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AIMS/HYPOTHESIS: It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m2) and women with overweight (BMI ≥25 kg/m2) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM). METHODS: We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method. RESULTS: In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM. CONCLUSIONS/INTERPRETATION: GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment.
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Preeclampsia is related with elevated systolic blood pressure (SBP) in children. We studied if preeclampsia-exposed (PE) children develop alterations in heart rate variability (HRV) and if this is reflected in their blood pressure (BP), as well as overall associations with body size and composition, gestational and perinatal factors. We examined 182 PE (46 early-onset PE) and 85 unexposed (non-PE) children 8-12 yr after preeclampsia exposure. HRV monitoring was performed 5 min in supine followed by 5 min in standing position and compared with office, 24-h ambulatory, and central BPs in relation to body anthropometrics and composition, gestational, and perinatal data. There were no major differences in HRV between PE and non-PE children. HRV in supine position was strongly associated with office and ambulatory heart rates (HRs), and HR was independently associated with office BPs. However, HRV was not related with office or 24-h SBP and PP, nor with elevated SBP in PE compared with non-PE children [adjusted mean differences for office and 24-h SBP 4.8 (P < 0.001) and 2.5 mmHg (P = 0.049), respectively]. In supine position, high-frequency (HF) power [ß, -0.04 (95% CI -0.06 to -0.01)], root mean square of successive differences in R-R intervals (rMSSD) [-0.015 (-0.028 to -0.002)], and the ratio of low-frequency (LF) to HF power [0.03 (0.01-0.04)] were independently associated with child fat mass. LF and HF power and rMSSD displayed independent inverse associations with child age. There were no significant associations between child HRV and gestational and perinatal factors. During prepuberty, the HRV in children with PE is similar to that in non-PE children. Elevated SBP following preeclampsia exposure is not related with HRV. Child adiposity could be related to decreased cardiac vagal tone.NEW & NOTEWORTHY Heart rate variability in preadolescent children exposed to preeclampsia in utero is no different from age-matched controls. Preeclampsia-exposed children's elevated SBP is not related to alterations in heart rate variability, which is a noninvasive measure of the modulation of heart rate by autonomic tone. However, childhood adiposity might be coupled with diminished cardiac vagal tone.
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Criança , Frequência Cardíaca/fisiologia , Pré-Eclâmpsia/diagnóstico , Sistema Nervoso Autônomo/fisiologia , Coração , Pressão SanguíneaRESUMO
Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.
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Cromatina/metabolismo , Receptores de Glucocorticoides/metabolismo , Sumoilação , Sítios de Ligação , Regulação da Expressão Gênica , Células HEK293 , Humanos , Correpressor 1 de Receptor Nuclear/metabolismo , Coativador 1 de Receptor Nuclear , Mapeamento de Interação de Proteínas , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação/efeitos dos fármacosRESUMO
INTRODUCTION: Maternal metabolism changes substantially during pregnancy. However, few studies have used metabolomics technologies to characterize changes across gestation. OBJECTIVES AND METHODS: We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted metabolomics to determine whether the metabolic profile of serum differs throughout the pregnancy between pre-eclamptic and healthy women in the FINNPEC (Finnish Genetics of Preeclampsia Consortium) Study. Serum samples were available from early and late pregnancy. RESULTS: Progression of pregnancy had large-scale effects to the serum metabolite profile. Altogether 50 identified metabolites increased and 49 metabolites decreased when samples of early pregnancy were compared to samples of late pregnancy. The metabolic signatures of pregnancy were largely shared in pre-eclamptic and healthy women, only urea, monoacylglyceride 18:1 and glycerophosphocholine were identified to be increased in the pre-eclamptic women when compared to healthy controls. CONCLUSIONS: Our study highlights the need of large-scale longitudinal metabolomic studies in non-complicated pregnancies before more detailed understanding of metabolism in adverse outcomes could be provided. Our findings are one of the first steps for a broader metabolic understanding of the physiological changes caused by pregnancy per se.
