Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure: a Mendelian randomization study.

BACKGROUND: Observational studies have found associations between hypertensive disorders of pregnancy and an increased risk of cognitive dysfunction and reduced brain volume. However, the results of observational studies may have been influenced by confounding factors. This study applied two-sample Mendelian randomization (MR) to explore the causal associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure. METHODS: Summary data on hypertensive disorders of pregnancy and their main subtypes, cognition, dementia, and brain structure were obtained from recent European genome-wide association studies. We computed the inverse-variance weighted, MR-Egger, and weighted median MR estimates. Cochran's Q statistics and the MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of the instrumental variables. RESULTS: Genetically predicted preeclampsia or eclampsia was inversely associated with gray matter volume [beta = -0.072; 95% confidence interval (CI) = -0.131 to -0.014; P  = 1.53 × 10 -2 ]; possibly with brain volume (beta = -0.064; 95% CI = -0.117 to -0.012; P  = 1.68 × 10 -2 ). However, the association of hypertensive pregnancy disorders or gestational hypertension with brain structure was not significant. We did not find any significant association between hypertensive disorders of pregnancy, gestational hypertension, or preeclampsia or eclampsia and cognition and dementia-related outcomes. CONCLUSION: This study provided genetic evidence supporting an association between preeclampsia or eclampsia and reduced brain volume. This supports the view of PE as a risk factor for gray matter volume reduction.

Trophoblast cellular adhesion molecule expression regulated by different genes and their correlation with pregnancy-induced hypertension.

It was to study trophoblast cell (TC) adhesion molecules regulated by different genes in the placental tissue (PT) of patients with pregnancy-induced hypertension (PIH), and the correlation with the severity of PIH. 42 patients with PIH (13 cases in the mild PIH group, 11 cases in the moderate PIH group, and 18 cases in the severe PIH group) and 40 patients with normal pregnancy (NP group) were included. mRNA and protein levels in matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 of all patients were determined by semi-quantitative polymerase chain reaction (PCR) and Western blotting (WB), respectively. Compared to the NP group, MMP-9 and MMP-2 mRNA levels as well as their proteins in PT significantly decreased in PIH groups (P<0.05). MMP-9 mRNA was greatly lower in the severe PIH group than mild PIH group (P<0.05). MMP-2 mRNA in moderate and severe PIH groups was much lower than NP and mild PIH groups, and that in the severe PIH group was considerably lower than the moderate PIH group (P<0.05). TIMP-1 mRNA and its protein highly increased in PT in PIH groups than NP group (P<0.05). TIMP-2 mRNA was remarkably higher in the severe PIH group than in the NP group (P<0.05). mRNA and proteins of MMP-9 and MMP-2 decreased in PT of PIH patients, while TIMP-1 mRNA and its protein increased, which were correlated with the severity of PIH. MMP-9, MMP-2, and TIMP-1 were involved in the pathogenesis of PIH by regulating the infiltration of TCs.

Circulating inflammatory cytokines and hypertensive disorders of pregnancy: a two-sample Mendelian randomization study.

Background: Hypertensive disorders of pregnancy (HDP) pose a significant risk to maternal and fetal well-being; however, the etiology and pathogenesis of HDP remain ambiguous. It is now widely acknowledged that inflammatory response and the immune system are closely related to HDP. Previous research has identified several inflammatory cytokines are associated with HDP. This study applied Mendelian randomization (MR) analysis to further assess causality. Methods: Patients with HDP who participated in the MR analysis presented with four types of HDP: pre-eclampsia or eclampsia (PE); gestational hypertension (GH); pre-existing hypertension complicating pregnancy, childbirth and the puerperium (EH); and pre-eclampsia or poor fetal growth (PF). A two-sample MR analysis was used to analyze the data in the study. The causal relationship between exposure and outcome was analyzed with inverse variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode methods, where IVW was the primary method employed. Results: Our MR analysis demonstrated a reliable causative effect of Interleukin-9 (IL-9) and macrophage migration inhibitory factor (MIF) on reducing HDP risk, while macrophage inflammatory protein 1-beta (MIP1b), Interleukin-13 (IL-13), and Interleukin-16 (IL-16) were associated with promoting HDP risk. Conclusions: This study demonstrated that IL-9, MIF, MIP1b, IL-13, and IL-16 may be cytokines associated with the etiology of HDP, and that a number of inflammatory cytokines are probably involved in the progression of HDP. Additionally, our study revealed that these inflammatory cytokines have causal associations with HDP and may likely be potential therapeutic targets for HDP.

