IMPORTANCE: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. OBJECTIVE: To examine ...associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years’ postpartum. DESIGN, SETTING, AND PARTICIPANTS: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). EXPOSURES: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). MAIN OUTCOMES AND MEASURES: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). RESULTS: The analytic cohort included 4697 mothers (mean SD age, 41.7 5.7 years) and 4832 children (mean SD age, 11.4 1.2 years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio OR, 3.44 95% CI, 2.85 to 4.14; risk difference RD, 25.7% 95% CI, 21.7% to 29.7%). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, −0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). CONCLUSIONS AND RELEVANCE: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.
IMPORTANCE: Pregnancy may be a key window to optimize cardiovascular health (CVH) for the mother and influence lifelong CVH for her child. OBJECTIVE: To examine associations between maternal ...gestational CVH and offspring CVH. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study (examinations: July 2000-April 2006) and HAPO Follow-Up Study (examinations: February 2013-December 2016). The analyses included 2302 mother-child dyads, comprising 48% of HAPO Follow-Up Study participants, in an ancillary CVH study. Participants were from 9 field centers across the United States, Barbados, United Kingdom, China, Thailand, and Canada. EXPOSURES: Maternal gestational CVH at a target of 28 weeks’ gestation, based on 5 metrics: body mass index, blood pressure, total cholesterol level, glucose level, and smoking. Each metric was categorized as ideal, intermediate, or poor using pregnancy guidelines. Total CVH was categorized as follows: all ideal metrics, 1 or more intermediate (but 0 poor) metrics, 1 poor metric, or 2 or more poor metrics. MAIN OUTCOMES AND MEASURES: Offspring CVH at ages 10 to 14 years, based on 4 metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Total CVH was categorized as for mothers. RESULTS: Among 2302 dyads, the mean (SD) ages were 29.6 (2.7) years for pregnant mothers and 11.3 (1.1) years for children. During pregnancy, the mean (SD) maternal CVH score was 8.6 (1.4) out of 10. Among pregnant mothers, the prevalence of all ideal metrics was 32.8% (95% CI, 30.6%-35.1%), 31.7% (95% CI, 29.4%-34.0%) for 1 or more intermediate metrics, 29.5% (95% CI, 27.2%-31.7%) for 1 poor metric, and 6.0% (95% CI, 3.8%-8.3%) for 2 or more poor metrics. Among children of mothers with all ideal metrics, the prevalence of all ideal metrics was 42.2% (95% CI, 38.4%-46.2%), 36.7% (95% CI, 32.9%-40.7%) for 1 or more intermediate metrics, 18.4% (95% CI, 14.6%-22.4%) for 1 poor metric, and 2.6% (95% CI, 0%-6.6%) for 2 or more poor metrics. Among children of mothers with 2 or more poor metrics, the prevalence of all ideal metrics was 30.7% (95% CI, 22.0%-40.4%), 28.3% (95% CI, 19.7%-38.1%) for 1 or more intermediate metrics, 30.7% (95% CI, 22.0%-40.4%) for 1 poor metric, and 10.2% (95% CI, 1.6%-20.0%) for 2 or more poor metrics. The adjusted relative risks associated with 1 or more intermediate, 1 poor, and 2 or more poor (vs all ideal) metrics, respectively, in mothers during pregnancy were 1.17 (95% CI, 0.96-1.42), 1.66 (95% CI, 1.39-1.99), and 2.02 (95% CI, 1.55-2.64) for offspring to have 1 poor (vs all ideal) metrics, and the relative risks were 2.15 (95% CI, 1.23-3.75), 3.32 (95% CI,1.96-5.62), and 7.82 (95% CI, 4.12-14.85) for offspring to have 2 or more poor (vs all ideal) metrics. Additional adjustment for categorical birth factors (eg, preeclampsia) did not fully explain these significant associations (eg, relative risk for association between 2 or more poor metrics among mothers during pregnancy and 2 or more poor metrics among offspring after adjustment for an extended set of birth factors, 6.23 95% CI, 3.03-12.82). CONCLUSIONS AND RELEVANCE: In this multinational cohort, better maternal CVH at 28 weeks’ gestation was significantly associated with better offspring CVH at ages 10 to 14 years.
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring ...of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
Gestational diabetes (GDM) is one of the most common complications of pregnancy, affecting as many as one in six pregnancies. It is associated with both short- and long-term adverse outcomes for the ...mother and fetus and has important implications for the life course of affected women. Advances in genetics and epigenetics have not only provided new insight into the pathophysiology of GDM but have also provided new approaches to identify women at high risk for progression to postpartum cardiometabolic disease. GDM and type 2 diabetes share similarities in their pathophysiology, suggesting that they also share similarities in their genetic architecture. Candidate gene and genome-wide association studies have identified susceptibility genes that are shared between GDM and type 2 diabetes. Despite these similarities, a much greater effect size for
in GDM compared to type 2 diabetes and association of
, which encodes a hexokinase, with GDM but not type 2 diabetes suggest some differences in the genetic architecture of GDM. Genetic risk scores have shown some efficacy in identifying women with a history of GDM who will progress to type 2 diabetes. The association of epigenetic changes, including DNA methylation and circulating microRNAs, with GDM has also been examined. Targeted and epigenome-wide approaches have been used to identify DNA methylation in circulating blood cells collected during early, mid-, and late pregnancy that is associated with GDM. DNA methylation in early pregnancy had some ability to identify women who progressed to GDM, while DNA methylation in blood collected at 26-30 weeks gestation improved upon the ability of clinical factors alone to identify women at risk for progression to abnormal glucose tolerance post-partum. Finally, circulating microRNAs and long non-coding RNAs that are present in early or mid-pregnancy and associated with GDM have been identified. MicroRNAs have also proven efficacious in predicting both the development of GDM as well as its long-term cardiometabolic complications. Studies performed to date have demonstrated the potential for genetic and epigenetic technologies to impact clinical care, although much remains to be done.
