotheliosis, the unique histopathologic feature of the condition (Fisher et al., 1981). A distinct form of severe preeclampsia is characterized by hemolysis, elevated liver enzymes, and low platlets (HELLP syndrome) (Brown et al., 2000). - Genetic Heterogeneity of Preeclampsia/Eclampsia Susceptibility loci for preeclampsia/eclampsia include PEE1 on chromosome 2p13, PEE2 (609402) on chromosome 2p25, and PEE3 (609403) on chromosome 9p13. PEE4 (609404) is caused by mutation in the STOX1 gene (609397) on chromosome 10q22. PEE5 (614595) is caused by mutation in the CORIN gene (605236) on chromosome 4p12. An association with PEE has been found with the EPHX1 gene (132810) on chromosome 1q.
In 627 families with preeclampsia (including 398 maternal triads and 536 fetal triads), the GOPEC Consortium (2005) analyzed 7 candidate genes previously reported as conferring susceptibility to preeclampsia: angiotensinogen (AGT; 106150), the angiotensin receptors AGTR1 (106165) and AGTR2 ... In 627 families with preeclampsia (including 398 maternal triads and 536 fetal triads), the GOPEC Consortium (2005) analyzed 7 candidate genes previously reported as conferring susceptibility to preeclampsia: angiotensinogen (AGT; 106150), the angiotensin receptors AGTR1 (106165) and AGTR2 (300034), factor V Leiden variant (612309.0001), methylenetetrahydrofolate reductase (MTHFR; 607093), nitric oxide synthase (NOS3; 163729), and tumor necrosis factor-alpha (TNF; 191160). Using the transmission disequilibrium test, no genotype risk ratio achieved the prespecified criteria for statistical significance (posterior probability less than 0.05). The GOPEC Consortium (2005) concluded that none of the genetic variants tested confers a high risk of preeclampsia. Uz et al. (2007) found extremely skewed X-inactivation (greater than or equal to 90:10) in peripheral blood cells of 10 (22%) of 46 Caucasian women with preeclampsia and in 2 (2.33%) of 86 controls, suggesting a role for the X chromosome in the pathogenesis of the disorder in some patients. - Association with HLA Kilpatrick et al. (1989) studied a group of 56 women who had had proteinuric preeclampsia and who had parous sisters. In the first pregnancy, proteinuric preeclampsia was more common in the sisters than in the maternity hospital population; the relative risk was 6.0. Frequency of HLA-DR4 (see 142860) was higher in sisters with pregnancy-induced hypertension than in sisters with normotensive pregnancies and more of them shared HLA-DR4 with their spouses. Kilpatrick et al. (1989) referred to a study of unrelated women in which they confirmed the association between DR4 and proteinuric preeclampsia. They proposed the hypothesis that preeclampsia occurs when both mother and fetus are homozygous for an HLA-linked recessive gene. Wilton et al. (1990), however, excluded close linkage of an eclampsia susceptibility gene with HLA. Liston and Kilpatrick (1991) examined 6 simple mendelian models of inheritance and rejected all except the one in which both mother and fetus must express the same recessive gene to confer susceptibility. They considered this model to be consistent with the putative association with HLA-DR4. Based on the hypothesis that preeclampsia occurs in women who are homozygous for a relatively common susceptibility gene, Hayward et al. (1992) constructed an exclusion map by using both candidate genes and random DNA markers on a panel of 2-generation families in which preeclampsia was rigorously defined. No evidence was found for linkage to the HLA region or to several genes implicated in the pathogenesis of hypertension, e.g., pronatriodilatin (108780), sodium-hydrogen ion antiporter (107310), mineralocorticoid receptor (600983), or glucocorticoid receptor (138040). Van Meter and Weaver (1993) commented on the study of Hayward et al. (1992). See 106150.0001 for information concerning the association of preeclampsia with a met235-to-thr mutation of the angiotensinogen gene, which maps to 1q. Preeclampsia is a pregnancy complication in which the fetus receives an inadequate blood supply due to failure of trophoblast invasion. Hiby et al. (2004) noted that the only polymorphic histocompatibility antigens on the trophoblast surface are HLA-C molecules (142840), including the paternal allele, which are recognized by members of the highly polymorphic KIR (see KIR2DL1; 604936) family of natural killer cell receptors. There are 2 distinct KIR haplotypes, termed A and B. Haplotype A has 1 activating and 6 inhibitory KIRs, whereas haplotype B has 5 activating and 2 inhibitory KIRs. Hiby et al. (2004) found that mothers with an AA KIR genotype and a fetus with HLA-C2 were at greatly increased risk of preeclampsia. KIR2DL5 (605305), a haplotype B gene encoding an inhibitory receptor, was significantly less frequent in preeclampsia mothers. The KIR-HLA-C2 interaction appeared to be physiologic rather than immunologic, in that maternal HLA-C type was of no consequence. Hiby et al. (2004) found that different human populations have reciprocal relationships between KIR AA frequency