The role and expression of pro/antiangiogenic factors and microRNAs in gestational hypertension and pre-eclampsia.

OBJECTIVE: Pre-eclampsia and gestational hypertension are two common hypertensive disorders of pregnancy with pre-eclampsia accounting for high foetal and maternal morbidity and mortality rate. These disorders have an unknown aetiology and their hypertensive and end-organ pathophysiology may present too late in pregnancy. This makes the identification of early detection and differentiation markers vital. MicroRNAs have strongly been associated with pregnancy and their imbalance has been associated with the angiogenic dysregulation seen in pre-eclampsia. This study assesses the expression of pro- and antiangiogenic factors and their corresponding microRNAs in the maternal circulation of patients with pre-eclampsia and gestational hypertension. STUDY DESIGN: We analyzed angiogenic factors expression (sEng, TGF-ß, VEGF) normalized against housekeeping gene ß-actin and microRNAs (miRs: 210, 29B, 126) normalized against miR U6, potentially associated with pre-eclampsia and gestational hypertension using the targeted qPCR technique. These analytes were examined from early-onset (<34 weeks) (EOPE) (n = 12), late-onset (>34 weeks) (LOPE) (n = 12) pre-eclampsia, gestational hypertension (GH) (n = 12) and two gestationally matched normotensive groups (NG1 and 2) (n = 12) each in South African women of African ancestry. Group comparisons of experimental vs. control groups were assessed using t-test analysis for significance and represented as fold change expression. RESULTS: The relative expression in group comparisons showed significant (p < 0.05) fold change of VEGF, TGF-ß, sEng and miR126 in the EOPE vs. NG1. The GH vs. NG1 exhibited significant changes in VEGF, TGF-ß, miR126, miR210 and miR29B. The LOPE vs. NG2 showed significant relative expression in all the angiogenic factors (VEGF, TGF-ß and sEng). The GH vs. NG2 showed significant expression in VEGF and miR29B. The LOPE vs. EOPE showed significant fold changes in VEGF and miR210. Finally, only the GH vs. EOPE showed significant differences in miR210 and miR29B (p < 0.05). CONCLUSION: This study provides better insights into angiogenic factors and microRNAs specificity to the subtypes of gestational hypertensive disorders in pregnancy. Relative expression analysis of angiogenic factors and microRNAs showed possible novel characteristics of gestational hypertension, and potential common molecular and pathological profiles with pre-eclampsia. Furthermore, we postulate that sEng and miR29B could be early detection markers for pre-eclampsia and gestational hypertension, respectively.

Gut microbiota and hypertensive disorders in pregnancy: evidence from the Mendelian randomization study.

