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1.
Am J Epidemiol ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31497855

RESUMO

Prenatal maternal smoking is a risk factor for lower birth weight. We performed epigenome-wide association analyses of placental DNA methylation (DNAm) at 720077 Cytosine-phosphate-Guanine-sites (CpGs) and prenatal maternal smoking among 441 mother-infant pairs (2010-2014) and evaluated if DNAm mediates the association between smoking and birth weight using mediation analysis. Mean (SD) birth weight was 3443 grams (423) and 38 mothers (8.6%) reported smoking at a mean of 9.4 weeks of gestation. Prenatal maternal smoking was associated with a 175-gram lower birth weight (95% CI: -305.5, -44.8) and with differential DNAm of 71 CpGs in placenta robust to latent-factor adjustment reflecting cell-types (Bonferroni-P<6.94x10-8). Of the 71 CpGs, seven mediated the association between prenatal smoking and birth weight (MDS2, PBX1, CYP1A2, VPRBP, WBP1L, CD28 and CDK6 genes) and prenatal smoking by DNAm interactions on birthweight were observed for five CpGs. The strongest mediator, cg22638236, was annotated the PBX1 gene body involved in skeletal patterning and programming with a mediated effect of 301-gram lower birth weight (95% CI: -543, -86) among smokers but no mediated effect for non-smokers (ß= -38-gram; 95% CI: -88, 9). Prenatal maternal smoking might interact with placental DNAm at specific loci mediating the association with lower infant birth weight.

2.
Hum Mol Genet ; 28(13): 2245-2254, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220271

RESUMO

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited disorder caused by expansion of a germline and somatically unstable CTG repeat in the DMPK gene. Previously, CTG repeat length at birth has been correlated to patient age at symptom onset. Attempts to correlate CTG repeat length with progressive DM1 phenotypes, such as muscle power, have proven difficult. To better correlate genotype with progressive phenotypes, we have measured CTG repeat tract length and screened for interrupting variant repeats in 192 study participants from a well-characterized Canadian cohort. We have assessed genotype-phenotype correlations with nine progressive measures of skeletal muscle power and respiratory function. We have built statistical models that include confounding factors such as sex, age, height and weight to further explain variation in muscle power. Our analysis reveals a strong correlation between DM1 genotype and respiratory function and skeletal muscle power, as part of a complex model that includes additional modulators such as sex, age, height, weight and the presence or absence of interrupting variant repeats. Distal skeletal muscle measurements, such as hand pinch and grip strength, show the strongest correlation with disease genotype. Detailed analysis of CTG repeat length, and incorporation of confounding factors, greatly improves the predictive ability of these models. They reveal a greater genetic influence on individual progressive phenotypes than on age at symptom onset and for clinical trials will help optimize stratification and explain patient variability. They will also help practitioners prioritize assessment of the muscular power measurements that correlate best with disease severity.

3.
Epigenetics ; 14(12): 1177-1182, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31250700

RESUMO

Illumina HumanMethylation450 BeadChip (450K) has been commonly used to investigate DNA methylation in human tissues. Recently, it has been replaced by Illumina HumanMethylationEPIC BeadChip (EPIC) covering over 850,000 CpGs distributed genome-wide. Many consortia have now datasets coming from both arrays and aspire to analyze the two together. The placenta shows a high number of intermediate methylation levels and is often investigated for obstetric/birth outcomes, and potentially for long-term programming in offspring. We performed a systematic comparison between the two arrays using 108 duplicate placental samples from Gen3G birth cohort. We find that placenta shows a high per-sample correlation between the arrays, and higher median correlations at individual CpGs than those reported for blood. We identify 26,340 probes with absolute difference in per cent methylation >10%. We conclude that EPIC and 450K placental data can be combined, and we provide two lists of CpGs that should be excluded to avoid misleading results.