and HLA-C2 frequency, suggesting that this combination may be selected against and that reproductive success may have influenced the evolution and maintenance of KIR and HLA-C polymorphisms. - Association with MTHFR Sohda et al. (1997) studied the 677C-T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR; 607093.0003) in preeclampsia. They found an increased frequency of the 677T allele and the 677T homozygous genotype in patients as compared with controls. The 677T variant of MTHFR had been identified as a risk factor in vascular disease in other studies. Rajkovic et al. (2000) found no statistically significant association between the maternal MTHFR genotype at the 677C-T polymorphism (607093.0003) and risk of preeclampsia. Conversely, Rajkovic et al. (2000) found a strong graded association between maternal plasma folate concentration and risk of preeclampsia. Women with plasma folate concentrations of less than 5.7 nmol/L experienced a 10.4-fold increase in risk of preeclampsia. There was no clear pattern of preeclampsia risk and vitamin B12 concentrations. - Association with EPHX1 Zusterzeel et al. (2001) studied genetic variability in the EPHX1 gene (132810) in women with a history of preeclampsia. They found that the high activity genotype tyr113/tyr113 (132810.0001) was significantly more common in women with a history of preeclampsia (OR, 2.0, 95% CI, 1.2-3.7) as compared to controls. No difference in the frequency of the polymorphism was found between groups who did or did not develop the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Laasanen et al. (2002) studied 2 single-nucleotide polymorphisms (SNPs) in the EPHX1 gene in 133 Finnish preeclamptic and 115 healthy control women with at least 2 normal pregnancies. The T allele of the exon 3 T-C polymorphism (tyr113 to his; 132810.0001) was overrepresented among the preeclampsia group (0.74) when compared with the control group (0.66), displaying a borderline association (P = 0.05). Haplotype analysis using this polymorphism and the exon 4 A-G polymorphism (his139 to arg; 132810.0002) showed that the high activity haplotype T/A (tyr113/his139) was significantly overrepresented in the preeclampsia group (P = 0.01; odds ratio 1.61, 95% C.I. 1.12-2.32). The authors supported the feasibility of haplotype estimation analysis for detecting association more efficiently than single-point association analysis in terms of detection power. - Association with GSTP1 Zusterzeel et al. (1999) found that glutathione S-transferase P1 (GSTP1; 134660) is the main GST isoform in normal placental and decidual tissue. In preeclamptic women, they found lower median placental and decidual GSTP1 levels compared to those in controls. Zusterzeel et al. (1999) suggested that reduced levels of GSTP1 in preeclampsia may indicate a decreased capacity of the detoxification system, resulting in a higher susceptibility to preeclampsia. Among 113 preeclampsia trios (mother, father, and baby), Zusterzeel et al. (2002) found an increased frequency of the GSTP1 val105 polymorphism (see 134660.0002) in mothers, fathers, and offspring of preeclamptic pregnancies compared to controls. There was no significant difference of the GSTP1 allele frequencies in preeclamptic mothers, fathers, and offspring. The authors emphasized the paternal contribution to the risk for preeclampsia. - Association with Coagulation Factor V Brenner et al. (1996) identified the factor V Leiden mutation (R506Q; 612309.0001) in 2 patients with the HELLP syndrome, and Kupferminc et al. (1999) found an association between that mutation and a variety of obstetrical complications, including preeclampsia. Lindqvist et al. (1998), however, found no significant difference in the prevalence of the Leiden mutation between women with preeclampsia and/or intrauterine growth retardation and a control group. In a study of Finnish women, Faisel et al. (2004) found that susceptibility to preeclampsia was associated with a factor V R485K polymorphism but not with the Leiden mutation. - Association with NOS3 In a study of 150 'coloured' South African patients, 50 with normal pregnancies, 50 with severe preeclampsia, and 50 with abruptio placentae, Hillermann et al. (2005) found that the combined frequency of the GT and TT NOS3 variant genotypes was significantly higher in the abruptio placentae group than in the control group (p = 0.006). Among preeclamptic patients who subsequently developed abruptio placentae, the T allele emerged as a major risk factor for the development of abruptio placentae (p less than 0.0001); the T variant did not seem to affect the risk of preeclampsia itself, however.
Preeclampsia complicates 3 to 8% of pregnancies in Western countries and causes 10 to 15% of maternal deaths. Incidence ranges from 3 to 7% for nulliparas and 1 to 3% for multiparas (summary by Uzan et al., 2011). ... Preeclampsia complicates 3 to 8% of pregnancies in Western countries and causes 10 to 15% of maternal deaths. Incidence ranges from 3 to 7% for nulliparas and 1 to 3% for multiparas (summary by Uzan et al., 2011).