BACKGROUND: Recent studies have shown that gut microbiota (GM) is related to hypertensive disorders in pregnancy (HDP). However, the causal relationship needs to be treated with caution due to confounding factors and reverse causation. METHODS: We obtained genetic variants from genome-wide association studies including GM (N = 18,340) in MiBioGen Consortium as well as HDP (7,686 cases/115,893 controls) and specific subtypes in FinnGen Consortium. Then, Inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS methods were applied to examine the causal association. Reverse Mendelian randomization (RMR) and multivariable MR were performed to confirm the causal direction and adjust the potential confounders, respectively. Furthermore, sensitivity analyses including Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and the leave-one-out analysis were conducted to detect the potential heterogeneity and horizontal pleiotropy. RESULTS: The present study found causalities between eight gut microbial genera and HDP. The HDP-associated gut microbial genera identified by MR analyses varied in different subtypes. Specifically, our study found causal associations of LachnospiraceaeUCG010, Olsenella, RuminococcaceaeUCG009, Ruminococcus2, Anaerotruncus, Bifidobacterium, and Intestinibacter with GH, of Eubacterium (ruminantium group), Eubacterium (ventriosum group), Methanobrevibacter, RuminococcaceaeUCG002, and Tyzzerella3 with PE, and of Dorea and RuminococcaceaeUCG010 with eclampsia, respectively. CONCLUSIONS: This study first applied the MR approach to detect the causal relationships between GM and specific HDP subtypes. Our findings may promote the prevention and treatment of HDP targeted on GM and provide valuable insights to understand the mechanism of HDP in different subtypes from the perspective of GM.

Fatty acids and pregnancy-induced hypertension: a Mendelian randomization study.

BACKGROUND: It is well known that pregnancy-induced hypertension (PIH) contributes significantly to the mortality rates of both mothers and babies during pregnancy. The relationship between fatty acids (FAs) and PIH remains debatable, with the causality between the two yet to be definitively established. METHODS: Two-sample univariable and multivariable Mendelian Randomization (MR) analyses were executed, based on pooled data from Genome-Wide Association Studies (GWAS), to investigate any causal impact of FAs on PIH. A suite of methods was employed to assess causality, including inverse variance weighting (IVW), weighted median, MR Egger, simple mode, and weighted mode. Subsequently, the data underwent a sensitivity analysis (using Leave-One-Out analysis), a heterogeneity test (with MR-PRESSO and Cochran's Q test), as well as a multiple validity test (using MR-Egger regression). In multivariable analyses, fatty acids were first grouped to observe the effect of individual FAs on PIH. Subsequently, factors such as diabetes, high blood pressure, and body mass index (BMI) were incorporated into a multivariable examination of the impact of each FA on PIH. During this process, the IVW, weighted median, MR-Lasso, and MR-Egger methods were employed. RESULTS: A systematic investigation was conducted into the causal impact of each FA on PIH. The findings indicated that Polyunsaturated Fatty Acids (PUFA), Omega3, the ratio of Omega6 to Omega3, and Docosahexaenoic Acid (DHA) have a causal relationship with PIH. Increases in PUFA, Omega3, and DHA could potentially reduce the risk of PIH, while an increase in the Omega6/Omega3 ratio could heighten the risk. The impacts of other FAs (including Total Fatty Acids, Monounsaturated Fatty Acids (MUFA), Saturated Fatty Acids (SFA), and Omega 6) on PIH were not substantiated by the MR analysis. In the univariate leave-one-out analysis, rs174564 was identified in PUFA, Omega3, and DHA as having a significant role. The tests with MR-Egger and MR-PRESSO found that the results were not influenced by pleiotropy and heterogeneity. After adjusting for BMI, Diabetes Mellitus, and pre-existing hypertension in the multivariable analysis, the results mirrored those obtained univariable. CONCLUSION: The research implies that elevated levels of circulating PUFA, DHA, and Omega3 may serve as a protective mechanism against PIH, while higher Omega6/Omega3 ratios could potentially increase the risk of PIH. These findings may inform clinical strategies for PIH prevention.

Natriuretic Peptide Signaling in Uterine Biology and Preeclampsia.