4.
Epigenomics ; 11(8): 917-934, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31144512

RESUMO

Aim: To comprehensively characterize the high-density lipoproteins (HDLs) microtranscriptome and to assess whether it is distinct from that of plasma and different between women and men. Methods: RNA was extracted from ultracentrifugation-purified HDLs and plasma from 17 healthy women and men couples, and libraries were sequenced on a HiSeq2500 platform. Results: On average, 310 ± 64 and 355 ± 31 miRNAs were detected (≥1 read per million) in HDLs and plasma, respectively. A total of 62 and 134 miRNAs were over-represented (e.g., miR-150-5p; fold change = 7.52; padj = 5.41 × 10-111) and under-represented (e.g., miR-22-3p; fold change = -5.28; padj = 2.11 × 10-154) in HDLs compared with plasma. These miRNAs were enriched in lipid metabolism and cellular processes-related pathways. Conclusion: HDLs exhibit a sex-independent miRNA profile distinct from that of plasma. These miRNAs may contribute to the HDLs' physiology.

5.
Epigenetics ; 14(4): 405-420, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30885044

RESUMO

DNA methylation is known to be responsive to prenatal exposures, which may be a part of the mechanism linking early developmental exposures to future chronic diseases. Many studies use blood to measure DNA methylation, yet we know that DNA methylation is tissue specific. Placenta is central to fetal growth and development, but it is rarely feasible to collect this tissue in large epidemiological studies; on the other hand, cord blood samples are more accessible. In this study, based on paired samples of both placenta and cord blood tissues from 169 individuals, we investigated the methylation concordance between placenta and cord blood. We then employed a machine-learning-based model to predict locus-specific DNA methylation levels in placenta using DNA methylation levels in cord blood. We found that methylation correlation between placenta and cord blood is lower than other tissue pairs, consistent with existing observations that placenta methylation has a distinct pattern. Nonetheless, there are still a number of CpG sites showing robust association between the two tissues. We built prediction models for placenta methylation based on cord blood data and documented a subset of 1,012 CpG sites with high correlation between measured and predicted placenta methylation levels. The resulting list of CpG sites and prediction models could help to reveal the loci where internal or external influences may affect DNA methylation in both placenta and cord blood, and provide a reference data to predict the effects on placenta in future study even when the tissue is not available in an epidemiological study.

6.
Can J Physiol Pharmacol ; 97(3): 147-154, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661367

RESUMO

Childhood obesity is a predictor of adult obesity and has its roots in the pre-pregnancy or pregnancy period. This review presents an overview of the prenatal risk factors for childhood obesity, which were categorized into 2 groups: biological risk factors (maternal pre-pregnancy body mass index, gestational weight gain, diabetes in pregnancy, and caesarean section), and environmental and behavioural risk factors (maternal smoking and exposure to obesogens, maternal dietary patterns, maternal intestinal microbiome and antibiotics exposure, and maternal psychosocial stress). Identifying modifiable predisposing prenatal factors for obesity will inform further development of inventions to prevent obesity over the life course, and future directions for research and intervention are discussed.


Assuntos
Obesidade Pediátrica/etiologia , Animais , Feminino , Humanos , Gravidez , Complicações na Gravidez/etiologia , Fatores de Risco
7.
Can J Cardiol ; 34(12): 1665-1673, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527156

RESUMO

BACKGROUND: Regular monitoring of the population's food and nutrient intake is essential to develop effective nutrition-focused public health policies. The aim of this study was to provide dietary intake estimates using an age- and sex-representative sample of French-speaking adults with Internet access from 5 administrative regions in the province of Quebec, Canada. METHODS: PRÉDicteurs Individuels, Sociaux et Environnementaux (PREDISE) is a multicentre cross-sectional study that used a Web-based approach to collect individual, social, and environmental data on factors associated with adherence to dietary recommendations. Dietary intake was estimated from the average of 3 validated Web-based 24-hour recalls. RESULTS: Mean (± SD) age of the 1147 participants (50.2% women) was 43.2 ± 4.6 years and median body mass index was 26.3 (interquartile range, 23.3-30.3). Less than 25% of participants met Canada's Food Guide recommendations for vegetables and fruit intake (prevalence, 23.6%; 95% confidence interval [CI], 21.1-26.0). Most participants reported consuming more than 2300 mg of sodium (prevalence, 80.5%; 95% CI, 78.2-82.7) and more than 10% energy as saturated fats (prevalence, 74.2%; 95% CI, 71.6-76.7). Mean Canadian Healthy Eating Index score on a scale of 0-100 was 54.5 (95% CI, 53.8-55.2), reflecting relatively poor diet quality according to current dietary recommendations. CONCLUSIONS: Self-reported dietary intakes measured using a new validated Web-based 24-hour recall in this sample of French-speaking adults from Quebec and with access to Internet suggest low adherence to current Canadian dietary guidelines. These data emphasize the need for more effective nutrition-focused public health policies to maximize cardiovascular disease prevention at the population level.