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Cromatografia Líquida/métodos , Metabolômica/métodos , Pré-Eclâmpsia/sangue , Gravidez/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , MetabolomaRESUMO
BACKGROUND: While several studies have demonstrated that obesity increases the risk of pre-eclampsia (PE), the mechanisms have yet to be elucidated. We assessed the association between maternal/paternal obesity and PE and hypothesized that maternal body mass index (BMI) would be associated with an adverse inflammatory and angiogenic profile. High-sensitivity C-reactive protein (hs-CRP) and following serum angiogenic markers were determined: soluble endoglin (sEng), soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF). METHODS: Data on BMI were available from 1450 pregnant women with PE and 1065 without PE. Serum concentrations of hs-CRP and angiogenic markers were available from a subset at first and third trimesters. RESULTS: Prepregnancy BMI was higher in the PE group than in controls (mean ± SD) 25.3 ± 5.2 vs. 24.1 ± 4,4, p < 0.001, adjusted for parity, mother's age, and smoking status before pregnancy. Increased hs-CRP concentrations were observed in both PE and non-PE women similarly according to BMI category. In women with PE, a higher BMI was associated with lower sFlt-1 and sEng concentrations throughout the pregnancy (p = 0.004, p = 0.008, respectively). There were no differences in PlGF in PE women according to BMI. CONCLUSIONS: We confirmed increased pre-pregnancy BMI in women with PE. Enhanced inflammatory state was confirmed in all women with overweight/obesity. Partly paradoxically we observed that PE women with obesity had less disturbed levels of angiogenic markers than normal weight women with PE. This should be taken into account when angiogenic markers are used in PE prediction.
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Inflamação/fisiopatologia , Obesidade/fisiopatologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/fisiopatologia , Complicações na Gravidez/fisiopatologia , Adulto , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Endoglina/metabolismo , Feminino , Finlândia/epidemiologia , Humanos , Inflamação/etiologia , Obesidade/complicações , Obesidade/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/metabolismo , Valor Preditivo dos Testes , Gravidez , Complicações na Gravidez/metabolismo , Primeiro Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Receptores Imunológicos/metabolismoRESUMO
Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.
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Edema Encefálico/genética , Edema Encefálico/patologia , Cerebelo/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Atrofia Óptica/genética , Atrofia Óptica/patologia , Espasmos Infantis/genética , Espasmos Infantis/patologia , Animais , Complexo do Signalossomo COP9 , Movimento Celular/genética , Movimento Celular/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Cerebelo/metabolismo , Edema/complicações , Edema/genética , Exoma/genética , Edição de Genes , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Microcefalia/complicações , Microcefalia/genética , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Neurônios/metabolismo , Proteínas Nucleares/biossíntese , Análise de Sequência de DNA , Fatores de Transcrição/biossíntese , Peixe-ZebraRESUMO
Androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in the development and growth of prostate carcinoma. PIAS1 is an AR- and SUMO-interacting protein and a putative transcriptional coregulator overexpressed in prostate cancer. To study the importance of PIAS1 for the androgen-regulated transcriptome of VCaP prostate cancer cells, we silenced its expression by RNAi. Transcriptome analyses revealed that a subset of the AR-regulated genes is significantly influenced, either activated or repressed, by PIAS1 depletion. Interestingly, PIAS1 depletion also exposed a new set of genes to androgen regulation, suggesting that PIAS1 can mask distinct genomic loci from AR access. In keeping with gene expression data, silencing of PIAS1 attenuated VCaP cell proliferation. ChIP-seq analyses showed that PIAS1 interacts with AR at chromatin sites harboring also SUMO2/3 and surrounded by H3K4me2; androgen exposure increased the number of PIAS1-occupying sites, resulting in nearly complete overlap with AR chromatin binding events. PIAS1 interacted also with the pioneer factor FOXA1. Of note, PIAS1 depletion affected AR chromatin occupancy at binding sites enriched for HOXD13 and GATA motifs. Taken together, PIAS1 is a genuine chromatin-bound AR coregulator that functions in a target gene selective fashion to regulate prostate cancer cell growth.
