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Introduction: Inflammation is a normal physiological process that increases to harmful levels in preeclampsia. It affects the interaction between maternal immune cells and fetal trophoblasts at both sites of the maternal-fetal interface; decidua and placenta. The pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD)1 is expressed at both sites. This study aimed to characterize the cellular expression and functionality of NOD1 at the maternal-fetal interface of normal and preeclamptic pregnancies.Methods: Women with normal or preeclamptic pregnancies delivered by caesarean section were included. Decidual (n = 90) and placental (n = 91) samples were analyzed for NOD1 expression by immunohistochemistry and an automated image-based quantification method. Decidual and placental explants were incubated with or without the NOD1-agonist iE-DAP and cytokine responses measured by ELISA.Results: NOD1 was markedly expressed by maternal cells in the decidua and by fetal trophoblasts in both decidua and placenta, with trophoblasts showing the highest NOD1 expression. Preeclampsia with normal fetal growth was associated with a trophoblast-dependent increase in decidual NOD1 expression density. Compared to normal pregnancies, preeclampsia demonstrated stronger correlation between decidual and placental NOD1 expression levels. Increased production of interleukin (IL)-6 or IL-8 after in vitro explant stimulation confirmed NOD1 functionality.Discussion: These findings suggest that NOD1 contributes to inflammation at the maternal-fetal interface in normal pregnancies and preeclampsia and indicate a role in direct maternal-fetal communication. The strong expression of NOD1 by all trophoblast types highlights the importance of combined assessment of decidua and placenta for overall understanding of pathophysiological processes at the maternal-fetal interface. [ABSTRACT FROM AUTHOR]

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement. [ABSTRACT FROM AUTHOR]

Introduction: Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8.Methods: Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum.Results: We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1.Discussion: This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: Preeclampsia is a heterogeneous gestational disease characterized by maternal hypertension and proteinuria, affecting 2-7% of pregnancies. The disorder is initiated by insufficient placental development, but studies characterizing the placental disease components are lacking.Methods: Our aim was to phenotype the preeclamptic placenta using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS MRS). Placental samples collected after delivery from women with preeclampsia (n = 19) and normotensive pregnancies (n = 15) were analyzed for metabolic biomarkers including amino acids, osmolytes, and components of the energy and phospholipid metabolism. The metabolic biomarkers were correlated to clinical characteristics and inflammatory biomarkers in the maternal sera.Results: Principal component analysis showed inherent differences in placental metabolic profiles between preeclamptic and normotensive pregnancies. Significant differences in metabolic profiles were found between placentas from severe and non-severe preeclampsia, but not between preeclamptic pregnancies with fetal growth restricted versus normal weight neonates. The placental metabolites correlated with the placental stress marker sFlt-1 and triglycerides in maternal serum, suggesting variation in placental stress signaling between different placental phenotypes.Discussion: HR-MAS MRS is a sensitive method for defining the placental disease component of preeclampsia, identifying several altered metabolic pathways. Placental HR-MAS MRS analysis may improve insight into processes affected in the preeclamptic placenta, and represents a novel long-required tool for a sensitive placental phenotyping of this heterogeneous disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] Association analyses on the 2q22 preeclampsia susceptibility locus were performed. [•] Associations between cardiovascular risk factors and preeclampsia were observed. [•] This may reveal pathophysiological mechanisms relevant to both disorders. [Copyright &y& Elsevier]