Assuntos
Inquéritos sobre Dietas , Comportamento Alimentar , Política Nutricional , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Escolaridade , Feminino , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Quebeque/epidemiologia , Autorrelato , Fatores Sexuais , Adulto Jovem
8.
Metabolism ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30468781

RESUMO

Aim To characterize lipid profiles in women with different gestational diabetes mellitus (GDM) physiologic subtypes. METHODS: We measured seven lipid markers (total cholesterol, LDL, HDL, triglycerides, non-esterified fatty acids (NEFA), ApoA, ApoB) in fasting plasma collected in a prospective cohort of 805 pregnant women during second trimester. We estimated insulin sensitivity and secretion using oral glucose tolerance test-based validated indices. We categorized GDM physiologic subtypes by insulin sensitivity and secretion defects defined as values below the 25th percentile among women with normal glucose tolerance (NGT), as previously established. We compared lipid markers across NGT and GDM subtypes. We explored associations between lipid markers and newborns anthropometry in the overall group and stratified by glucose tolerance status. RESULTS: Among 805 women, 67 (8.3%) developed GDM. Women with GDM had higher body mass index (BMI; 29.3 vs. 26.6 kg/m2), while ethnicity (97.3% vs. 97.0% European ancestry) and age (28 vs. 29 years) were similar. In comparison to women with NGT, women with GDM characterized by a predominant insulin sensitivity defect had significantly higher triglycerides (2.20 vs. 1.82, P = 0.002), lower HDL (1.64 vs. 1.90, P = 0.01) and higher NEFA (0.34 vs. 0.24, P < 0.0001). GDM women with a predominant insulin secretion defect differed from women with NGT with respect to NEFA (0.32 vs. 0.24, P = 0.003) while other lipid markers were similar. These associations remained significant after adjusting for maternal age and BMI. Greater maternal levels of NEFA were associated with higher birth weight z-scores in women with an insulin secretion defect (BMI-adjusted r = 0.58, P = 0.01). We did not find significant associations between other lipid markers and newborn anthropometry in other groups. CONCLUSION: Women with GDM have distinct lipid profiles based on their GDM physiologic subtype which may not be apparent when investigating GDM as a single group.

9.
PLoS One ; 13(11): e0207632, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30462720

RESUMO

PURPOSE: Scientific evidence on the long-term impact of gestational diabetes mellitus (GDM) on offspring's myocardial relaxation is scarce. Studies have linked GDM with transient ventricular hypertrophy in newborns resulting in diastolic dysfunction, but long-term assessment is lacking. The main objective of this study was to evaluate myocardial relaxation in 3-year-old children in relation to the degree of insulin resistance of their mother during pregnancy. METHODS: We prospectively assessed myocardial relaxation by echocardiography imaging on 106 children at 3 years of age. Subjects were divided into 3 groups [GDM, insulin resistance (IR) and normoglycemic (CTRL)], based on their mother's 75g-OGTT and HOMA-IR results at second trimester screening. We collected information on children adiposity and body size, maternal characteristics and maternal and cord blood measurement of C-peptide and insulin. RESULTS: The study population comprised 29 children from GDM mothers, 36 children from IR mothers and 41 CTRL children. Compared to the CTRL group, we found that a higher proportion of children in the IR group and the GDM group met the criteria for impaired myocardial relaxation, but this did not reach statistical significance (odds ratio adjusted for heart rate and body surface area of 1.4 [0.2-9.5] and 3.5 [0.6-20.6], respectively). CONCLUSION: We did not detect an increased risk of impaired myocardial relaxation at three years of age in children exposed in-utero to IR and GDM, compared to children from normoglycemic mothers.

