Maternal and fetal variants in the TGF-beta3 gene and risk of pregnancy-induced hypertension in a predominantly Latino population

Wilson, Melissa L.; Desmond, Daniel; Goodwin, T. Murphy; Miller, David A.; Ingles, Sue A.

doi:10.1016/j.ajog.2009.05.038

Cited by 22 publications

(29 citation statements)

References 16 publications

(17 reference statements)

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“…Congruent with previous studies, the allele frequencies of the two polymorphisms did not differ between women with PE and controls [15,27,29]. Nevertheless, unlike the earlier reports, data obtained in our study exhibited a significant difference in the genotype frequencies of the C-509T polymorphism between patients with preeclampsia and normal healthy pregnant women.…”

Section: Discussionsupporting

confidence: 55%

“…Scandinavian Journal of Immunology, 2015, 82, 390-397 394 TGFB1 Gene in Susceptibility to Pre-eclampsia disparity could possibly be due to the relatively smaller sample size and ethnic background of the study populations [15,27,29]. Regarding the C-509T polymorphism, under the overdominant model, the CT genotype conferred a highly significant protective influence.…”

Section: Discussionmentioning

confidence: 99%

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TGFB1 Functional Gene Polymorphisms (C‐509T and T869C) in the Maternal Susceptibility to Pre‐eclampsia in South Indian Women

et al. 2015

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Pre-eclampsia (PE), a pregnancy-specific vascular disorder characterized by hypertension and proteinuria, is hypothesized to be the result of inadequate placental angiogenesis with attendant systemic inflammation. The pleiotropic cytokine, Transforming Growth Factor-b1 (TGF-b1), is considered to be a key candidate gene in the molecular pathogenesis of PE by virtue of its ability to not only regulate angiogenesis and apoptosis of target cells, but also by acting as a master controller of Th1/Th2 cytokine balance and production of the antiinflammatory peripheral regulatory T cells (FOXP3+ Tregs). Based on this presumption, we screened a total of 469 pregnant women from South India that include 239 patients with PE and 230 healthy controls for the two functional polymorphisms of TGFB1 gene (C-509T and T869C). The genotype frequencies of these two polymorphisms differed significantly between the PE and control groups (P = 0.01 and P = 0.002, for the TGFB1 C-509T and T869C polymorphisms, respectively). Under the over-dominant model, the CT genotype of the TGFB1 C509T polymorphism showed a high protective effect (P = 3e-04), while the TT genotype of the same variant appeared to be the predisposing genotype (P = 0.003). The T-T and C-C haplotypes were found to be the risk haplotypes blocks towards PE (OR = 4.72; P = 0.031, OR = 5.39; P = 0.03), respectively. Strong linkage disequilibrium was seen between the two polymorphisms. Our investigations revealed a significant influence of TGFB1 C-509T and T869C polymorphisms on the PE risk in South Indian women. The study represents one of the first of its kind from the Indian subcontinent.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

TGFB1 Functional Gene Polymorphisms (C‐509T and T869C) in the Maternal Susceptibility to Pre‐eclampsia in South Indian Women

et al. 2015

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“…This conclusion is supported by the recent identification of a fetal variant in the Gcm1 gene that is associated with gestational hypertension in human pregnancy. 40 …”

Section: Discussionmentioning

confidence: 99%

Effects of Reduced Gcm1 Expression on Trophoblast Morphology, Fetoplacental Vascularity, and Pregnancy Outcomes in Mice