Introduction Preeclampsia is characterized by reduced trophoblast invasion in the uterine wall decidua, harmful placental inflammation, and elevated systemic inflammation and sFlt-1 levels. Danger sensors like toll-like receptor (TLR)2, TLR4 and the nod-like receptor protein (NLRP)3 inflammasome initiate inflammation. These sensors have been associated with placental inflammation in preeclampsia, and maternal cholesterol and uric acid levels represent relevant activators. We have previously shown that trophoblasts have potent inflammatory properties, but it has not been determined how these sensors affects their communication with maternal immune cells in the decidua. Objectives We aimed to investigate cell specific inflammation through TLR2, TLR4 and NLRP3 in decidual trophoblasts and maternal immune cells, and assess the contribution to the harmful placental inflammation in preeclampsia. Methods Decidual biopsies obtained from 44 normal and 48 preeclamptic pregnancies during cesarean sections were analyzed by immunohistochemistry for cell markers and TLR2, TLR4, NLRP3 and IL1-β expression. Automated protein quantification was done in MATLAB. Decidual explants and trophoblasts were primed and stimulated with cholesterol crystals in vitro. IL-1β response was quantified by ELISA. Serum total cholesterol, uric acid, sFlt-1 and C-reactive protein (CRP) were measured by enzymatic assays or ELISA. Results TLR4, NLRP3 and IL1-β were markedly expressed by both trophoblasts and maternal immune cells in the decidua, while TLR2 was mainly expressed by maternal immune cells. Cholesterol crystals induced IL-1β in trophoblasts. Serum cholesterol levels were elevated in preeclamptic compared to healthy pregnancies, correlating to concentrations of hsCRP and sFlt-1. Quantification of danger sensor protein expression comparing normal and preeclamptic pregnancies will be presented. Discussion The expression and function of TLR4 and NLRP3 in trophoblasts and maternal immune cells suggests an inflammatory role in intercellular decidual maternal-fetal communication with potential involvement in preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction Preeclampsia is a complex genetic disease of pregnancy including new-onset hypertension with proteinuria. Research has demonstrated that after preeclamptic pregnancies these women are at increased risk for cardiovascular diseases (CVD) later in life. Although the link between the diseases is currently obscure, the pathophysiology of both conditions incorporates dysregulated inflammation. Objectives In this study we aimed to identify genetic components of the shared pathophysiology of preeclampsia and the CVD risk factor chronic hypertension. Methods A cohort from the Norwegian HUNT Study was selected, containing 1006 women with a history of preeclampsia and 816 women with non-preeclamptic pregnancies. From significant findings in existing genome-wide association studies on either chronic hypertension or inflammation we identified 122 candidate single nucleotide polymorphisms (SNPs). These SNPs were genotyped on the Sequenom MassArray System and tested for association with preeclampsia and chronic hypertension in the selected HUNT Study cohort in a multiple logistic regression model in PLINK software. Results After Bonferroni-adjustment the minor allele of the intronic SNP rs17367504 in the methylenetetrahydrofolate reductase (MTHFR) gene was significantly associated with a protective effect on preeclampsia (minor allele frequency 13%, OR 0.65, CI 95% 0.53–0.80, p = 3.52 × 10 −5 ). This SNP did not demonstrate a significant association with chronic hypertension in our data set. Conclusion Our study demonstrates a genetic link between PE and CVD. The MTHFR enzyme has been linked repeatedly to the regulation of folic acid while the minor allele of the MTHFR SNP rs17367504 is known to be associated with a protective effect on chronic hypertension in CVD-based cohorts. We have identified a novel effect of the MTHFR SNP rs17367504, finding this SNP to be associated with reduced risk of preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives Preeclampsia (PE) is a gestational disease classified by reproducible hypertension (HT) with proteinuria occurring in 2–8% of pregnancies. The heterogenous disease includes severe outcomes for mother and fetus. After PE both women and children demonstrate doubled risk of atherothrombotic cardiovascular disease (aCVD). The etiology of PE and pathophysiological links with aCVD are incomplete, but shared inflammatory processes are indicated. Our aim was to identify shared