M385T polymorphism in the factor V gene, but not Leiden mutation, is associated with placental abruption in Finnish women

doi:10.1016/j.placenta.2004.02.006

Placenta

Volume 25, Issues 8–9, September–October 2004, Pages 730-734

https://doi.org/10.1016/j.placenta.2004.02.006 Get rights and content

Abstract

This study determines whether genetic variability in the gene encoding factor V contributes to differences in susceptibility to placental abruption. Allele and genotype frequencies of three single nucleotide polymorphisms (SNPs) in the factor V gene leading to nonsynonymous changes (M385T in exon 8, and R485K and R506Q [Leiden mutation] in exon 10) were studied in 116 Caucasian women with placental abruption and 112 healthy controls. Single-point analysis was expanded to haplotype analysis and haplotype frequencies were estimated using an expectation-maximisation (EM) algorithm. Comparison of single-point allele and genotype distributions of SNPs in exon 8 and exon 10 of the factor V gene revealed statistically significant differences in M385T allele (P=0.021) and genotype (P=0.013) frequencies between the patients and the control subjects. The C allele of SNP M385T was significantly less frequent among the patients (7%) vs. the control subjects (13%), at an odds ratio of 0.48 (95% CI 0.25–0.91). Allele and genotype differences between the patients and control subjects as regards R485K and Leiden mutation were not significant. In haplotype estimation analysis, there was a significantly lower frequency of haplotype T-R-R encoding the T385–R485–R506 variant in the group with placental abruption vs. the control group (P=0.038) at an odds ratio of 0.519 (95% CI 0.272–0.987). We conclude that T385 is less frequent among the patient group than in the control group. The M385T variant in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.

Introduction

Dahlback et al. [1] assigned the factor V gene to chromosome region 1q23. Activated Factor V (Factor Va) is an essential cofactor for the factor Xa-catalyzed activation of prothrombin to the clotting enzyme thrombin [2]. Activated protein C (APC) is a naturally occurring anticoagulant which selectively degrades coagulation factors Va and VIIIa [3]. The factor V Leiden mutation, a common point mutation in the factor V gene, encoding substitution of arginine for glutamate at position 506 of the factor V molecule, has been reported to be the site where activated protein C cleaves factor Va [4]. The factor V Leiden mutation and R485K polymorphism in the factor V gene (the less frequent A allele (K485)) have been reported to be a significant risk factor for thrombophilia [5], [6], [7], [8].

In obstetrics, the prevailing evidence suggests that the risk of placental abruption is increased two- to sixfold in women carrying the factor V Leiden mutation [9], [10]. The central mechanism is probably endothelial cell injury and dysfunction resulting from fibrin deposition and the formation of microthrombi [11]. We designed a controlled study to investigate the possible association between not only the Leiden mutation, but also the M385T and R485K polymorphisms of the factor V gene and placental abruption in Finnish women. We further analysed the haplotype structure in the critical area covering a region in the proximity of the Leiden mutation. The Finnish population is considered to be a genetic isolate and thus ideal for genetic association studies [12].

Section snippets

Materials and methods

Written approval for the study was obtained from the Ethics Committee of Kuopio University Hospital, and the Institutional Review Board approved the protocol. All subjects gave written informed consent, which was documented.

Information was collected retrospectively in connection with 117 pregnancies of parous women who had had placental abruption and 115 parous control women with no history of placental abruption who delivered at Kuopio University Hospital between January 1994 and December

Results

Selected clinical characteristics of affected women and controls are shown in Table 1. Of the 116 women with placental abruption, 45 were nulliparas, whereas all the (selected) controls had had two or more uncomplicated deliveries, in order to reduce the stratification bias that would have resulted from the fact that primiparous women may experience placental abruption in subsequent pregnancies. In cases of recurrent placental abruption (N=8), only the first incident was used for comparison.

