Metabolomics may identify biological pathways predisposing children to the risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in ...infancy and overweight in early childhood in four European birth cohorts.
Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood was defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed-effect models and controlling the false discovery rate (FDR) at 5%. In addition, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth.
In the Metabolome-Wide Association Study analysis, we identified three and eight metabolites associated with rapid growth and overweight, respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, were predictive of rapid growth (p = 1.6 × 10
). Lower levels of the branched-chain amino acid (BCAA) valine (p = 8.6 × 10
) were predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared with 0.69 and 0.69, respectively, for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P < 0.05) with rapid growth and overweight, respectively. The BCAA leucine, remained associated (1.6 × 10
) with overweight after FDR correction.
The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Unintentional injuries such as falls, are particularly frequent in early childhood. To date, epidemiological studies in this field have been carried out using routine data sources or registries and ...many studies were observational studies with a cross-sectional design. The aims of the study are to describe unintentional injuries in the first two years of life in the Piccolipiù birth cohort, and to investigate the association between mother and children characteristics and the First Event of Raised surface Fall (FERF). This longitudinal observational study included 3038 children from an Italian birth cohort. Data on socio-demographic factors, socio-economic indicators, maternal health and lifestyle characteristics and child's sleeping behavior, obtained from questionnaires completed at birth, 12 and 24 months of age, were considered in the analyses as potential risk factors of FERF. Time of occurrence of FERF was analyzed using the Kaplan-Meier method. The multivariable analysis for time to event was carried out using a Cox proportional hazards model. Falls from raised surfaces are the leading cause of unintentional injuries in the cohort with 610 (21.1%) and 577 (20.0%) cases among children during the first and second year of life, respectively. An increased risk of FERF was associated with several risk factors: maternal psychological distress (HR 1.41, 95%CI 1.10-1.81), maternal alcohol intake (HR 1.26, 95%CI 1.10-1.45), and child's sleeping problems (HR 1.28, 95%CI 1.09-1.51). Children with older aged mothers (HR 0.98, 95%CI 0.96-0.99) and living in northern Italy (HR 0.64, 95%CI 0.55-0.75) had a lower risk of FERF. The results of the study suggest that a higher risk of FERF is associated with socio-demographic factors, maternal characteristics and child sleeping behavior that could hinder parent empowerment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•There was no evidence of pregnancy or cumulative exposures associating with any DMP.•Surrounding greenness exposure was inversely associated with four DMRs.•Two of these DMRs were ...annotated to genes previously associated with green space.
Green space exposure has been associated with improved mental, physical and general health. However, the underlying biological mechanisms remain largely unknown. The aim of this study was to investigate the association between green space exposure and cord and child blood DNA methylation.
Data from eight European birth cohorts with a total of 2,988 newborns and 1,849 children were used. Two indicators of residential green space exposure were assessed: (i) surrounding greenness (satellite-based Normalized Difference Vegetation Index (NDVI) in buffers of 100 m and 300 m) and (ii) proximity to green space (having a green space ≥ 5,000 m2 within a distance of 300 m). For these indicators we assessed two exposure windows: (i) pregnancy, and (ii) the period from pregnancy to child blood DNA methylation assessment, named as cumulative exposure. DNA methylation was measured with the Illumina 450K or EPIC arrays. To identify differentially methylated positions (DMPs) we fitted robust linear regression models between pregnancy green space exposure and cord blood DNA methylation and between cumulative green space exposure and child blood DNA methylation. Two sensitivity analyses were conducted: (i) without adjusting for cellular composition, and (ii) adjusting for air pollution. Cohort results were combined through fixed-effect inverse variance weighted meta-analyses. Differentially methylated regions (DMRs) were identified from meta-analysed results using the Enmix-combp and DMRcate methods.
There was no statistical evidence of pregnancy or cumulative exposures associating with any DMP (False Discovery Rate, FDR, p-value < 0.05). However, surrounding greenness exposure was inversely associated with four DMRs (three in cord blood and one in child blood) annotated to ADAMTS2, KCNQ1DN, SLC6A12 and SDK1 genes. Results did not change substantially in the sensitivity analyses.