genetic risk factors for PE and aCVD development in a family-based PE cohort by determining presence of genetic changes associated with blood pressure (BP) regulation, inflammation and/or angiogenesis. Methods We selected 484 participants from the Norwegian PE Family Biobank which contain 138 families with increased occurrence of PE (including 338 parous women, 256 with PE). Individuals were phenotyped and phenotypic heritabilities were estimated for PE with subsets such as “born in PE pregnancy” (H2r = 0.25, p = 0.01), and related traits like aCVD (H2r = 0.31, p = 4.6 × 10 −3 ) and inflammatory conditions. Using two databases of genome-wide association studies we selected 115 SNPs associated either with BP regulation, inflammation and/or angiogenesis. A candidate SNP array was performed on Sequenom MassArray and genetic analyses were conducted using variance components and measured genotype procedures in SOLAR. Results The main finding was that individuals born in preeclamptic pregnancies demonstrated association with an intergenic SNP near BP regulator gene JAG1 ( p = 4.7 × 10 −4 ). This SNP is also associated with chronic HT ( p = 3.39 × 10 −3 ) in the families. Conclusions JAG1 has previously been associated with BP regulation in individuals with aCVD and was in our cohort found associated both with being born in a PE pregnancy and with chronic HT. Our finding demonstrates a novel genetic connection between PE and chronic HT. This is further supported by significant phenotypic heritability of these traits in the Norwegian families. Functional studies will be performed to elucidate the role of JAG1 in PE and aCVD. Disclosures L.V. Thomsen: None. N. McCarthy: None. P.E. Melton: None. K. Tollaksen: None. I. Lyslo: None. P. Solberg: None. L.T. Roten: None. O.K. Nygård: None. G. Cadby: None. R. Austgulen: None. E.K. Moses: None. A. Iversen: None. L. Bjørge: None. [ABSTRACT FROM AUTHOR]

Introduction Preeclampsia (PE) is characterized by an aberrant inflammatory response to pregnancy. A stressed and inflamed placenta will induce maternal systemic inflammation, leading to hypertension with proteinuria (i.e. PE). The harmful placental inflammation involves abnormal placental expression of danger-sensing pattern recognition receptors (PRRs). Increased maternal cholesterol and uric acid levels are also associated with PE development. Crystalline cholesterol and uric acid may activate the PRR named nod-like receptor protein (NLRP)3 inflammasome to release the potent inflammatory cytokine IL-1 β , resulting in vigorous inflammation. Objective We aimed to characterize crystal-induced NLRP3 activation in placental inflammation, and examine its role in PE development. Materials and methods Total cholesterol, uric acid, soluble fms-like tyrosine kinase-1 (sFlt-1) and high sensitivity C-reactive protein (hsCRP) were measured in serum from pregnant women with ( n = 34) or without ( n = 43) PE and non-pregnant women ( n = 28). Specific cell markers, central NLRP3 inflammasome pathway components (NLRP3, caspase 1 and IL-1 β ) , and complement factors (C5a and TCC) were detected by immunohistochemistry in third trimester placental samples from healthy ( n = 13) and PE pregnancies ( n = 23). Placental explants and the trophoblast cell line SGHPL-5 were primed with lipopolysaccharide (LPS) or C5a/tumor necrosis factor (TNF)- α and stimulated with cholesterol or uric acid crystals. Resulting IL-1 β response was quantified by ELISA. Results Cholesterol and uric acid levels were elevated in maternal serum from PE compared to healthy pregnancies and correlated with levels of hsCRP and sFlt-1. The NLRP3 inflammasome components and complement factors were expressed by placental syncytiotrophoblast (SCT), and the IL-1 β and TCC expression in SCT was significantly higher in PE compared to healthy pregnancies. C5a positive regions of the SCT were observed more frequently in PE placentas. Complement primed crystal stimulation induced NLRP3 dependent IL-1 β production in trophoblasts and explants cultures. [ABSTRACT FROM AUTHOR]