Endometrial decidualization is a uterine process essential for spiral artery remodeling, embryo implantation, and trophoblast invasion. Defects in endometrial decidualization and spiral artery remodeling are important contributing factors in preeclampsia, a major disorder in pregnancy. Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood volume and pressure. ANP is also generated in non-cardiac tissues, such as the uterus and placenta. In recent human genome-wide association studies, multiple loci with genes involved in natriuretic peptide signaling are associated with gestational hypertension and preeclampsia. In cellular experiments and mouse models, uterine ANP has been shown to stimulate endometrial decidualization, increase TNF-related apoptosis-inducing ligand expression and secretion, and enhance apoptosis in arterial smooth muscle cells and endothelial cells. In placental trophoblasts, ANP stimulates adenosine 5'-monophosphate-activated protein kinase and the mammalian target of rapamycin complex 1 signaling, leading to autophagy inhibition and protein kinase N3 upregulation, thereby increasing trophoblast invasiveness. ANP deficiency impairs endometrial decidualization and spiral artery remodeling, causing a preeclampsia-like phenotype in mice. These findings indicate the importance of natriuretic peptide signaling in pregnancy. This review discusses the role of ANP in uterine biology and potential implications of impaired ANP signaling in preeclampsia.

Association between Vitamin D receptor (VDR) gene polymorphisms and hypertensive disorders of pregnancy: a systematic review and meta-analysis.

Background: Hypertensive disorders of pregnancy (HDP) are currently one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Recent studies provide evidence that maternal Vitamin D receptor (VDR) gene polymorphisms probably play a key role by affecting the biological function of vitamin D in some adverse pregnancy outcomes, while the relationship between the VDR gene polymorphisms and the risk of HDP remains controversial in current studies. This systematic review and meta-analysis aimed to comprehensively evaluate the association of the VDR gene polymorphisms with HDP susceptibility. Methods: This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and a protocol has been registered in the PROSPERO (ID: CRD42022344383) before commencing this review. PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until January 21, 2023. Case-control and cohort studies that reported the association of the VDR gene polymorphisms with HDP were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of the five models (allele model, dominant model, recessive model, homozygous model, heterozygous model) were pooled respectively, and subgroup analysis was performed based on ethnicity. Results: A total of ten studies were included. The VDR gene ApaI polymorphism was associated with HDP susceptibility in the dominant model (OR: 1.38; 95% CI [1.07-1.79]; P = 0.014) and the heterozygote model (OR: 1.48; 95% CI [1.12-1.95]; P = 0.006). In subgroup analysis, the heterozygote model (OR: 2.06; 95% CI [1.21-3.52]; P = 0.008) of the ApaI polymorphism was associated with HDP in Asians, but not in Caucasians. Conclusion: The VDR gene ApaI polymorphism may be associated with HDP susceptibility. Insufficient evidence to support the existence of ethnic differences in this association.

Effects of genetic polymorphisms of CYP2J2, CYP2C9, CYP2C19, CYP4F2, CYP4F3 and CYP4A11 enzymes in preeclampsia and gestational hypertension.

INTRODUCTION: The aim of this study was to investigate the effects of cytochrome P450 (CYP) 2J2, CYP2C9, CYP2C19 and CYP4F2, CYP4F3 and CYP4A11 genetic polymorphisms in preeclampsia and gestational hypertension (GHT) patients in a sample of Turkish population. MATERIALS-METHODS: Patients (n = 168; 110 GHT and 58 preeclampsia) and healthy pregnant women (n = 155, controls) participated in the study. For genotyping, polymerase chain reaction (PCR) and restriction analysis (RFLP) were used. Substance levels were measured using LC-MS. RESULTS: Plasma DHET levels in GHT and preeclampsia patients were significantly lower than those in the control group (62.7%, 66.3% vs.100.0%, respectively, p < 0.0001). An increase in CYP2J2*7 allele frequency was observed in the preeclampsia group, as compared to GHT group (12.1% vs. 4.5%; odds ratio, O.R. = 2.88, p < 0.01). The frequencies of CYP2C19*2 and*17 alleles were higher in GHT group as compared to the control group (17.7% vs. 11.6%, O.R. = 1.99, p < 0.01; and 28.6% vs.18.4%, O.R. = 2.03, p < 0.01, respectively). An increased frequency of CYP4F3 rs3794987 G allele was found in GHT group as compared to the control group (48.0% vs. 38.0%; O.R. = 1.53, p < 0.01). DISCUSSION: DHET plasma levels were significantly reduced in hypertensive pregnant groups as compared to the control group. The allele frequency distributions for CYP2J2*7, CYP2C19 *2, *17 and CYP4F3 rs3794987 were significantly different in hypertensive pregnant patients as compared to the healthy control subjects. Our results may suggest that investigated genetic polymorphisms may be useful in diagnosis and clinical management of GHT and preeclampsia patients.