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Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Proteínas Inibidoras de STAT Ativados/metabolismo , Receptores Androgênicos/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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Proteínas Alimentares/administração & dosagem , Ingestão de Energia/genética , Obesidade/etnologia , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Adulto , Negro ou Afro-Americano , Idoso , Alelos , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Povo Asiático , Índice de Massa Corporal , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia , População BrancaRESUMO
BACKGROUND: The Finnish Pre-eclampsia Consortium (FINNPEC) case-control cohort consisting of 1447 pre-eclamptic and 1068 non-pre-eclamptic women was recruited during 2008-2011 to study genetic background of pre-eclampsia and foetal growth. Pre-eclampsia was defined by hypertension and proteinuria according to the American College of Obstetricians and Gynecologists (ACOG) 2002 classification. The ACOG Task Force Report on Hypertension in Pregnancy (2013) and The International Society for the Study of Hypertension in Pregnancy (ISSHP) (2014) have published new classifications, in which proteinuria is not necessary for diagnosis when specific symptoms are present. For diagnoses based on proteinuria, the ISSHP 2014 criteria raised its threshold to 2+ on dipstick. We studied how the new classifications would affect pre-eclampsia diagnoses in the FINNPEC cohort. METHODS: We re-evaluated pre-eclampsia diagnosis using the ACOG 2013 and the ISSHP 2014 classifications in pre-eclamptic women whose proteinuria did not exceed 1+ on dipstick (n = 68), in women with gestational hypertension (n = 138) and in women with chronic hypertension (n = 66). RESULTS: The number of women with pre-eclampsia increased 0.8 % (1459/1447) according to the ACOG 2013 criteria and 0.6 % (1455/1447) according to the ISSHP 2014 criteria. All 68 women with the amount of proteinuria not exceeding 1+ on dipstick diagnosed originally pre-eclamptic met the ACOG 2013 criteria but only 20 women (29.4 %) met the ISSHP 2014 criteria. Seven (5.1 %) and 35 (25.4 %) women with gestational hypertension were diagnosed with pre-eclampsia according to the ACOG 2013 and the ISSHP 2014 criteria, respectively. Correspondingly five (7.6 %) and 21 (31.8 %) women with chronic hypertension were diagnosed with pre-eclampsia according to the ACOG 2 013 and the ISSHP 2014 criteria. CONCLUSIONS: Only minor changes were observed in the total number of pre-eclamptic women in the FINNPEC cohort when comparing the ACOC 2002 classification with the ACOG 2013 and ISSHP 2014 classifications.
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Hipertensão Induzida pela Gravidez/classificação , Pré-Eclâmpsia/diagnóstico , Proteinúria/classificação , Avaliação de Sintomas/classificação , Adulto , Comitês Consultivos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Finlândia , Humanos , Pré-Eclâmpsia/classificação , Gravidez , Valores de Referência , Avaliação de Sintomas/métodosRESUMO
BACKGROUND: Clinical findings in children with premature adrenarche (PA) correlate only partly with circulating levels of adrenal androgens. It is not known whether the prepubertal low circulating concentrations of testosterone (T) and dihydrotestosterone, together with those of adrenal androgens, are capable of activating the androgen receptor. METHODS: This cross-sectional study was performed at a university hospital. Circulating androgen bioactivity was measured in 67 prepubertal children with clinical signs of PA and 94 control children using a novel androgen bioassay. RESULTS: Circulating androgen bioactivity was low in the PA and control children. In the subgroup of children (n = 28) with serum T concentration over the assay sensitivity (0.35 nmol/l) and a signal in the androgen bioassay, we found a positive correlation between androgen bioactivity and serum T (r = 0.50; P < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a negative correlation with serum sex hormone-binding globulin concentration (r = -0.41; P < 0.05). CONCLUSION: Peripheral metabolism of adrenal androgen precursors may be required for any androgenic effects in PA. However, the limitations in the sensitivity of the bioassay developed herein may hide some differences between the PA and control children.
