Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
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 Recently, it has been replaced by Illumina HumanMethylationEPIC BeadChip (EPIC) covering over 850,000 CpGs distributed genome-wide.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.

2.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
3.
Can J Diabetes ; 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30930072

RESUMO

OBJECTIVES: To compare: 1) 75 g oral glucose tolerance test (OGTT) and self-monitoring of blood glucose (SMBG) in identifying gestational diabetes mellitus (GDM) and other hyperglycemic statuses in pregnant women; 2) pregnancy outcomes according to glycemic status; and 3) participants' opinions regarding both methods. METHODS: A prospective study in women with a 50 g glucose load test ≥7.2 mmol/L at 24 to 28 weeks' gestation and singleton pregnancy. Women underwent OGTT (blinded) at day 1, followed by 7 days of SMBG (4 daily measurements: fasting and 2 h postprandially) without modifying diet or lifestyle. GDM (OGTT+) was diagnosed using the criteria of the International Association of the Diabetes and Pregnancy Study Groups, while pregnancy hyperglycemia (SMBG+) was defined as ≥4/7 glucose values ≥5.3 after fasting or ≥6.7 mmol/L 2 h postprandially for any meal of the day. Equivalent management was provided to women with GDM and/or pregnancy-related hyperglycemia. RESULTS: We divided 103 participants (age: 29.5±5.0 years; prepregnancy body mass index: 25.3±5.4 kg/m2) into 4 groups according to test results: OGTT+/SMBG+ (n=12, 11.7%); OGTT+/SMBG- (n=14, 13.6%); OGTT-/SMBG+ (n=9, 8.7%); and OGTT-/SMBG- (n=68, 66.0%). Clinical characteristics and maternal outcomes were statistically similar between groups. Neonatal complication rates were greater in groups with hyperglycemia than in the OGTT-/SMBG- group, notably neonatal hypoglycemia (9/12, 7/14, 5/9 vs. 6/68; p<0.001). Participants reported no convenience difference between methods but would prefer OGTT for a future pregnancy. CONCLUSIONS: More than half of the women with OGTT+ were normoglycemic in daily life. Conversely, 11.7% of women with OGTT- had pregnancy hyperglycemia. OGTT+ and/or SMBG+ were equally associated with greater neonatal complications. This study suggests that alongside OGTT, SMBG could improve the care of pregnant women.

4.
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.

5.
J Glob Antimicrob Resist ; 17: 112-116, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30553114

RESUMO

OBJECTIVES: Rates of infection following transrectal ultrasound-guided prostate biopsy (TRUSPB) are increasing. The aim of this study was to evaluate the effectiveness of fosfomycin tromethamine (FMT) prophylaxis in preventing post-TRUSPB infectious complications. METHODS: This nested case-control study included patients undergoing TRUSPB in a Canadian tertiary-care hospital who developed post-TRUSPB bacteraemia or urinary tract infection. Four prophylaxis periods were defined: (i) ciprofloxacin, low-resistance period (CIPRO-LOW), 2002-2009; (ii) ciprofloxacin, high-resistance period (CIPRO-HIGH), 2010-October 2013; (iii) oral FMT, one dose (FOSFO1), December 2013-September 2015; and (iv) oral FMT, two doses (FOSFO2), November 2015-June 2016. Incidence rates of the infection were calculated. RESULTS: TRUSPB (n=9391) resulted in 138 cases of urinary sepsis (58% with bacteraemia). The incidence rates were 1.8% (CIPRO-HIGH), 3.5% (FOSFO1; P=0.004 vs. CIPRO-HIGH) and 2.7% (FOSFO2; P=0.19 vs. CIPRO-HIGH). Although Escherichia coli remained the predominant pathogen with fosfomycin-based regimens, the proportion of infections caused by Klebsiella spp. was higher (20/66; 30.3%) than with ciprofloxacin-based regimens (2/77; 2.6%; P<0.0001). CONCLUSION: Independent risk factors for infection were the prophylactic regimen administered, presence of urological co-morbidities and diabetes. FMT was therefore not an effective alternative to ciprofloxacin for preventing post-TRUSPB urinary sepsis. These results highlight the need for novel antibacterial prophylaxis approaches.