Discussion

The genetic background behind placental abruption is supported by the observed high recurrence rate [14], [15] and genetic associations found between the disease and nitric oxide synthase polymorphisms, Leiden and 5,10-methylenetetrahydrofolate reductase gene mutations [16], [17], [18]. This genetic component is likely to be multifactorial in nature and furthermore, environmental factors probably modify the disease risk individually. In this study, the candidate gene was selected on the basis

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Abruptio placentae risk and genetic variations in mitochondrial biogenesis and oxidative phosphorylation: replication of a candidate gene association study
2018, American Journal of Obstetrics and Gynecology
Abruptio placentae is a complex multifactorial disease that is associated with maternal and neonatal death and morbidity. Abruptio placentae’s high recurrence rate, high prevalence of heritable thrombophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms in mitochondrial biogenesis and oxidative phosphorylation genes that potentially are associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, which results in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast and to several obstetrics complications that include abruptio placentae.
The purpose of this study was to determine whether the results of a candidate genetic association study that indicated a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated.
The study was conducted among participants (507 abruptio placentae cases and 1090 control subjects) of the Placental Abruption Genetic Epidemiology study. Weighted genetic risk scores were calculated with the use of abruptio placentae risk-increasing alleles of 11 single nucleotide polymorphisms in 9 mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12, and NDUFC2), which previously was reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the Placental Abruption Genetic Epidemiology study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1, <25th percentile; quartile 2, 25–50th percentile; quartile 3, 50–70th percentile, and quartile 4, >75th percentile) with risk of abruptio placentae, adjusted for population admixture (the first 4 principal components), maternal age, infant sex, and preeclampsia. The weighted genetic risk score was also modeled as a continuous predictor. To assess potential effect modification, analyses were repeated among strata that were defined by preeclampsia status, maternal age (≥35 vs 18–34 years), and infant sex.
Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age, and lower infant birthweight. Participants in quartile 2 (score, 12.6–13.8), quartile 3 (score, 13.9–15.0) and quartile 4 (score, ≥15.1) had a genetic risk score of 1.45-fold (95% confidence interval, 1.04–2.02; P=.03), a 1.42-fold (95% confidence interval, 1.02–1.98; P=.04), and a 1.75-fold (95% confidence interval, 1.27–2.42; P=7.0E-04) higher odds of abruptio placentae, respectively, compared with those in quartile 1 (score,<12.6; P-for trend=.0003). The risk of abruptio placentae was 1.12-fold (95% confidence interval, 1.05–1.19; P=3.0×10⁰⁴) higher per 1-unit increase in the score. Among women with preeclampsia, those in quartile 4 had a 3.92-fold (95% confidence interval, 1.48–10.36; P=.01) higher odds of abruptio placentae compared with women in quartile 1. Among normotensive women, women in quartile 4 had a 1.57-fold (95% confidence interval, 1.11–2.21; P=.01) higher odds of abruptio placentae compared with those in quartile 1 (P-for interaction=.12). We did not observe differences in associations among strata defined by maternal age or infant sex.
In this study, we replicated previous findings and provide strong evidence for DNA variants that encode for genes that are involved in mitochondrial biogenesis and oxidative phosphorylation pathways, which confers risk for abruptio placentae. These results shed light on the mechanisms that implicate DNA variants that encode for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of abruptio placentae can be enhanced by improved biologic understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways and identification of women who would be at high risk for abruptio placentae.
Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies
2018, Placenta
Citation Excerpt :
However, most PA cases do not exhibit these known risk factors [13]. PA tends to aggregate in first degree relatives of women with PA [14,15], suggesting a role for genetic predisposition [16–18]. Accumulating evidence from GWAS and candidate gene studies also suggest that there are underlying genetic risk factors in the pathogenesis of PA [19–23].
Accumulating epidemiological evidence points to strong genetic susceptibility to placental abruption (PA). However, characterization of genes associated with PA remains incomplete. We conducted a genome-wide association study (GWAS) of PA and a meta-analysis of GWAS.