10.
Diabetes ; 67(12): 2703-2709, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30257980

RESUMO

Many common genetic polymorphisms are associated with glycemic traits and type 2 diabetes (T2D), but knowledge about genetic determinants of glycemic traits in pregnancy is limited. We tested genetic variants known to be associated with glycemic traits and T2D in the general population for associations with glycemic traits in pregnancy and gestational diabetes mellitus (GDM). Participants in two cohorts (Genetics of Glucose regulation in Gestation and Growth [Gen3G] and Hyperglycemia and Adverse Pregnancy Outcome [HAPO]) underwent oral glucose tolerance testing at 24-32 weeks' gestation. We built genetic risk scores (GRSs) for elevated fasting glucose and insulin, reduced insulin secretion and sensitivity, and T2D, using variants discovered in studies of nonpregnant individuals. We tested for associations between these GRSs, glycemic traits in pregnancy, and GDM. In both cohorts, the fasting glucose GRS was strongly associated with fasting glucose. The insulin secretion and sensitivity GRSs were also significantly associated with these traits in Gen3G, where insulin measurements were available. The fasting insulin GRS was weakly associated with fasting insulin (Gen3G) or C-peptide (HAPO). In HAPO (207 GDM case subjects), all five GRSs (T2D, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity) were significantly associated with GDM. In Gen3G (43 GDM case subjects), both the T2D and insulin secretion GRSs were associated with GDM; effect sizes for the other GRSs were similar to those in HAPO. Thus, despite the profound changes in glycemic physiology during pregnancy, genetic determinants of fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk.

11.
Cardiovasc Res ; 114(11): 1525-1535, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726894

RESUMO

Aims: Calcific aortic valve disease (CAVD) is characterized by the osteogenic transition of valve interstitial cells (VICs). In CAVD, lysophosphatidic acid (LysoPA), a lipid mediator with potent osteogenic activity, is produced in the aortic valve (AV) and is degraded by membrane-associated phospholipid phosphatases (PLPPs). We thus hypothesized that a dysregulation of PLPPs could participate to the osteogenic reprograming of VICs during CAVD. Methods and results: The expression of PLPPs was examined in human control and mineralized AVs and comprehensive analyses were performed to document the gene regulation and impact of PLPPs on the osteogenic transition of VICs. We found that PLPP3 gene and enzymatic activity were downregulated in mineralized AVs. Multidimensional gene profiling in 21 human AVs showed that expression of PLPP3 was inversely correlated with the level of 5-methylcytosine (5meC) located in an intronic mammalian interspersed repeat (MIR) element. Bisulphite pyrosequencing in a larger series of 67 AVs confirmed that 5meC in intron 1 was increased by 2.2-fold in CAVD compared with control AVs. In isolated cells, epigenome editing with clustered regularly interspersed short palindromic repeats-Cas9 system containing a deficient Cas9 fused with DNA methyltransferase (dCas9-DNMT) was used to increase 5meC in the intronic enhancer and showed that it reduced significantly the expression of PLPP3. Knockdown experiments showed that lower expression of PLPP3 in VICs promotes an osteogenic programme. Conclusions: DNA methylation of a MIR-based enhancer downregulates the expression of PLPP3 and promotes the mineralization of the AV.

12.
Diabetes ; 67(8): 1673-1683, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29752424

RESUMO

Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] q <0.05) within the phosphodiesterase 4B gene (PDE4B). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the TNFRSF1B, LDLR, and BLM genes (FDR q <0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: PDE4B (r = 0.31, P < 0.01), TNFRSF1B (r = -0.24, P = 0.013), and LDLR (r = 0.32, P < 0.001). In an independent replication cohort (N = 65-108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in PDE4B and TNFRSF1B Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Metilação de DNA , Epigênese Genética , Resistência à Insulina , Placenta/metabolismo , Receptores de LDL/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Peso ao Nascer , Estudos de Coortes , Ilhas de CpG , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Humanos , Recém-Nascido , Placenta/enzimologia , Placentação , Gravidez , Estudos Prospectivos , RecQ Helicases/genética , RecQ Helicases/metabolismo , Receptores de LDL/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Nascimento a Termo , Adulto Jovem
13.
Genet Epidemiol ; 42(3): 233-249, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29423954

RESUMO

Predicting a phenotype and understanding which variables improve that prediction are two very challenging and overlapping problems in the analysis of high-dimensional (HD) data such as those arising from genomic and brain imaging studies. It is often believed that the number of truly important predictors is small relative to the total number of variables, making computational approaches to variable selection and dimension reduction extremely important. To reduce dimensionality, commonly used two-step methods first cluster the data in some way, and build models using cluster summaries to predict the phenotype. It is known that important exposure variables can alter correlation patterns between clusters of HD variables, that is, alter network properties of the variables. However, it is not well understood whether such altered clustering is informative in prediction. Here, assuming there is a binary exposure with such network-altering effects, we explore whether the use of exposure-dependent clustering relationships in dimension reduction can improve predictive modeling in a two-step framework. Hence, we propose a modeling framework called ECLUST to test this hypothesis, and evaluate its performance through extensive simulations. With ECLUST, we found improved prediction and variable selection performance compared to methods that do not consider the environment in the clustering step, or to methods that use the original data as features. We further illustrate this modeling framework through the analysis of three data sets from very different fields, each with HD data, a binary exposure, and a phenotype of interest. Our method is available in the eclust CRAN package.


Assuntos
Doença/genética , Modelos Genéticos , Adolescente , Algoritmos , Criança , Pré-Escolar , Análise por Conglomerados , Simulação por Computador , Bases de Dados como Assunto , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Imagem por Ressonância Magnética
14.
Hum Mol Genet ; 27(4): 742-756, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29309628

RESUMO

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

16.
Cancer Res ; 77(24): 6863-6879, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993410

RESUMO

Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. ©2017 AACR.


Assuntos
Processamento Alternativo/genética , Genes de Troca , Neoplasias/genética , Oncogenes , Pró-Proteína Convertases/genética , Serina Endopeptidases/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Metilação de DNA , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias/patologia , Oncogenes/genética , Pró-Proteína Convertases/metabolismo , Neoplasias da Próstata/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Serina Endopeptidases/metabolismo
17.
Epigenetics ; 12(8): 616-625, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28486003

RESUMO

Gestational diabetes mellitus (GDM) is associated with obesity in childhood. This suggests that consequences of in utero exposure to maternal hyperglycemia extend beyond the fetal development, possibly through epigenetic programming. The aims of this study were to assess whether placental DNA methylation (DNAm) marks were associated with maternal GDM status and to offspring body composition at 5 years old in a prospective birth cohort. DNAm levels were measured in the fetal side of the placenta in 66 samples (24 from GDM mothers) using bisDNA-pyrosequencing. Anthropometric and body composition (bioimpedance) were measured in children at 5 years of age. Mann-Whitney and Spearman tests were used to assess associations between GDM, placental DNAm levels at the lipoprotein lipase (LPL) locus and children's weight, height, body mass index (BMI), body fat, and lean masses at 5 years of age. Weight, height, and BMI z-scores were computed according to the World Health Organization growth chart. Analyses were adjusted for gestational age at birth, child sex, maternal age, and pre-pregnancy BMI. LPL DNAm levels were positively correlated with birth weight z-scores (r = 0.252, P = 0.04), and with mid-childhood weight z-scores (r = 0.314, P = 0.01) and fat mass (r = 0.275, P = 0.04), and negatively correlated with lean mass (r = -0.306, P = 0.02). We found a negative correlation between LPL DNAm and mRNA levels in placenta (r = -0.459; P < 0.001), which highlights the regulation of transcriptional activity by these epivariations. We demonstrated that alterations in fetal placental DNAm levels at the LPL gene locus are associated with the anthropometric profile in children at 5 years of age. These findings support the concept of fetal metabolic programming through epigenetic changes.


Assuntos
Composição Corporal/genética , Metilação de DNA , Diabetes Gestacional/genética , Lipase Lipoproteica/genética , Placenta/metabolismo , Adulto , Criança , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
18.
Epigenomics ; 9(5): 669-688, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28470118

RESUMO

AIM: High-density lipoproteins (HDLs) are associated to cardioprotection and transport functional miRNAs in circulation. The aim of this study is to assess whether consumption of trans fatty acids (TFAs) modifies the HDL-carried miRNA concentration and their contribution to the plasmatic pool. METHODS: In a double-blind, randomized crossover controlled study, nine healthy men were fed each of three isoenergetic 4-week diets: first, rich in industrial TFAs; second, rich in TFAs from ruminants; third, low in TFAs. miRNAs were extracted from plasma and purified HDLs, and quantified by the real-time quantitative PCR (n = 87). RESULTS: Seven HDL-carried miRNAs contributed to more than 15% of the plasmatic pool. Although no significant difference in HDL-carried miRNA concentration among diets was observed after adjustment for multiple testing, changes in the contribution to the plasmatic pool between diets were observed for miR-124-3p, miR-375, miR-150-5p and miR-31-5p (p FDR < 0.05). These miRNAs were enriched in lipid metabolism pathways. CONCLUSION: These microtranscriptomic variants might reflect physiological changes in HDL functions in response to diet.


Assuntos
Gorduras na Dieta/metabolismo , Lipoproteínas HDL/sangue , MicroRNAs/sangue , Proteínas de Ligação a RNA/sangue , Ácidos Graxos Trans/metabolismo , Adolescente , Adulto , Humanos , Lipoproteínas HDL/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/metabolismo , Ácidos Graxos Trans/administração & dosagem
19.
Curr Diab Rep ; 17(5): 35, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28378294

RESUMO

PURPOSE OF THE REVIEW: This review focuses on the recent emergence of microRNAs (miRNAs) as metabolic and developmental regulators in pregnancy and their role in the development of gestational diabetes mellitus (GDM). MiRNAs are short and stable RNA sequences that repress protein synthesis through interference with messenger RNA translation. RECENT FINDINGS: The placenta produces numerous miRNAs with some of them being released in the maternal circulation. These miRNA genes are encoded into specific clusters and expressed preferentially by placental cells, in a time-dependent manner. They were shown to be dysregulated in plasma and placenta from women suffering from GDM and associated with pregnancy and birth-related outcomes. The discovery of pregnancy-related miRNAs and their respective characterization will provide us with important information as to their function in maternal and placental metabolic regulation. More studies are needed to determine whether they will be useful for early screening of GDM.


Assuntos
Diabetes Gestacional/metabolismo , MicroRNAs/fisiologia , Placenta/metabolismo , Feminino , Humanos , Gravidez
20.
Obesity (Silver Spring) ; 25(5): 935-944, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28317342

RESUMO

OBJECTIVE: This study investigated genetic determinants of adiponectin during pregnancy to reveal novel biology of adipocyte regulation. METHODS: A genome-wide association study was conducted in 1,322 pregnant women from the Hyperglycemia and Adverse Pregnancy Outcome Study with adiponectin measured at ∼28 weeks of gestation. Variants reaching P < 5×10-5 for de novo genotyping in two replication cohorts (Genetics of Glycemic regulation in Gestation and Growth N = 522; ECOGENE-21 N = 174) were selected. RESULTS: In the combined meta-analysis, the maternal T allele of rs900400 located on chr3q25 (near LEKR1/CCNL1) was associated with lower maternal adiponectin (ß ± standard error [SE] = -0.18 ± 0.03 standard deviation [SD] of adiponectin per risk allele; P = 1.5 ×10-8 ; N = 2,004; multivariable adjusted models). In contrast, rs900400 showed only nominal association with adiponectin in a large sample of nonpregnant women (ß ± SE = -0.012 ± 0.006; P = 0.05; N = 16,678 women from the ADIPOgen consortium). The offspring rs900400 T risk allele was associated with greater neonatal skinfold thickness (ß ±SE = 0.19 ± 0.04 SD per risk allele; P = 4.1×10-8 ; N = 1,489) and higher cord blood leptin (ß ± SE = 0.28 ± 0.05 log-leptin per risk allele; P = 8.2 ×10-9 ; N = 502), but not with cord blood adiponectin (P = 0.23; N = 495). The T allele of rs900400 was associated with higher expression of TIPARP in adipocytes. CONCLUSIONS: These investigations of adipokines during pregnancy and early life suggest that rs900400 has a role in adipocyte function.


Assuntos
Adiponectina/genética , Adiponectina/sangue , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Gravidez
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