6.
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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30269415

RESUMO

BACKGROUND: Published data about nonagenarians with acute coronary syndrome (ACS) were mainly descriptive and limited by small sample sizes and unadjusted outcomes. We aim to describe the characteristics, management, and the impact of an invasive strategy on major adverse events in elderly patients hospitalized with ACS with focus on the nonagerians. METHODS AND RESULTS: We analyzed data collected as part of the AMI-OPTIMA study, a cluster-randomized study of knowledge translation intervention versus usual care on optimal discharge medications in patients admitted with ACS at 24 Canadian hospitals. To determine whether an invasive strategy improved outcomes in the elderly, we used inverse probability weighting to adjust for confounders between patients who underwent invasive versus conservative strategies. Of 4,569 consecutive patients: 2,395 (52%) were <70 years old, 1,031 (23%) were septuagenarians, 941 (21%) were octogenarians, and 202 (4.4%) were nonagenarians. An invasive strategy was associated with reduced in-hospital all-cause mortality in all age groups: 1.1% versus 3.8% in patients <70 years old (P < 0.001), 2.9% versus 7.4% in septuagenarians (P < 0.001), 5.1% versus 14.7% in octogenarians (P < 0.001), and 12.0% versus 25.1% in nonagenarians (P = 0.001). An invasive strategy was also associated with higher thrombolysis in myocardial infarction major bleeds in the nonagenarians (9.0% vs. 2.0%; P = 0.003). CONCLUSIONS: The reduction in in-hospital mortality associated with an invasive strategy in elderly and nonagenarians presented with ACS is generating hypothesis and merits further studies to confirm these benefits and to guide clinicians in the management of these high-risk patients.

8.
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.

9.
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
10.
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.

11.
Hum Mol Genet ; 26(20): 4067-4085, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29016858

RESUMO

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.


Assuntos
Herança Materna/genética , Obesidade/complicações , Resultado da Gravidez/genética , Adulto , Índice de Massa Corporal , Estudos de Coortes , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Humanos , Recém-Nascido , Masculino , Herança Materna/fisiologia , Mães , Gravidez/fisiologia , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo
12.
J Nutr ; 147(6): 1145-1151, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28424259

RESUMO

Background: Maternal vitamin D insufficiency (plasma 25-hydroxyvitamin D [25(OH)D] <75 nmol/L) may play a role in ethnic disparities in rates of preterm and spontaneous preterm births.Objective: We explored the relation between maternal plasma 25(OH)D concentration in the first trimester (8-14 wk of gestation) and the risk of preterm and spontaneous preterm births (<37 wk of gestation) by ethnicity.Methods: We designed a case-control study that included 120 cases of preterm birth (<37 wk of gestation) and 360 term controls (≥37 wk of gestation) of singleton pregnancies from the 3D cohort, a multicenter study in 2456 pregnant women in Quebec, Canada. Plasma 25(OH)D was measured by LC-mass spectrometry. We compared the distribution of vitamin D status between cases and controls for 8 ethnic minority subgroups. We explored the association between maternal plasma 25(OH)D concentration and preterm and spontaneous preterm births with the use of splines in logistic regression by ethnicity.Results: The distributions of maternal vitamin D status (<50, 50-75, and >75 nmol/L) were different in preterm and spontaneous preterm birth cases compared with controls but only in women of ethnic minority (P-trend = 0.003 and 0.024, respectively). Among ethnic subgroups, sub-Saharan Africans (P-trend = 0.030) and Arab-West Asians (P-trend = 0.045) showed an inverse relation between maternal vitamin D status and the risk of preterm birth. Maternal plasma 25(OH)D concentrations of 30 nmol/L were associated with 4.05 times the risk of preterm birth in the total ethnic minority population (95% CI: 1.16, 14.12; P = 0.028) relative to participants with a concentration of 75 nmol/L. In contrast, there was no such association among nonethnic women (OR: 0.94; 95% CI: 0.48, 1.82; P = 0.85). There was no association when we considered only spontaneous preterm births in the total ethnic minority population (OR: 1.75; 95% CI: 0.39, 7.79; P = 0.46).Conclusion: Vitamin D insufficiency is associated with an increased risk of preterm birth in ethnic minority women in Canada.