Maternal and fetal mitochondrial gene dysregulation in hypertensive disorders of pregnancy.

Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.NEW & NOTEWORTHY This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.

Polygenic prediction of preeclampsia and gestational hypertension.

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and child outcomes. Current tools for prediction, prevention and treatment are limited. Here we tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 control individuals and with gestational hypertension in 11,027 cases and 412,788 control individuals across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are new (for example, MTHFR-CLCN6, WNT3A, NPR3, PGR and RGL3), including two loci (PLCE1 and FURIN) identified in the multitrait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external cohorts, independent of clinical risk factors, and reclassified eligibility for low-dose aspirin to prevent preeclampsia. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and have the potential to advance pregnancy risk stratification.

Association between angiotensin converting enzyme gene polymorphism (rs4343) and susceptibility to gestational hypertension and preeclampsia in pregnant women.

Hypertension is the most frequent medical complication of pregnancy, and the most severe clinical presentation of hypertensive disorders of pregnancy (HDP) is preeclampsia (PE). PE is a condition significantly associated with maternal and perinatal morbidity and mortality. The etiology of PE remains unknown. However, it has been found that genetic factors cause a defective immune adaptation, which in turn leads to inadequate trophoblast invasion and inappropriate placenta development. This study involved 30 patients with gestational hypertension (GH), 30 patients with PE and 30 normotensive pregnant women as controls. We aimed to evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism (rs4343) and susceptibility to GH and PE. Genotyping for rs4343 polymorphism was performed by real-time polymerase chain reaction. The differences of genotypes and allele frequencies were analyzed as well as the relationship between ACE polymorphism and susceptibility to PE. The GG genotype of ACE gene rs4343 and G allele frequency were significantly associated with increased risk of PE [OR (95% CI) 10.3125 (2.1043 to 50.5388), p=0.004 and OR (95% CI) 3.4714 (1.6352 to 7.3697), p = 0.001, respectively]. Also, G allele frequency was significantly associated with severity of PE [OR (95% CI) 15.5455 (1.8938 to 127.6075), p = 0.011]. However, the GG genotype and G allele frequency were not associated with GH. In conclusion, ACE rs4343 polymorphism may be associated with PE susceptibility and severity but not with GH.

Genome-wide polygenic risk scores for hypertensive disease during pregnancy can also predict the risk for long-term cardiovascular disease.

BACKGROUND: Hypertensive disorders during pregnancy are associated with the risk of long-term cardiovascular disease after pregnancy, but it has not yet been determined whether genetic predisposition for hypertensive disorders during pregnancy can predict the risk for long-term cardiovascular disease. OBJECTIVE: This study aimed to evaluate the risk for long-term atherosclerotic cardiovascular disease according to polygenic risk scores for hypertensive disorders during pregnancy. STUDY DESIGN: Among UK Biobank participants, we included European-descent women (n=164,575) with at least 1 live birth. Participants were divided according to genetic risk categorized by polygenic risk scores for hypertensive disorders during pregnancy (low risk, score ≤25th percentile; medium risk, score 25th∼75th percentile; high risk, score >75th percentile), and were evaluated for incident atherosclerotic cardiovascular disease, defined as the new occurrence of one of the following: coronary artery disease, myocardial infarction, ischemic stroke, or peripheral artery disease. RESULTS: Among the study population, 2427 (1.5%) had a history of hypertensive disorders during pregnancy, and 8942 (5.6%) developed incident atherosclerotic cardiovascular disease after enrollment. Women with high genetic risk for hypertensive disorders during pregnancy had a higher prevalence of hypertension at enrollment. After enrollment, women with high genetic risk for hypertensive disorders during pregnancy had an increased risk for incident atherosclerotic cardiovascular disease, including coronary artery disease, myocardial infarction, and peripheral artery disease, compared with those with low genetic risk, even after adjustment for history of hypertensive disorders during pregnancy. CONCLUSION: High genetic risk for hypertensive disorders during pregnancy was associated with increased risk for atherosclerotic cardiovascular disease. This study provides evidence on the informative value of polygenic risk scores for hypertensive disorders during pregnancy in prediction of long-term cardiovascular outcomes later in life.

Associations of polygenic risk scores for preeclampsia and blood pressure with hypertensive disorders of pregnancy.

BACKGROUND: Preexisting hypertension increases risk for preeclampsia. We examined whether a generic blood pressure polygenic risk score (BP-PRS), compared with a preeclampsia-specific polygenic risk score (PE-PRS), could better predict hypertensive disorders of pregnancy. METHODS: Our study sample included 141 298 genotyped FinnGen study participants with at least one childbirth and followed from 1969 to 2021. We calculated PRSs for SBP and preeclampsia using summary statistics for greater than 1.1 million single nucleotide polymorphisms. RESULTS: We observed 8488 cases of gestational hypertension (GHT) and 6643 cases of preeclampsia. BP-PRS was associated with GHT [multivariable-adjusted hazard ratio for 1SD increase in PRS (hazard ratio 1.38; 95% CI 1.35-1.41)] and preeclampsia (1.26, 1.23-1.29), respectively. The PE-PRS was also associated with GHT (1.16; 1.14-1.19) and preeclampsia (1.21, 1.18-1.24), but with statistically more modest magnitudes of effect (P = 0.01). The model c-statistic for preeclampsia improved when PE-PRS was added to clinical risk factors (P = 4.6 × 10-15). Additional increment in the c-statistic was observed when BP-PRS was added to a model already including both clinical risk factors and PE-PRS (P = 1.1 × 10-14). CONCLUSION: BP-PRS is strongly associated with hypertensive disorders of pregnancy. Our current observations suggest that the BP-PRS could capture the genetic architecture of preeclampsia better than the current PE-PRSs. These findings also emphasize the common pathways in the development of all BP disorders. The clinical utility of a BP-PRS for preeclampsia prediction warrants further investigation.

Increased angiotensin II coupled with decreased Adra1a expression enhances cardiac hypertrophy in pregnancy-associated hypertensive mice.

Cardiac hypertrophy is a crucial risk factor for hypertensive disorders during pregnancy, but its progression during pregnancy remains unclear. We previously showed cardiac hypertrophy in a pregnancy-associated hypertensive (PAH) mouse model, in which an increase in angiotensin II (Ang II) levels was induced by human renin and human angiotensinogen, depending on pregnancy conditions. Here, to elucidate the factors involved in the progression of cardiac hypertrophy, we performed a comprehensive analysis of changes in gene expression in the hearts of PAH mice and compared them with those in control mice. We found that alpha-1A adrenergic receptor (Adra1a) mRNA levels in the heart were significantly reduced under PAH conditions, whereas the renin-angiotensin system was upregulated. Furthermore, we found that Adra1a-deficient PAH mice exhibited more severe cardiac hypertrophy than PAH mice. Our study suggests that Adra1a levels are regulated by renin-angiotensin system and that changes in Adra1a expression are involved in progressive cardiac hypertrophy in PAH mice.

Association of Hypertensive Disorders of Pregnancy With Future Cardiovascular Disease.

Conclusions and Relevance: The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease. Design, Setting, and Participants: A genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release). Exposures: Uncorrelated (r2<0.001) single-nucleotide variants (SNVs) were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Importance: Hypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias. Main Outcomes and Measures: Genetic association estimates for outcomes were extracted from genome-wide association studies of 122 733 cases for coronary artery disease, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation. Objective: To investigate the association of HDPs with multiple cardiovascular diseases. Results: Genetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P = .002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P = .04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P = .03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10-4). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P = .02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P = .008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P = .79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P = .71).

The relationship between arginine vasopressin gene polymorphisms and plasma copeptin and hypertensive disorders of pregnancy: a nested case-control study.

OBJECTIVES: This study aims to explore the relationship between polymorphism of the arginine vasopressin (AVP) gene and plasma copeptin concentration with the occurrence of hypertension in pregnancy. METHODS: We conducted a matched nested case-control study in Chinese women. The genotypes of rs3729965, rs3761249, rs1410713, rs2740204, and rs2282018 loci of AVP gene and plasma copeptin at 16-20 gestational weeks were detected in 288 patients with gestational hypertension (GH), 82 with preeclampsia (PE), and 14 with chronic hypertension with superimposed preeclampsia (CH-PE) and their healthy matched controls. RESULTS: For every natural logarithm unit increment in copeptin, the risks of GH and PE/CH-PE increased by 5.556 (adjusted odds ratio [aOR]: 6.556, 95% confidence interval [CI]: 2.734-15.717) and 3.312 times (aOR: 4.312, 95% CI: 1.168-15.914). Under the dominant model, the genotype CC + CT of rs2282018 and GG + GT of rs3761249 had higher risks of GH than genotype TT, with aORs of 1.757 (95% CI: 1.077-2.867) and 1.814 (95% CI: 1.111-2.963). Allele A of rs3729965 loci had a lower risk of PE/CH-PE than allele G (aOR: 0.441, 95% CI: 0.199-0.978). However, the frequencies of rs1410713 and rs2740204 genotypes were not significantly different between cases and controls. The model of copeptin combined with the AVP gene and traditional factors (TFs) had a higher ability than the TFs model in predicting GH and PE/CH-PE. CONCLUSION: Our study confirms that higher plasma copeptin and AVP gene variants are associated with the occurrence of GH and PE/CH-PE. The detection of copeptin and AVP gene in the early second trimester improves the predictive ability of TFs for GH and PE/CH-PE.

Expression and clinical significance of lncRNA NORAD in patients with gestational hypertension.

OBJECTIVES: Gestational hypertension (GH), the most common type of hypertensive disorders in pregnancy, often occurs in women during pregnancy. The purpose of this study was to investigate the expression and clinical significance of lncRNA NORAD in gestational hypertension, and to discuss the possibility of lncRNA NORAD as a diagnostic marker of gestational hypertension. MATERIAL AND METHODS: A total of 219 participants were involved in the study. Basic clinical information of all participants was collected, and the expression of NORAD in serum was detected by RT-qPCR. ROC curves were drawn to evaluate the diagnostic value of NORAD expression for gestational hypertension. Multiple linear regression analysis was done to explore the relationship between NORAD and clinical variables. Logistic regression analysis was conducted to analyze the independent influence of different variables on the development of gestational hypertension into preeclampsia. RESULTS: The expression level of NORAD in gestational hypertension was higher than that of healthy individuals, and the expression level of NORAD in preeclampsia was higher than that of gestational hypertension and healthy individuals. The ROC curve suggested that the expression of NORAD has a higher diagnostic value for gestational hypertension. Multiple linear regression analysis showed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were correlated with the expression of NORAD. SBP, DBP and NORAD were all factors that affect the development of gestational hypertension to preeclampsia, which were known by Logistic regression analysis. CONCLUSIONS: LncRNA NORAD may be used as a biomarker for gestational hypertension diagnosis and can influence its progression into preeclampsia.