Overall, we found little evidence of the association between green space exposure and blood DNA methylation. Although we identified associations between surrounding greenness exposure with four DMRs, these findings require replication.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bariatric surgery (BS) is an effective intervention for severe obesity and associated comorbidities. Although several studies have addressed the clinical and metabolic effects of BS, an integrative ...analysis of the complex body response to surgery is still lacking. We conducted a longitudinal data study with 36 patients with severe obesity who were tested before, 6 and 12 months after restrictive BS for more than one hundred blood biomarkers, including clinical, oxidative stress and metabolic markers, peptide mediators and red blood cell membrane lipids. By using a synthetic data-driven modeling based on principal component and correlation analyses, we provided evidence that, besides the early, well-known glucose metabolism- and weight loss-associated beneficial effects of BS, a tardive, weight-independent increase of the hepatic cholesterol metabolism occurs that is associated with potentially detrimental inflammatory and metabolic effects. Canonical correlation analysis indicated that oxidative stress is the most predictive feature of the BS-induced changes of both glucose and lipids metabolism. Our results show the power of multi-level correlation analysis to uncover the network of biological pathways affected by BS. This approach highlighted potential health risks of restrictive BS that are disregarded with the current practice to use weight loss as surrogate of BS success.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Between 25% and 30% of children and adolescents experience sleep disorders. These disorders are complex phenotypes that are regulated by many genes, the environment, and gene-environment ...interactions. The objective of this study was to evaluate the contribution of genetic and environmental factors to sleep behaviors in early childhood and to contribute to the knowledge on appropriate therapeutic approaches, using a twin design.
Data on sleeping behavior were collected from 314 18-month-old twin pairs (127 monozygotic and 187 dizygotic)using a parent-rated questionnaire. We used structural equation modeling to estimate genetic and environmental variance components for different sleep behaviors (cosleeping, sleep duration, and night awakenings).
Shared environment explained almost all (98.3%) of the total variance in cosleeping. Sleep duration was substantially influenced by shared environmental factors (64.1% nocturnal sleep and 61.2% diurnal sleep), with a moderate contribution of additive genetic effects (30.8% and 36.3% for nocturnal and diurnal sleep, respectively). For nocturnal waking episodes, we found a shared environmental contribution of 63.2% and a heritability estimate of 35.3%.
Most sleep disturbances during early childhood are explained by common shared environmental factors, and behavioral interventions adopted by parents and focused on modifying sleep behavior could contribute to solving sleep disturbances in this age group. However, the influence of genetic factors should not be underestimated, and research in this area could clarify the physiologic architecture of sleeping and contribute to selecting appropriate personalized therapeutic approaches.
Psoriatic disease is a multifactorial inflammatory condition spanning from skin and nail psoriasis (Pso) to spine and joint involvement characterizing psoriatic arthritis (PsA). Monozygotic twins ...provide a model to investigate genetic, early life environmental exposure and stochastic influences to complex diseases, mainly mediated by epigenetics.
We performed a genome-wide DNA methylation study on whole blood of monozygotic twins from 7 pairs discordant for Pso/PsA using the Infinium Methylation EPIC array (Illumina). MeDiP-qPCR was used to confirm specific signals. Data were replicated in an independent cohort of seven patients with Pso/PsA and 3 healthy controls. Transcriptomic profiling was performed by RNAsequence on the same 7 monozygotic twin pairs.
We identified 2,564 differentially methylated positions between psoriatic disease and controls, corresponding to 1,703 genes, 59% within gene bodies. There were 19 regions with at least two DMPs within 1 kb of distance and significant within-pair Δ
-values (
< 0.005), among them SNX25, BRG1 and SMAD3 genes, all involved in TGF-β signaling pathway, were identified. Co-expression analyses on transcriptome data identified IL-6/JAK/STAT3 and TNF-α pathways as important signaling axes involved in the disease, and they also suggested an altered glucose metabolism in patients' immune cells, characteristic of pro-inflammatory T lymphocytes.
The study suggests the presence of an epigenetic signature in affected individuals, pointing to genes involved in immunological and inflammatory responses. This result is also supported by transcriptome data, that altogether suggest a higher activation state of the immune system, that could promote the disease status.
The Italian Twin Register has been in place for more than 10 years. Since its establishment, it has been focusing, on the one hand, on a continuous update of the existing information, and on the ...other hand, on new phenotypes and sample collection. Demographic data on about 140,000 twins have been updated using the municipality registries. The Italian Twin Register has been carrying out several new studies during the last few years. A birth cohort of twins, Multiple Births Cohort Study, has been started and the enrollment is ongoing. For this cohort, data on pregnancy and birth are collected, and periodical follow-ups are made. DNA is being collected for the twins and their parents. In the area of behavioral genetics, most efforts have been directed to psychological well being assessed with self-reported tools. Research on age-related traits continues with studies on arteriosclerosis development, early biomarkers in mild cognitive impairment, and the relation between lifestyle habits and mutagen sensitivity. The Italian Twin Register biobanking has grown in its size and in its know-how in terms of both technical issues and ethical procedures implementation. Furthermore, attitudes toward biobank-based research, together with willingness and motivation for donation, are being investigated. A valuable key resource for the Italian Twin Register is the possibility of linking twin data with disease registries. This approach has been yielding several important results, such as the recent study on the heritability of type 1 diabetes.
Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations.
Methods: Information on all ...malformed infants (1990–1996) with maternal first‐trimester drug exposure was collected by the International Clearinghouse for Birth Defects and Monitoring Systems (ICBDMS). Cases were defined as infants presenting with a specific malformation, and controls were defined as infants presenting with any other birth defect. Exposure was defined by the use of AEDs during the first trimester of pregnancy. The association of AEDs with malformations was then estimated by calculating the odds ratios with 95% confidence intervals and testing their homogeneity among registries.
Results: Among 8005 cases of malformations, 299 infants were exposed in utero to AEDs. Of those exposed to monotherapy, 65 were exposed to phenobarbital, 10 to methylphenobarbital, 80 to valproic acid, 46 to carbamazepine, 24 to phenytoin, and 16 to other AEDs. Associations were found for spina bifida with valproic acid. Infants exposed to phenobarbital and to methylphenobarbital showed an increased risk of oral clefts. Cardiac malformations were found to be associated with phenobarbital, methylphenobarbital, valproic acid, and carbamazepine. Hypospadias was associated with valproic acid. Porencephaly and other specified anomalies of brain, anomalies of face, coarctation of aorta, and limb reduction defects were found to be associated with valproic acid.
Conclusions: Using the MADRE system, we confirmed known teratogenic effects of AEDs. We also found increased risks for malformations that had never been reported associated with AEDs or for which the association was suggested by case reports.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A number of studies have provided evidence of a significant familial aggregation for both asthma and hay fever, and have reported a substantial comorbidity between the two conditions. However, far ...fewer, especially in Italy, have aimed at clarifying the origins of such comorbidity. The main aims of the present study were (a) to estimate heritability of asthma and hay fever, (b) to measure the association between asthma and hay fever at the individual level, and (c) to assess the extent to which genetic and environmental factors, shared by the two conditions, mediate this association. The twin method was used. The study sample was derived from the Italian Twin Registry, and included 392 twin pairs aged 8 to 17 years. Data collection was performed through parent self-administered questionnaire. Bivariate structural equation twin modeling was applied to asthma and hay fever. Genetic factors accounted for 92% and 78% of the variance in liability to asthma and hay fever, respectively, with the remaining contributions due to unique environmental influences. The within-individual association between asthma and hay fever was substantial. The genetic correlation between the two conditions was .58, whereas no evidence of overlapping unique environmental effects was found. In conclusion, this study showed a high heritability of asthma and hay fever in the Italian child and adolescent population. It also indicated that asthma and hay fever share, to a large extent, a common genetic background, and environmental factors are not relevant to explain the comorbidity.
Despite the actual availability of COVID-19 vaccines to combat the pandemic, many people are still vacillating in their decision to vaccinate. In this study, we considered the effect of two relevant ...contextual issues on vaccination intention: the number of people infected with COVID-19 is increasing, and the pace of vaccination is gaining speed. Specifically, we hypothesized that having already contracted SARS-CoV-2 (post-positive reluctance) could lead people to underestimate the importance of vaccination. Moreover, as the number of vaccinated people increases, more hesitant people could fall into the free-riding intention category, benefitting from the immunity provided by others' vaccinations. Vaccine hesitancy becomes more critical as the vaccination campaign proceeds: at one point, it will be inevitable to deal with hesitant people. This study is part of a WHO Regional Office for Europe project and involved a representative sample of 5006 Italians interviewed in January–February 2021. In case of post-positive reluctance, both young age and female gender increase vaccine hesitancy, while a high level of education reduces free-riding intention. Considering post-positive reluctance and free riding, a protective effect on hesitancy is associated with negative affective states, adherence to protective behaviors, trust in health information sources, and resilience. In contrast, increased vaccine hesitancy is associated with a high level of conspiracy-mindedness and trust in media information sources. Recognizing and studying the post-positive reluctance and the phenomenon of free-riding people can help us to become more efficient in combatting the virus.
•An Italian representative sample (N = 5006) answered a survey promoted by the WHO.•We investigated factors predicting vaccine hesitancy and vacillation.•We focused on post-positive reluctance (after people had tested positive for COVID-19).•We also focused on free-riding intention (counting on others getting vaccinated).•Trust in media information sources and conspiracy-mindedness drove vaccine hesitancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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