Participants of the Placental Abruption Genetic Epidemiology (PAGE) study, a population based case-control study of PA conducted in Lima, Peru, were genotyped using the Illumina HumanCore-24 BeadChip platform. Genotypes were imputed using the 1000 genomes reference panel, and >4.9 million SNPs that passed quality control were analyzed. We performed a GWAS in PAGE participants (507 PA cases and 1090 controls) and a GWAS meta-analysis in 2512 participants (959 PA cases and 1553 controls) that included PAGE and the previously reported Peruvian Abruptio Placentae Epidemiology (PAPE) study. We fitted population stratification-adjusted logistic regression models and fixed-effects meta-analyses using inverse-variance weighting.
Independent loci (linkage-disequilibrium<0.80) suggestively associated with PA (P-value<5e-5) included rs4148646 and rs2074311 in ABCC8, rs7249210, rs7250184, rs7249100 and rs10401828 in ZNF28, rs11133659 in CTNND2, and rs2074314 and rs35271178 near KCNJ11 in the PAGE GWAS. Similarly, independent loci suggestively associated with PA in the GWAS meta-analysis included rs76258369 near IRX1, and rs7094759 and rs12264492 in ADAM12. Functional analyses of these genes showed trophoblast-like cell interaction, as well as networks involved in endocrine system disorders, cardiovascular diseases, and cellular function.
We identified several genetic loci and related functions that may play a role in PA risk. Understanding genetic factors underlying pathophysiological mechanisms of PA may facilitate prevention and early diagnostic efforts.
Inherited Thrombophilias and Adverse Pregnancy Outcomes. A Review of Screening Patterns and Recommendations
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No significant association exists between FVL G1691A and preeclampsia or small gestational age.15,16 Associations between placental abruption and FVL G1691A are also lacking.17–19 However, a more recent MFM network case control study, although confirming a lack of association with placental abruption, did find an increase in fetal hypoxia-inducing factors in the placentas of mothers with FVL G1691A compared with age-matched controls.20
Factor v Leiden mutation and pregnancy-related complications
2010, American Journal of Obstetrics and Gynecology
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However, our results did not support the assumption that FVL carriership raises the relative risk of these complications, and it is more important to consider the absolute risks when assessing such rare events. Two prospective studies failed to detect any association between FVL carriership and placental abruption,10,19 as did 2 of the 3 largest retrospective studies.26-28 The largest case-control study found a significantly elevated risk for fetal loss after 22 gestational weeks29 but the largest cohort study did not.30
The objective of the study was to determine the prevalence of the factor V Leiden (FVL) mutation and its association with obstetric complications, blood loss during delivery, and venous thromboembolism (VTE).
This was a prospective, observational, case-cohort study of 491 FVL carriers and 1055 controls derived from 6003 screened women. Data were analyzed with a Student t test and cross-tabulation.
FVL carriership prevalence was 8.3%. Gestational age at delivery, birthweight deviation, gestational hypertension, and preeclampsia incidences did not differ between groups. The incidences of placental abruption, neonatal asphyxia, eclampsia, intrauterine fetal death, intrapartum death, and unexplained late miscarriage were low. The incidence of major blood loss at delivery was lower in carriers. There were 3 VTEs among carriers and none among controls.
FVL carriership did not influence pregnancy-induced hypertension, birthweight, or prematurity but raised the risk of venous thromboembolism and lowered the risk of major blood loss.
Inherited and acquired thrombophilias and adverse pregnancy outcomes
2016, Recurrent Pregnancy Loss: Evidence-Based Evaluation, Diagnosis and Treatment
The 1691 G > A (Factor V Leiden) and 1328 T > C V Coagulation Factor polymorphisms and recurrent miscarriages
2015, Ginekologia Polska

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View full text

M385T polymorphism in the factor V gene, but not Leiden mutation, is associated with placental abruption in Finnish women

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Blood

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Assignment of gene for coagulation factor V to chromosome 1 in man and to chromosome 13 in rat

Somat Cell Mol Genet

Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C

Proc Natl Acad Sci U S A

Mutation in blood coagulation factor V associated with resistance to activated protein C

Nature

Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C

J Clin Invest

Activated protein C resistance assay detects thrombotic risk factors other than factor V Leiden

Am J Clin Pathol