et al. 2012

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Abstract-Preeclampsia is a life-threatening disorder characterized by maternal gestational hypertension and proteinuria that results from placental dysfunction. Placental abnormalities include abnormal syncytiotrophoblast and a 50% reduction in placental expression of the transcription factor Gcm1. In mice, homozygous deletion of Gcm1 prevents syncytiotrophoblast differentiation and is embryonic lethal. We used heterozygous Gcm1 mutants (Gcm1 ϩ/Ϫ ) to test the hypothesis that hypomorphic expression of placental Gcm1 causes defective syncytiotrophoblast differentiation and maternal and placental phenotypes that resemble preeclampsia. We mated wild-type female mice with Gcm1 ϩ/Ϫ fathers to obtain wild-type mothers carrying Ϸ50% Gcm1 ϩ/Ϫ conceptuses. Gcm1 ϩ/Ϫ placentas had syncytiotrophoblast abnormalities including reduced gene expression of Gcm1-regulated SynB, elevated expression of sFlt1, a thickened interhemal membrane separating maternal and fetal circulations, and electron microscopic evidence in syncytiotrophoblast of necrosis and impaired maternal-fetal transfer. Fetoplacental vascularity was quantified by histomorphometry and microcomputed tomography imaging. In Gcm1, it was Ϸ30% greater than wild-type littermates, whereas placental vascular endothelial growth factor A (Vegfa) expression and fetal and placental weights did not differ. Wild-type mothers carrying Gcm1 ϩ/Ϫ conceptuses developed late gestational hypertension (118Ϯ2 versus 109.6Ϯ0.7 mm Hg in controls; PϽ0.05). We next correlated fetoplacental vascularity with placental Gcm1 expression in human control and pathological pregnancies and found that, as in mice, fetoplacental vascularity increased when GCM1 protein expression decreased (R 2 ϭϪ0.45; PϽ0.05). These results support a role for reduced placental Gcm1 expression as a causative factor in defective syncytiotrophoblast differentiation and maternal and placental phenotypes in preeclampsia in humans. (Hypertension. 2012;59:732-739.) • Online Data Supplement Key Words: syncytin Ⅲ placenta Ⅲ preeclampsia Ⅲ angiogenesis Ⅲ VEGFA Ⅲ placental growth factor Ⅲ sFlt1 P lacental dysfunction is believed to be the major cause of one of the most common and serious complications of human pregnancy, preeclampsia (PE). 1 This potentially lifethreatening hypertensive disorder adversely impacts Յ5% of all pregnancies and has no known cure. In PE, growing evidence implicates abnormalities in syncytiotrophoblast (SynT) in the villous exchange region of the placenta. [1][2][3][4][5][6] SynTs are thin, fetal-derived cells that lie between the maternal blood flowing through the villous exchange region of the placenta and the fetal blood flowing through fetal vessels in the highly vascularized villi. This surface is essential for fetomaternal communication and exchange and is formed through the differentiation of SynT from the underlying villous cytotrophoblast cells under the control of the transcription factor GCM1 (glial cells missing 1). 7 Gcm1 in the conceptus is almost exclusively expressed in a subset of trop...

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“…This was presumably related to the selective expression of GCM1 in the placenta being where the modulation of risk emerges [56] and the fact that most of the placenta is of fetal origin [6]. The same group who found the fetal GCM1 association had previously found an association between the risk of maternal preeclampsia and a fetal SNP in the transforming growth factor (TGF)-b3 (TGFB3) gene in the same group of women [57]. The odds ratio for the mother developing preeclampsia when the fetus was carrying at least one of minor allele of the SNP rs11466414 was 0.32 (0.14-0.77 95% CI).…”

Section: Human Studiesmentioning

confidence: 99%

“…However, in a small American study of predominantly Hispanic women, the fetal genotype for a single nucleotide polymorphism (SNP) (rs9349655) in the GCM1 (glial cells missing, drosophila, homologue of) gene was associated with a reduced risk of the development of preeclampsia: odds ratio of 0.41 (0.20-0.85 95% CI) for group sizes of 136 with preeclampsia and 169 without any form of pregnancyinduced hypertension [55]. There was no such association between the maternal genotype and the risk of preeclampsia, however.…”

Section: Human Studiesmentioning

confidence: 99%

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

Petry

Beardsall

2014

Journal of Hypertension

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The heritability of pregnancy-induced hypertension (encompassing both gestational hypertension and preeclampsia) is around 0.47, suggesting that there is a genetic component to its development. However, the maternal genetic risk variants discovered so far only account for a small proportion of the heritability. Other genetic variants that may affect maternal blood pressure in pregnancy arise from the fetal genome, for example wild-type pregnant mice carrying offspring with Cdkn1c or Stox1 disrupted develop hypertension and proteinuria. In humans, there is a higher risk for preeclampsia in women carrying fetuses with Beckwith-Wiedemann syndrome (including those fetuses with CDKN1C mutations) and a lower risk for women carrying babies with trisomy 21. Other risk may be associated with imprinted fetal growth genes and genes that are highly expressed in the placenta such as GCM1. This article reviews the current state of knowledge linking the fetal genotype with maternal blood pressure in pregnancy.

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Maternal and fetal variants in the TGF-beta3 gene and risk of pregnancy-induced hypertension in a predominantly Latino population

Cited by 22 publications

References 16 publications

TGFB1 Functional Gene Polymorphisms (C‐509T and T869C) in the Maternal Susceptibility to Pre‐eclampsia in South Indian Women

TGFB1 Functional Gene Polymorphisms (C‐509T and T869C) in the Maternal Susceptibility to Pre‐eclampsia in South Indian Women

Effects of Reduced Gcm1 Expression on Trophoblast Morphology, Fetoplacental Vascularity, and Pregnancy Outcomes in Mice

The potential impact of the fetal genotype on maternal blood pressure during pregnancy

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