Introduction: The first trimester of pregnancy is characterised by a mild pro-inflammatory environment, however excessive inflammation threatens placental development and function. Toll-like receptors (TLRs) are crucial in initiating inflammation. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are expressed on the cell surface, and respond to microbial infection and cell damage and stress signals. Recent findings of TLRs in trophoblasts indicate a role in inflammation during pregnancy, but further studies are warranted. Objectives: To investigate gene expression and function of cell surface TLRs in first trimester trophoblasts, to extend knowledge on the role of trophoblast TLRs during placental development. Methods: Primary trophoblasts were isolated from first trimester placentas (n =6) by enzyme degradation and density gradient centrifugation. Gene expression of TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 was quantified by RT-qPCR in primary first trimester trophoblasts and the trophoblast cell line BeWo. Trophoblasts were stimulated with cell surface TLR ligands and pro-inflammatory cytokine release was analysed by multiplex immunoassay. Results: Primary first trimester trophoblasts expressed all cell surface TLR mRNAs, and activation of TLR2/1, TLR4 and TLR5 induced IL-6 and/or IL-8. Conclusion: The broad expression of functional cell surface TLRs in primary first trimester trophoblasts suggests a central role for trophoblasts in placental inflammation and immune activation. [Copyright &y& Elsevier]

Introduction: Preeclampsia (PE) affects about 3% of pregnancies. The syndrome cannot be accurately predicted, and large variation complicates the search for early biomarkers. Metabolites are components of the metabolism; the chemical interactions in the body necessary for life. Metabolomics, the study of metabolism, has been used to characterize diabetes, cancer and cardiovascular disease (CVD). Objectives: Explore the use of magnetic resonance (MR) metabolomics on PE, and to elucidate potential clues to PE etiology and pathogenesis. Methods: Serum and urine from non-pregnant women (n =10) and pregnant women with PE (n =10) or normal pregnancies (n =10), was analyzed with MR spectroscopy and subjected to multivariate analysis (MVA). Metabolites were quantified and compared between groups. Results: Urine and serum samples revealed differences between PE and both control groups. Ten urine metabolites were significantly different between the three groups. Urine samples from women with early-onset PE clustered together in MVA. PE serum spectra had higher levels of low and very-low density lipoproteins, and lower high-density lipoproteins compared to control groups. Conclusion: PE and control samples were effectively discriminated using MR metabolomics, suggesting that MR metabolomics is a useful method for improved sub-phenotyping of PE in larger studies. Information relevant to the disease was found both for serum and urine samples, and indicated similarities between PE and CVD.▪ [Copyright &y& Elsevier]

Introduction Pregnancy is considered a natural inflammatory condition, but pregnancy complications such as preeclampsia and miscarriage are linked to excessive inflammation in the placenta. Toll-like receptors (TLRs) serve as sensors for danger signals and are crucial for initiating inflammation. A successful pregnancy depends on proper function of fetal trophoblasts, the main cell type in the placenta. We have shown broad functional TLR expression in primary first trimester trophoblasts (Tangerås et al., J. Reprod. Immunol., 2014), and trophoblast TLR activation may contribute substantially to placental inflammation. Trophoblast cell lines are commonly used as surrogates for primary trophoblasts for in vitro research. With respect to TLR mediated inflammation, the translatability of trophoblast cell lines warrants examination. Objectives This study aimed to assess TLR1-10 gene expression and activation in seven trophoblast cell lines of different origins and compare to primary first trimester trophoblasts. Methods The choriocarcinoma trophoblast cell lines BeWo, JAR, JEG-3, AC1M-32 and ACH-3P and the SV40 transformed extravillous trophoblast cell lines HTR-8/SVneo and SGHPL-5 were included and compared to primary first trimester trophoblasts ( n = 6).Gene expression of TLR1-10 was analyzed using RT-qPCR. Following specific TLR ligand activation for 24 hours, trophoblast release of interleukin (IL)-1 β , IL-6, IL-8, IL-9, IL-10, IL-12 (p70), interferon (IFN)- γ -inducible protein (IP)-10, tumor necrosis factor (TNF)- α , IFN- γ , and vascular endothelial growth factor (VEGF)-A was measured by multiplex immunoassay. Results All choriocarcinoma cell lines demonstrated broad TLR gene expression, but lacked functional cytokine response to TLR ligand activation. On the contrary, the