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Adrenarca/sangue , Androgênios/sangue , Adolescente , Glândulas Suprarrenais/metabolismo , Adulto , Animais , Bioensaio , Células COS , Estudos de Casos e Controles , Criança , Chlorocebus aethiops , Estudos Transversais , Di-Hidrotestosterona/sangue , Feminino , Genes Reporter , Humanos , Masculino , Puberdade Precoce/sangue , Receptores Androgênicos/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Adulto JovemRESUMO
INTRODUCTION: Effect of physical activity in pregnancy on preeclampsia (PE) and angiogenic markers is not well understood. We studied the association of physical activity and PE in a case-control setting and assessed whether exercise in PE and non-PE women associate with maternal serum concentrations of soluble fms-like tyrosine kinase 1 (s-Flt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and sFlt-1/PlGF ratio in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort. MATERIALS AND METHODS: Participants completed a questionnaire on their background information and serum samples were collected from a subset. Questionnaire data on physical activity were available from 708 PE women and 724 non-PE women. Both first trimester serum samples and questionnaire data on physical activity were available from 160 PE women and 160 non-PE women, and second/third trimester serum samples and questionnaire data on physical activity were available from 139 PE women and 47 non-PE women. The PE and non-PE women were divided into categories of physically active (exercise 2 - 3 times/week or more) and physically inactive (exercise less than 2 - 3 times/week). RESULTS: A total of 43.4% of the PE women and 42.4% of the non-PE women were categorized as physically active. There were no differences in physical activity and exercise habits between the groups. The physically active women were more often nulliparous and non-smokers and had a lower body mass index. There were no differences in the concentrations of angiogenic markers (sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio) between the groups who exercised more or less than 2 - 3 times/week. CONCLUSIONS: In the FINNPEC study cohort, there was no association between physical activity and PE and no associations of physical activity in pregnant women with and without PE with maternal serum concentrations of sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio.
This is the first study to investigate the association of physical activity in pregnancy with concentrations of angiogenic markers while comparing pregnant women with and without preeclampsia.There were no differences in the physical activity and exercise habits in pregnancy between women with and without preeclampsia in the FINNPEC cohort.Physical activity of pregnant women with or without preeclampsia did not associate with the concentrations of angiogenic markers (sFlt-1, PlGF and sEng and sFlt-1/PlGF ratio).
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Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Pré-Eclâmpsia/genética , Fator de Crescimento Placentário , Finlândia/epidemiologia , Biomarcadores , Endoglina/genética , Exercício Físico , Receptor 1 de Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Centrally collected Finnish national health register data on adverse pregnancy outcomes are available for research, but the validity of the data is largely unknown. Our aim was to compare the diagnoses of preeclampsia (PE), gestational diabetes (GDM), and preterm delivery from hospital records with the registry based diagnoses from the Finnish Care Register for Health Care (FCR). Data on gestational age at delivery from the Medical Birth Registry (MBR) was also studied. METHODS: The Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) Study cohort was used as a data source. Each diagnosis was ascertained from electronic hospital records. The validity of diagnoses obtained by record linkage of FCR and MBR was assessed against the classification previously confirmed independently by a research nurse and a study physician. RESULTS: Sensitivity of PE diagnoses in FCR was 80.3 % (95 % CI 78.3 % to 82.2 %) andspecificity 95.3 % (95 % CI 93.9 % to 96.4 %). Sensitivity for GDM was 64.1 % (95 % CI: 58.7 % - 69.3 %) and specificity 98.5 % (95 % CI: 97.9 % - 98.9 %), whereas sensitivity and specificity for preterm delivery were 32.4 % (95 % CI: 29.0 % - 36.0 %) and 99.7 % (95 % CI: 99.3 % - 99.9 %). Sensitivity of preterm delivery in the MBR was 99.1 % and specificity 99.9 %. CONCLUSIONS: FCR registry diagnoses for PE have satisfactory sensitivity and high specificity. Diagnoses for GDM and preterm delivery have lower sensitivity limiting their use in studies, and data from MBR should be preferred when studying preterm deliveries.