Assuntos
Grupo com Ancestrais do Continente Africano , Árabes , Grupo com Ancestrais do Continente Asiático , Grupos Minoritários , Resultado da Gravidez , Nascimento Prematuro/etiologia , Deficiência de Vitamina D/complicações , Adulto , África ao Sul do Saara , Ásia Ocidental , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Modelos Logísticos , Razão de Chances , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/etnologia , Complicações na Gravidez/etiologia , Quebeque , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etnologia
13.
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
14.
Neonatology ; 111(4): 344-352, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28095377

RESUMO

BACKGROUND: During pregnancy, maternal circulating leptin is released by maternal adipose tissue and the placenta, and may have a role in fetal development. OBJECTIVES: We investigated maternal leptinemia and glycemia associations with neonatal adiposity, taking into account pregravid weight status. METHODS: We included 235 pregnant women from the Genetics of Glucose Regulation in Gestation and Growth prospective cohort with data: blood samples collected during the 2nd trimester, an oral glucose tolerance test (OGTT), and the measured leptin and glucose levels. As an integrated measure of maternal leptin exposure, we calculated the area under the curve for maternal leptin at the OGTT (AUCleptin). Within 72 h of delivery, we measured the triceps, biceps, subscapular, and suprailiac skinfold thicknesses (SFTs); the sum of these SFTs represented neonatal adiposity. We conducted a regression analysis to assess the maternal metabolic determinants of neonatal adiposity, adjusting for parity, smoking status, maternal triglyceride levels, gestational weight gain, placental weight, delivery mode, neonate sex, and gestational age at delivery. RESULTS: The pregravid BMI of the participating women was 23.3 (21.2-27.0). In the 2nd trimester, maternal AUCleptin was 1,292.0 (767.0-2,222.5) (ng × min)/mL, and fasting glucose levels were 4.2 ± 0.4 mmol/L. At delivery, the neonatal sum of 4 SFTs was 17.9 ± 3.3 mm. Higher maternal leptinemia was associated with higher neonatal adiposity (ß = 4.23 mm [SE = 1.77] per log-AUCleptin; p = 0.02) in mothers with a BMI ≥25, independently of confounders and maternal glycemia, but not in mothers with a BMI <25. Higher maternal fasting glucose was associated with higher neonatal adiposity (ß = 0.88 mm [SE = 0.30] per SD glucose; p = 0.005) in mothers with a BMI <25, independently of confounders and maternal leptinemia. CONCLUSION: Maternal leptinemia may be associated with neonatal adiposity in offspring from overweight/obese mothers, independently of maternal glycemia.


Assuntos
Adiposidade/fisiologia , Desenvolvimento Fetal/fisiologia , Leptina/sangue , Mães , Adulto , Biomarcadores/sangue , Peso ao Nascer/fisiologia , Glicemia/análise , Índice de Massa Corporal , Feminino , Sangue Fetal , Idade Gestacional , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Gravidez , Estudos Prospectivos , Quebeque , Adulto Jovem
15.
Epigenetics ; 11(11): 773-779, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27668573

RESUMO

Cord blood is widely used as surrogate tissue in epigenome-wide association studies of prenatal conditions. Cell type composition variation across samples can be an important confounder of epigenome-wide association studies in blood that constitute a mixture of cells. We evaluated a newly developed cord blood reference panel to impute cell type composition from DNA methylation levels, including nucleated red blood cells (nRBCs). We estimated cell type composition from 154 unique cord blood samples with available DNA methylation data as well as direct measurements of nucleated cell types. We observed high correlations between the estimated and measured composition for nRBCs (r = 0.92, R2 = 0.85), lymphocytes (r = 0.77, R2 = 0.58), and granulocytes (r = 0.72, R2 = 0.52), and a moderate correlation for monocytes (r = 0.51, R2 = 0.25) as well as relatively low root mean square errors from the residuals ranging from 1.4 to 5.4%. These results validate the use of the cord blood reference panel and highlight its utility and limitations for epidemiological studies.