Aims/hypothesis
Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy ...with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort.
Methods
The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10–14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA
1c
values during pregnancy.
Results
Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA
1c
measures, ORs for each child adiposity outcome were in the range of 1.05–1.16 for maternal fasting glucose, 1.11–1.19 for 1 h glucose, 1.09–1.21 for 2 h glucose and 1.12–1.21 for HbA
1c
. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls.
Conclusions/interpretation
Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.
BACKGROUND : Construction of networks from cross-sectional biological data is increasingly common. Many recent methods have been based on Gaussian graphical modeling, and prioritize estimation of ...conditional pairwise dependencies among nodes in the network. However, challenges remain on how specific paths through the resultant network contribute to overall 'network-level' correlations. For biological applications, understanding these relationships is particularly relevant for parsing structural information contained in complex subnetworks. RESULTS: We propose the pair-path subscore (PPS), a method for interpreting Gaussian graphical models at the level of individual network paths. The scoring is based on the relative importance of such paths in determining the Pearson correlation between their terminal nodes. PPS is validated using human metabolomics data from the Hyperglycemia and adverse pregnancy outcome (HAPO) study, with observations confirming well-documented biological relationships among the metabolites. We also highlight how the PPS can be used in an exploratory fashion to generate new biological hypotheses. Our method is implemented in the R package pps, available at https://github.com/nathan-gill/pps . CONCLUSIONS: The PPS can be used to probe network structure on a finer scale by investigating which paths in a potentially intricate topology contribute most substantially to marginal behavior. Adding PPS to the network analysis toolkit may enable researchers to ask new questions about the relationships among nodes in network data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge ...of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.
This study examined associations of maternal glycemia during pregnancy with childhood glucose outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort.
HAPO was an observational ...international investigation that established associations of maternal glucose with adverse perinatal outcomes. The HAPO Follow-up Study included 4,832 children ages 10-14 years whose mothers had a 75-g oral glucose tolerance test (OGTT) at ∼28 weeks of gestation. Of these, 4,160 children were evaluated for glucose outcomes. Primary outcomes were child impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Additional outcomes were glucose-related measures using plasma glucose (PG), A1C, and C-peptide from the child OGTT.
Maternal fasting plasma glucose (FPG) was positively associated with child FPG and A1C; maternal 1-h and 2-h PG were positively associated with child fasting, 30 min, 1-h, and 2-h PG, and A1C. Maternal FPG, 1-h, and 2-h PG were inversely associated with insulin sensitivity, whereas 1-h and 2-h PG were inversely associated with disposition index. Maternal FPG, but not 1-h or 2-h PG, was associated with child IFG, and maternal 1-h and 2-h PG, but not FPG, were associated with child IGT. All associations were independent of maternal and child BMI. Across increasing categories of maternal glucose, frequencies of child IFG and IGT, and timed PG measures and A1C were higher, whereas insulin sensitivity and disposition index decreased.
Across the maternal glucose spectrum, exposure to higher levels in utero is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes.
Context: Inflammatory mediators are associated with type 2 and gestational diabetes. It is unknown whether there are associations with glucose in pregnant women with lesser degrees of hyperglycemia.
...Objective: The objective of the study was to examine associations of inflammatory mediators with maternal glucose levels and neonatal size in a subset of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.
Design: Eligible pregnant women underwent a 75-g oral glucose tolerance test between 24 and 32 wk gestation, and levels of C-peptide, adiponectin, plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), and resistin were measured in fasting serum samples. Associations of inflammatory mediators with maternal glucose and with birth size were assessed using multiple linear regression analyses, adjusting for maternal body mass index (BMI), fasting C-peptide, and other potential confounders.
Results: Mean levels of adiponectin declined, and PAI-1 and CRP increased across increasing levels of maternal glucose, BMI, and C-peptide. For example, for fasting plasma glucose less than 75 mg/dl and fasting plasma glucose of 90 mg/dl or greater, adiponectin was 22.5 and 17.4 μg/ml and PAI-1 was 30.9 and 34.2 ng/ml, respectively. Associations with 1- and 2-h plasma glucose remained significant for adiponectin (P < 0.001), PAI-1 (P < 0.05), and CRP (P < 0.01) after adjustment for BMI and C-peptide. Adiponectin and CRP were inversely associated with birth weight, sum of skinfolds and percent body fat, and PAI-1 with sum of skinfolds (all P < 0.05) after adjustment for confounders. Resistin was not associated with 1- or 2-h glucose or birth size.
Conclusion: Levels of inflammatory mediators are associated with levels of maternal glucose in pregnant women without overt diabetes.
Levels of inflammatory mediators are associated with levels of maternal glucose in pregnant women without overt diabetes.
The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that ...in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis.
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