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Diabetes Gestacional , Pré-Eclâmpsia , Nascimento Prematuro , Gravidez , Recém-Nascido , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/epidemiologia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/epidemiologia , Finlândia/epidemiologia , Resultado da Gravidez/epidemiologiaRESUMO
BACKGROUND: We evaluated how elevated blood pressure in children exposed to preeclampsia (PE) impacted on their cardiac structure and function, as well as relations with maternal, gestational, and perinatal factors and child body size and composition. METHODS AND RESULTS: A total of 182 PE (46 early-onset preeclampsia) and 85 unexposed (non-PE) children were examined in the FINNCARE study 8 to 12 years after the index pregnancy with echocardiography; office, central, and 24-hour ambulatory blood pressures; and body anthropometrics and composition. PE children had lower right ventricular basal sphericity index (mean difference, -0.26 95% CI, -0.39 to -0.12) and lower mitral lateral E'-wave peak velocity (-1.4 cm/s [95% CI, -2.1 to -0.6]), as well as higher E to E' ratio (0.40 [95% CI, 0.15-0.65]) and indexed tricuspid annular plane systolic excursion (0.03 [95% CI, 0.01-0.05]) compared with non-PE children. These differences were accentuated in early-onset PE children. Left ventricular mass (LVM) or left atrial volume were not different between PE and non-PE children. Lean body mass, body fat percentage, and 24-hour systolic blood pressure were independent predictors of LVM. Lean body mass and body fat percentage were independent predictors of left atrial volume. No significant associations between LVM or left atrial volume and maternal, gestational, or perinatal parameters were found. CONCLUSIONS: Preadolescent PE children display a more globular-shaped right ventricle with higher longitudinal systolic displacement as well as mildly altered diastolic indices, with the alterations being pronounced in early-onset preeclampsia. Lean body mass and adiposity are independently related with LVM and left atrial volume, and systolic blood pressure with LVM in both PE and non-PE children. These unfavorable associations indicate remodeling of cardiac structure in young children also reflected in mild functional changes in PE children. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04676295.
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Pressão Sanguínea , Pré-Eclâmpsia , Efeitos Tardios da Exposição Pré-Natal , Humanos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/diagnóstico , Feminino , Gravidez , Criança , Masculino , Pressão Sanguínea/fisiologia , Ecocardiografia , Função Ventricular Direita/fisiologia , Função Ventricular Esquerda/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Adulto , Monitorização Ambulatorial da Pressão ArterialRESUMO
Recent genome-wide association studies have identified multiple loci associated with BMI or the waist:hip ratio (WHR). However, evidence on gene-lifestyle interactions is still scarce, and investigation of the effects of well-documented dietary and other lifestyle data is warranted to assess whether genetic risk can be modified by lifestyle. We assessed whether previously established BMI and WHR genetic variants associate with obesity and weight change in the Finnish Diabetes Prevention Study, and whether the associations are modified by dietary factors or physical activity. Individuals (n 459) completed a 3 d food record and were genotyped for twenty-six BMI- and fourteen WHR-related variants. The effects of the variants individually and in combination were investigated in relation to obesity and to 1- and 3-year weight change by calculating genetic risk scores (GRS). The GRS were separately calculated for BMI and the WHR by summing the increasing alleles weighted by their published effect sizes. At baseline, the GRS were not associated with total intakes of energy, macronutrients or fibre. The mean 1- and 3-year weight changes were not affected by the BMI or WHR GRS. During the 3-year follow-up, a trend for higher BMI by the GRS was detected especially in those who reported a diet low in fibre (P for interaction=0·065). Based on the present findings, it appears unlikely that obesity-predisposing variants substantially modify the effect of lifestyle modification on the success of weight reduction in the long term. In addition, these findings suggest that the association between the BMI-related genetic variants and obesity could be modulated by the diet.
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Índice de Massa Corporal , Dieta , Comportamentos Relacionados com a Saúde , Estilo de Vida , Obesidade/genética , Relação Cintura-Quadril , Redução de Peso/genética , Alelos , Fibras na Dieta/administração & dosagem , Epigênese Genética , Exercício Físico , Feminino , Finlândia , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Fatores de RiscoRESUMO
Background and aim: Pre-eclampsia (PE) is related to elevated blood pressure (BP) in children. The study aims to investigate if elevated BP is reflected in child arterial health and how anthropometrics, body composition, and gestational and perinatal factors influenced this. Methods: In this prospective cohort study, we assessed the arteries of 182 children exposed (46 had an early onset, with a diagnosis before 34 gestational weeks, and 136 had a late onset) and 85 children unexposed (non-PE) to PE at 8-12 years from delivery using ultra-high-frequency ultrasound in addition to ambulatory and central BPs, body composition and anthropometrics, and tonometry-derived pulse wave velocity (PWV). Results: No differences were found in intima-media thickness (IMT), adventitia thickness (AT), lumen diameter (LD), local carotid artery stiffness, distensibility, or wall stress between PE-exposed and non-PE-exposed children. All children's brachial, radial, and femoral artery IMTs were associated with 24-h systolic BP (SBP) and pulse pressure, carotid-femoral PWV, and anthropometric measures. The 24-h SBP and anthropometrics, notably lean body mass, were independent predictors of peripheral artery IMTs (brachial R2 = 0.217, radial R2 = 0.208, femoral R2 = 0.214; p < 0.001). Head circumference predicted carotid artery IMT and LD (ß = 0.163, p = 0.009; ß = 0.417, p < 0.001, respectively), but carotid artery IMT was not associated with BP. No independent associations were found for peripheral artery ATs. Local carotid artery stiffness, distensibility, and wall stress were independently associated with adiposity. No significant associations were found between gestational or perinatal factors and child vascular health parameters. Conclusions: The peripheral artery IMT of PE-exposed children is identical to that of non-PE-exposed children, but associated with BP. Adiposity is related to local carotid artery stiffness. These adverse associations in arterial health may reflect the early progression of cardiovascular disease in PE-exposed children.
RESUMO
OBJECTIVE: To identify the combination of maternal characteristics in women with hypertensive disorders of pregnancy (HDP) associated with hypertensive and other cardiovascular diseases (CVDs) within ten years following delivery. The aim is to understand who should receive the most intensive primary cardiovascular disease prevention. STUDY DESIGN: A prospective cohort study. MAIN OUTCOME: The population was the FINNPEC cohort (2008-2011), including women with (n = 1837) and without (n = 847) HDP. The main exposures were maternal hypertensive pregnancy complications linked with maternal pregnancy data from hospital records. The outcomes were hypertensive diseases and other CVDs (International Classification of Diseases, Tenth Revision). RESULTS: Women with de novo pre-eclampsia (PE) had an elevated risk for hypertensive diseases within ten years following delivery. The risk of CVD was increased in women with superimposed PE and chronic hypertension (CHT) only. Women with de novo PE and hypertensive diseases were more often primiparous (41.4% vs. 23.0%, p = 0.020), had gestational diabetes (GDM) (31.0% vs. 11.7%, p = 0.002), and higher pre-pregnancy body mass index (BMI) (28.7 ± 5.8 vs. 24.6 ± 4.8 kg/m2, p = 0.001), compared with women who remained normotensive. Women with superimposed PE with CVD had more likely early-onset PE, preterm delivery and were older than women without later CVD. CONCLUSIONS: Healthcare professionals should target early prevention of CVDs in women with chronic hypertension during pregnancy; of those who developed superimposed PE prior to 34th weeks of gestation and who delivered preterm. Women with de novo PE who are overweight/obese, primiparous, and with concurrent GDM need regular blood pressure monitoring.
Assuntos
Doenças Cardiovasculares , Diabetes Gestacional , Hipertensão Induzida pela Gravidez , Hipertensão , Pré-Eclâmpsia , Complicações na Gravidez , Gravidez , Recém-Nascido , Feminino , Humanos , Estudos Prospectivos , Hipertensão/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Hipertensão Induzida pela Gravidez/epidemiologiaRESUMO
OBJECTIVES: The aim was to study if children following preeclampsia (PE) develop alterations in blood pressure (BP) and arterial stiffness already early in life, and how this is associated with gestational, perinatal and child cardiovascular risk profiles. METHODS: One hundred eighty-two PE (46 early-onset with diagnosis before 34 gestational weeks, and 136 late-onset) and 85 non-PE children were assessed 8-12âyears from delivery. Office and 24-h ambulatory BP, body composition, anthropometrics, lipids, glucose, inflammatory markers, and tonometry-derived pulse wave velocity (PWV) and central BPs were assessed. RESULTS: Office BP, central BPs, 24-h systolic BP (SBP) and pulse pressure (PP) were higher in PE compared with non-PE. Early-onset PE children had the highest SBP, SBP-loads, and PP. SBP nondipping during night-time was common among PE. The higher child 24-h mean SBP among PE was explained by maternal SBP at first antenatal visit and prematurity (birth weight or gestational weeks), but child 24-h mean PP remained related with PE and child adiposity after adjustments. Central and peripheral PWVs were elevated in late-onset PE subgroup only and attributed to child age and anthropometrics, child and maternal office SBP at follow-up, but relations with maternal antenatal SBPs and prematurity were not found. There were no differences in body anthropometrics, composition, or blood parameters. CONCLUSIONS: PE children develop an adverse BP profile and arterial stiffness early in life. PE-related BP is related with maternal gestational BP and prematurity, whereas arterial stiffness is determined by child characteristics at follow-up. The alterations in BP are pronounced in early-onset PE.Clinical Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT04676295ClinicalTrials.gov Identifier: NCT04676295.
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Doenças Cardiovasculares , Hipertensão , Pré-Eclâmpsia , Rigidez Vascular , Criança , Feminino , Humanos , Gravidez , Pressão Arterial , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Pré-Eclâmpsia/epidemiologia , Análise de Onda de Pulso , Fatores de Risco , Rigidez Vascular/fisiologiaRESUMO
Importance: A genetic contribution to preeclampsia susceptibility has been established but is still incompletely understood. Objective: To disentangle the underlying genetic architecture of preeclampsia and preeclampsia or other maternal hypertension during pregnancy with a genome-wide association study (GWAS) of hypertensive disorders of pregnancy. Design, Setting, and Participants: This GWAS included meta-analyses in maternal preeclampsia and a combination phenotype encompassing maternal preeclampsia and preeclampsia or other maternal hypertensive disorders. Two overlapping phenotype groups were selected for examination, namely, preeclampsia and preeclampsia or other maternal hypertension during pregnancy. Data from the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC, 1990-2011), Finnish FinnGen project (1964-2019), Estonian Biobank (1997-2019), and the previously published InterPregGen consortium GWAS were combined. Individuals with preeclampsia or other maternal hypertension during pregnancy and control individuals were selected from the cohorts based on relevant International Classification of Diseases codes. Data were analyzed from July 2020 to February 2023. Exposures: The association of a genome-wide set of genetic variants and clinical risk factors was analyzed for the 2 phenotypes. Results: A total of 16â¯743 women with prior preeclampsia and 15â¯200 with preeclampsia or other maternal hypertension during pregnancy were obtained from FINNPEC, FinnGen, Estonian Biobank, and the InterPregGen consortium study (respective mean [SD] ages at diagnosis: 30.3 [5.5], 28.7 [5.6], 29.7 [7.0], and 