Assuntos
Metilação de DNA/genética , Epigenômica , Eritroblastos/metabolismo , Sangue Fetal/metabolismo , Adulto , Ilhas de CpG/genética , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Granulócitos/metabolismo , Humanos , Recém-Nascido , Contagem de Leucócitos , Monócitos/metabolismo
16.
Clin Epigenetics ; 8: 72, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27340502

RESUMO

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) are at a higher risk of developing obesity and type 2 diabetes. This susceptibility might involve brown adipose tissue (BAT), which is suspected to protect against obesity. The objective of this study is to assess whether fetal exposure to maternal hyperglycemia is associated with DNA methylation variations in genes involved in BAT genesis and activation. METHODS: DNA methylation levels at the PRDM16, BMP7, CTBP2, and PPARGC1α gene loci were measured in placenta samples using bisulfite pyrosequencing in E-21 (n = 133; 33 cases of GDM) and the HumanMethylation450 array in Gen3G (n = 172, all from non-diabetic women) birth cohorts. Glucose tolerance was assessed in all women using an oral glucose tolerance test at the second trimester of pregnancy. Participating women were extensively phenotyped throughout pregnancy, and placenta and cord blood samples were collected at birth. RESULTS: We report that maternal glycemia at the second and third trimester of pregnancy are correlated with variations in DNA methylation levels at PRDM16, BMP7, and PPARGC1α and with cord blood leptin levels. Variations in PRDM16 and PPARGC1α DNA methylation levels were also correlated with cord blood leptin levels. Mediation analyses support that DNA methylation variations at the PPARGC1α gene locus explain 0.8 % of the cord blood leptin levels variance independently of maternal fasting glucose levels (p = 0.05). CONCLUSIONS: These results suggest that maternal glucose in pregnancy could produce variations in DNA methylation in BAT-related genes and that some of these DNA methylation marks seem to mediate the impact of maternal glycemia on cord blood leptin levels, an adipokine regulating body weight.


Assuntos
Metilação de DNA , Diabetes Gestacional/genética , Leptina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Placenta/metabolismo , Adulto , Epigênese Genética , Feminino , Sangue Fetal/metabolismo , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Gravidez , Trimestres da Gravidez
17.
Diabetes Care ; 39(6): 1052-5, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27208340

RESUMO

OBJECTIVE: To characterize physiologic subtypes of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Insulin sensitivity and secretion were estimated in 809 women at 24-30 weeks' gestation, using oral glucose tolerance test-based indices. In women with GDM (8.3%), defects in insulin sensitivity or secretion were defined below the 25th percentile in women with normal glucose tolerance (NGT). GDM subtypes were defined based on the defect(s) present. RESULTS: Relative to women with NGT, women with predominant insulin sensitivity defects (51% of GDM) had higher BMI and fasting glucose, larger infants (birth weight z score 0.57 [-0.01 to 1.37] vs. 0.03 [-0.53 to 0.52], P = 0.001), and greater risk of GDM-associated adverse outcomes (57.6 vs. 28.2%, P = 0.003); differences were independent of BMI. Women with predominant insulin secretion defects (30% of GDM) had BMI, fasting glucose, infant birth weights, and risk of adverse outcomes similar to those in women with NGT. CONCLUSIONS: Heterogeneity of physiologic processes underlying hyperglycemia exists among women with GDM. GDM with impaired insulin sensitivity confers a greater risk of adverse outcomes.


Assuntos
Peso ao Nascer , Glicemia/metabolismo , Diabetes Gestacional/metabolismo , Resistência à Insulina , Insulina/metabolismo , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Jejum , Feminino , Idade Gestacional , Teste de Tolerância a Glucose , Humanos , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Adulto Jovem
18.
J Obstet Gynaecol Can ; 38(2): 108-17, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27032734