SV40 transformed cell lines showed restricted TLR gene expression, and responded to activation of TLR2, TLR3 and/or TLR4 by significantly upregulated production of inflammatory cytokines such as IL-6, IL-8 and/or IFN- γ . The primary first trimester trophoblasts demonstrated both a broad TLR gene expression profile and prominent cytokine response to TLR ligand activation. Only SGHPL-5 showed a TLR activated cytokine response comparable to primary first trimester trophoblasts. Conclusion Most of the trophoblast cell lines tested showed markedly lower inflammatory TLR properties compared to primary first trimester trophoblasts, and SGHPL-5 and HTR8/SVneo were most TLR responsive. This warrants caution when translating trophoblast immune function from cell line studies. [ABSTRACT FROM AUTHOR]

Introduction New methods are required for improved prediction of preeclampsia. Metabolomics is the study of low molecular weight metabolites in tissues or biofluids. Objectives To evaluate early prediction of preeclampsia and gestational hypertension by 1H nuclear magnetic resonance (NMR) metabolomics. Methods 1H NMR spectra of urine and serum samples from 599 women with medium-to high risk of preeclampsia in weeks 11–14 of pregnancy were analyzed by principal component analysis and partial least squares discriminant analysis. Variable selection was applied on the metabolic profiles to find the best markers of prediction. Preeclampsia developed in 26 of the women and gestational hypertension in 21 women. Selected metabolites were combined with maternal characteristics in a logistic regression model. Results Using urine metabolomic profiles, preeclampsia could be predicted at 51.3% sensitivity, gestational hypertension at 40% sensitivity and both combined at 37% sensitivity at 10% false positive rate (FPR). Increased creatinine and decreased hippurate were the main discriminating metabolites in urine. Using serum metabolomic profiles, preeclampsia could be predicted at 15% sensitivity, gestational hypertension at 33% sensitivity and both combined at 30% sensitivity at 10% FPR. Women who later developed preeclampsia or gestational hypertension had increased serum VLDL and decreased HDL. Combining maternal markers (age >35 or <20, and mean arterial blood pressure) and selected urinary metabolite ratios (hippurate and creatinine) in a logistic regression model, preeclampsia could be predicted with a sensitivity of 42% at 10% FPR. Conclusion First trimester metabolomic profiles in urine and serum can independently predict hypertensive disorders of pregnancy. A panel of metabolites measured in urine in the first trimester may improve prediction rates for preeclampsia in combination with maternal biophysical markers. [ABSTRACT FROM AUTHOR]

Introduction Preeclampsia is characterized by an aberrant inflammatory response to pregnancy, leading to hypertension and proteinuria after mid-gestation. Although the pathogenesis remains unclear, there is a strong association between abnormal placentation and excessive inflammation in preeclampsia. Toll-like receptors (TLRs) serve as sensors for danger signals and are crucial for initiating inflammation. The danger signal high-mobility group box 1 (HMGB1) induces inflammation through TLR2 and TLR4 and has been linked to inflammatory diseases, such as atherosclerosis. Studies have suggested involvement of HMGB1 both in the placenta and maternal circulation in preeclampsia, albeit with conflicting results. Objective The aim of this study was to investigate HMGB1 expression and activation in the placenta and maternal serum of normal and preeclamptic pregnancies. Methods Third trimester placental samples from 36 pregnancies were obtained after cesarean delivery (23 preeclamptic and 13 uncomplicated pregnancies). Placental expression of TLR2, TLR4 and HMGB1 was analyzed by immunohistochemistry. Maternal blood samples were taken before delivery from 34 preeclamptic and 43 healthy pregnant women, and 28 healthy non-pregnant women. HMGB1 serum levels were measured by ELISA and ten selected cytokines were analyzed by multiplex immunoassay. Explant cultures of isolated placental chorionic villi from five normal pregnancies and the trophoblast cell line SGHPL-5 were incubated for 24 h with or without addition of HMGB1, and cytokine release in the culture supernatant was measured by multiplex immunoassay. Results Maternal serum HMGB1 was significantly higher in normal and preeclamptic pregnancies compared to non-pregnant women. HMGB1 and its receptor TLR4 were expressed by the syncytiotrophoblast in all placentas. TLR4 expression in the syncytiotrophoblast was significantly increased in preeclamptic pregnancies, while cytoplasmic HMGB1 expression was significantly increased in preeclamptic pregnancies when combined with fetal growth restriction. HMGB1 stimulation of chorionic villi explants and SGHPL-5 trophoblasts induced release of the inflammatory cytokine IL-8. In addition, the level of IL-8 in maternal serum was significantly higher in preeclampsia compared to normal pregnancies. Conclusions Our findings demonstrate a role for HMGB1 in promoting inflammation both in normal and complicated pregnancies. HMGB1 activation of TLR4 may represent an important mechanism linking harmful placental and systemic inflammation in preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: A mild systemic inflammation may be beneficial to normal pregnancy, however exaggerated inflammation may contribute to pregnancy complications. Infections and cell stress or damage may evoke placental inflammation by activation of Toll-like receptors (TLRs). TLR3, TLR7, TLR8 and TLR9 are located intracellulary on endosomes and are activated by nucleic acids from microbes and damaged cells. Trophoblasts play a crucial role during placentation, and the role of TLRs in first trimester trophoblasts needs to be determined. Objectives: To characterize endosomal TLR gene expression and activation in first trimester trophoblasts, to extend knowledge of endosomal TLR involvement in placental inflammation. Methods: Primary trophoblasts were isolated from six first trimester placentas by enzyme degradation and gradient centrifugation. Gene expression of TLR3, TLR7, TLR8 and TLR9 in primary first trimester trophoblasts and the trophoblast cell line BeWo was quantified by RT-qPCR. The trophoblasts were stimulated with ligands for endosomal TLRs, and release of pro-inflammatory cytokines was analyzed by multiplex. Results: Primary first trimester trophoblasts showed gene expression of all endosomal TLRs, and endosomal TLR activation gave increased production of the pro-inflammatory cytokines IL-6, IL-8, and IP-10. Conclusion: Primary first trimester trophoblasts express functional endosomal TLRs, indicating TLR-mediated trophoblast involvement in early placental inflammation. [Copyright &y& Elsevier]

Introduction: It is well established that preeclampsia (PE) increases later life cardiovascular disease (CVD) risk. Consequently, PE has started to gain a role as an early screening criterion for CVD. PE and CVD share several risk factors, pathological features and metabolic abnormalities. These common antecedents have drawn attention to the likelihood of shared genetic susceptibility. Objectives: Results from our previous PE GWAS identified a significant association with the rs7579169 SNP and maternal PE susceptibility (odds ratio 1.57). This SNP resides near the Inhibin, beta B (INHBB) gene on chromosome 2q14. Therefore, this study sought to interrogate this PE susceptibility SNP against several CVD risk traits in an effort to highlight additional empirical evidence of likely shared PE/CVD genetic mechanisms. Methods: The rs7579169 SNP was genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of fasting blood samples from 1246 mothers and 1461 adolescents (14- and 17-year-old) and clinical parameters pertaining, but not limited, to anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of rs7579169 against the Raine CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action. Results: Significant associations (p <0.05) for rs7579169 with CVD-related risk traits were detected, both for the mothers and the adolescents. Specifically, the minor rs7579169-T allele (MAF 0.400) was found to be significantly associated with elevated levels of triglycerides, total and LDL cholesterol, a greater average waist:hip circumference ratio and a greater average hip circumference. Conclusion: We have previously identified rs7579169 located near the INHBB gene on chromosome 2q14 to significantly associate with maternal PE susceptibility. We have now demonstrated that this SNP is also significantly associated with several CVD-related risk traits in an independent Caucasian population. We hereby present additional empirical evidence of possible shared genetic risk factors underlying both PE and CVD related traits. [Copyright &y& Elsevier]