28 [not available] years). The analysis found 19 genome-wide significant associations, 13 of which were novel. Seven of the novel loci harbor genes previously associated with blood pressure traits (NPPA, NPR3, PLCE1, TNS2, FURIN, RGL3, and PREX1). In line with this, the 2 study phenotypes showed genetic correlation with blood pressure traits. In addition, novel risk loci were identified in the proximity of genes involved in the development of placenta (PGR, TRPC6, ACTN4, and PZP), remodeling of uterine spiral arteries (NPPA, NPPB, NPR3, and ACTN4), kidney function (PLCE1, TNS2, ACTN4, and TRPC6), and maintenance of proteostasis in pregnancy serum (PZP). Conclusions and Relevance: The findings indicate that genes related to blood pressure traits are associated with preeclampsia, but many of these genes have additional pleiotropic effects on cardiometabolic, endothelial, and placental function. Furthermore, several of the associated loci have no known connection with cardiovascular disease but instead harbor genes contributing to maintenance of successful pregnancy, with dysfunctions leading to preeclampsialike symptoms.
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Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Humanos , Feminino , Gravidez , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/diagnóstico , Estudo de Associação Genômica Ampla , Canal de Cátion TRPC6/genética , Placenta , Fatores de RiscoRESUMO
Paralleling the increasing trends of maternal obesity, gestational diabetes (GDM) has become a global health challenge with significant public health repercussions. In addition to short-term adverse outcomes, such as hypertensive pregnancy disorders and fetal macrosomia, in the long term, GDM results in excess cardiometabolic morbidity in both the mother and child. Recent data suggest that women with GDM are characterized by notable phenotypic and genotypic heterogeneity and that frequencies of adverse obstetric and perinatal outcomes are different between physiologic GDM subtypes. However, as of yet, GDM treatment protocols do not differentiate between these subtypes. Mapping the genetic architecture of GDM, as well as accurate phenotypic and genotypic definitions of GDM, could potentially help in the individualization of GDM treatment and assessment of long-term prognoses. In this narrative review, we outline recent studies exploring genetic risk factors of GDM and later type 2 diabetes (T2D) in women with prior GDM. Further, we discuss the current evidence on gene-lifestyle interactions in the development of these diseases. In addition, we point out specific research gaps that still need to be addressed to better understand the complex genetic and metabolic crosstalk within the mother-placenta-fetus triad that contributes to hyperglycemia in pregnancy.
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Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Feminino , Humanos , Gravidez , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Gestacional/etiologia , Macrossomia Fetal/etiologia , Estilo de Vida , Fatores de RiscoRESUMO
Only a few studies have explored the role of microbiota-dependent metabolite trimethylamine N-oxide (TMAO) in non-complicated pregnancy and in pre-eclampsia (PE). We enrolled 139 PE and 29 healthy pregnant women in a nested case control study. We hypothesized that elevated levels of circulating TMAO and its precursors choline and glycine betaine in the late second or in third trimester might contribute to the PE and are associated with the onset of the disease and clinical features such as elevated blood pressure. The association with a few available lifestyle factors (use of fish and physical activity) was also evaluated. In contrast with the previous findings, there was no difference in TMAO concentration between PE and healthy women. In addition, TMAO concentration was not associated with any of the PE related clinical features, angiogenic or inflammatory markers. In future, it is crucial to obtain longitudinal data on TMAO in both non-complicated and in PE pregnancies before we could have more detailed understanding of TMAO.