RESUMO

OBJECTIVE: Excessive gestational weight gain (GWG) is associated with increased birth weight and neonatal adiposity. However, timing of excessive GWG may have a differential impact on birth outcomes. The objective of this study was to compare the effect of early and mid/late excessive GWG on newborn anthropometry in the context of the Canadian clinical recommendations that are specific for first trimester and for second/third trimesters based on maternal pre-pregnancy BMI. METHODS: We included 607 glucose-tolerant women in our main analyses, after excluding women who had less than the recommended total GWG. Maternal body weight was measured in early pregnancy, mid-pregnancy, and late pregnancy. Maternal and fetal clinical outcomes were collected, including newborn anthropometry. Women were divided into four groups according to the Canadian guidelines for GWG in the first and in the second/third trimesters: (1) "overall non-excessive" (reference group); (2) "early excessive GWG"; (3) "mid/late excessive GWG"; and (4) "overall excessive GWG." Differences in newborn anthropometry were tested across GWG categories. RESULTS: Women had a mean (±SD) pre-pregnancy BMI of 24.7 ± 5.2 kg/m(2) and total GWG of 15.3 ± 4.4 kg. Women with mid/late excessive GWG gave birth to heavier babies (gestational age-adjusted birth weight z-score 0.33 ± 0.91) compared with women in the reference group (0.00 ± 0.77, P = 0.007), whereas women with early excessive GWG gave birth to babies of similar weight (gestational age-adjusted z-score 0.01 ± 0.86) to the reference group (0.00 ± 0.77, P = 0.84). When we stratified our analyses and investigated women who gained within the recommendations for total GWG, mid/late excessive GWG specifically was associated with greater newborn size, similar to our main analyses. CONCLUSION: Excessive GWG in mid/late pregnancy in women who did not gain weight excessively in early pregnancy is associated with increased birth size, even in those who gained within the Canadian recommendations for total GWG.


Assuntos
Peso ao Nascer/fisiologia , Peso Corporal/fisiologia , Gravidez/estatística & dados numéricos , Ganho de Peso/fisiologia , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos , Adulto Jovem
19.
JAMA ; 315(11): 1129-40, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26978208

RESUMO

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.


Assuntos
Peso ao Nascer/genética , Glicemia/genética , Índice de Massa Corporal , Jejum/sangue , Obesidade/genética , Adulto , Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Humanos , Recém-Nascido , Análise da Randomização Mendeliana , Obesidade/sangue , Obesidade/etnologia , Polimorfismo de Nucleotídeo Único , Gravidez , Triglicerídeos/genética
20.
BMJ Open ; 6(2): e010031, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26842272

RESUMO

PURPOSE: We initiated the Genetics of Glucose regulation in Gestation and Growth (Gen3G) prospective cohort to increase our understanding of biological, environmental and genetic determinants of glucose regulation during pregnancy and their impact on fetal development. PARTICIPANTS: Between January 2010 and June 2013, we invited pregnant women aged ≥ 18 years old who visited the blood sampling in pregnancy clinic in Sherbrooke for their first trimester clinical blood samples: 1034 women accepted to participate in our cohort study. FINDINGS TO DATE: At first and second trimester, we collected demographics and lifestyle questionnaires, anthropometry measures (including fat and lean mass estimated using bioimpedance), blood pressure, and blood samples. At second trimester, women completed a full 75 g oral glucose tolerance test and we collected additional blood samples. At delivery, we collected cord blood and placenta samples; obstetrical and neonatal clinical data were abstracted from electronic medical records. We also collected buffy coats and extracted DNA from maternal and/or offspring samples (placenta and blood cells) to pursue genetic and epigenetic hypotheses. So far, we have found that low adiponectin and low vitamin D maternal levels in first trimester predict higher risk of developing gestational diabetes. FUTURE PLANS: We are now in the phase of prospective follow-up of mothers and offspring 3 and 5 years postdelivery to investigate the consequences of maternal dysglycaemia during pregnancy on offspring adiposity and metabolic profile. TRIAL REGISTRATION NUMBER: NCT01623934.


Assuntos
Glicemia/metabolismo , Diabetes Gestacional/epidemiologia , Epigênese Genética/genética , Obesidade/epidemiologia , Deficiência de Vitamina D/epidemiologia , Adiponectina/metabolismo , Adulto , Composição Corporal , Índice de Massa Corporal , Canadá/epidemiologia , Diabetes Gestacional/metabolismo , Feminino , Sangue Fetal/metabolismo , Teste de Tolerância a Glucose , Humanos , Recém-Nascido , Resistência à Insulina , Masculino , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/metabolismo , Estudos Prospectivos , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismo , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deficiência de Vitamina D/metabolismo , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA