Risk factors and cardio-metabolic outcomes associated with metabolic-associated fatty liver disease in childhood

Background Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as increased liver fat percentage, and is the most common chronic liver disease in children. Rather than NAFLD, Metabolic-Associated Fatty Liver Disease (MAFLD), defined as increased liver fat with presence of adverse cardio-metabolic measures, might have more clinical relevance in children. We assessed the prevalence, risk-factors and cardio-metabolic outcomes of MAFLD at school-age. Methods This cross-sectional analysis was embedded in an ongoing population-based prospective cohort study started in 2001, in the Netherlands. In 1910 children of 10 years, we measured liver fat fraction by magnetic resonance imaging (MRI), body mass index (BMI), blood pressure, and lipids, insulin, and glucose concentrations. Childhood lifestyle factors were obtained through questionnaires. MAFLD was defined as ≥2% liver fat in addition to excess adiposity (BMI or visceral adiposity), presence of metabolic risk (blood pressure, triglycerides and HDL-concentrations) or prediabetes (glucose). Findings Of all children, 49.6% had ≥2% liver fat, and 25.2% fulfilled the criteria of MAFLD. Only non-European descent was associated with increased odds of MAFLD at nominal significance (Odds Ratio 1.38, 95% Confidence Interval 1.04, 1.82). Compared to children with <2% liver fat, those with MAFLD had increased odds of cardio-metabolic-risk-factor clustering (Odds Ratio 7.65, 95% Confidence Interval 5.04, 11.62). Interpretation In this study, no NAFLD-associated childhood risk factors were associated with increased odds of childhood MAFLD, yet the findings suggest that ethnicity could be, despite mostly explained by socio-economic factors. Use of MAFLD criteria, rather than NAFLD, may identify children at risk for impaired cardio-metabolic health. Funding Erasmus University MC, the Netherlands Organisation for Health Research and Development, the Ministry of Health, Welfare, and Sport, and the European Research Council.The general design of the Generation R Study was made possible by financial support from the Erasmus University Medical Center, the Netherlands Organisation for Health Research and Development, and the Ministry of Health, Welfare, and Sport. The study was supported by the European Research Council (Consolidator Grant ERC-2014-CoG-648916), and the European Union’s Horizon 2020 research and innovation program (Grant Agreement No. 733206 LifeCycle). We gratefully acknowledge the contribution of the participating children, their mothers, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. We additionally would like to thank the staff of the data collection team and data-management team of Generation R for their work that resulted in the population data

Associations of maternal obesity and excessive weight gain during pregnancy with subcutaneous fat mass in infancy

Background: Not much is known about the associations of maternal obesity and excessive gestational weight gain with body fat in infancy. Objective: To examine the associations of maternal pre-pregnancy body mass index and gestational weight gain with infant subcutaneous fat. Methods: In a population-based prospective cohort study among 845 mothers and their infants, we obtained maternal pre-pregnancy body mass index and measured maternal weight during pregnancy. At 1.5, 6 and 24 months, we estimated infant total subcutaneous fat (sum of biceps, triceps, suprailiacal and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat). Results: Maternal body mass index was positively associated with higher infant body mass index from 6 months onwards. Maternal body mass index was not associated with infant subcutaneous fat measures at 1.5 or 6 months. A 1-standard deviation scores (SDS) higher maternal body mass index was associated with a 0.09 (95% Confidence Interval 0.01, 0.17) SDS higher infant total subcutaneous fat at 24 months, but not with central-to-total subcutaneous fat ratio. No associations were present for maternal total or period-specific gestational weight gain with infant fat. Conclusion: Maternal body mass index was positively associated with infant body mass index and total subcutaneous fat in late infancy. Maternal total and period-specific gestational weight gain were not associated with infant body fat mass measures.The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement n°289346. Susana Santos received a grant from the Portuguese Foundation for Science and Technology (SFRH/BD/81123/2011). Vincent Jaddoe received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361) and Consolidator Grant from the European research Council (ERC-2014-CoG-648916)

Subcutaneous fat mass in infancy and cardiovascular risk factors at school-age: The generation R study

OBJECTIVE:To examine the associations of infant subcutaneous fat with cardiovascular risk factors at school-age. METHODS:In a population-based prospective cohort study among 808 children, total subcutaneous fat (sum of biceps, triceps, suprailiacal, and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat) at 1.5 and 24 months were estimated. At 6 years, body mass index, blood pressure, cholesterol, triglycerides, and insulin levels were measured. RESULTS:Infant subcutaneous fat measures were not associated with childhood blood pressure, triglycerides, or insulin levels. A 1-standard-deviation score (SDS) higher total subcutaneous fat at 1.5 months was, independently of body mass index, associated with lower low-density lipoprotein (LDL)-cholesterol levels at 6 years. In contrast, a 1-SDS higher total subcutaneous fat at 24 months was associated with higher total-cholesterol [difference 0.13 (95% confidence interval (CI) 0.03, 0.23) SDS] and LDL-cholesterol levels [difference 0.12 (95% CI 0.02, 0.21) SDS] at 6 years. There were no associations of central-to-total subcutaneous fat ratio with childhood cholesterol levels. CONCLUSIONS:These results suggest that infant total subcutaneous fat is weakly associated with cholesterol levels at school-age. Further studies are needed to assess the long-term cardiometabolic consequences of infant body fat

Associations of Infant Subcutaneous Fat Mass with Total and Abdominal Fat Mass at School-Age: The Generation R Study

BACKGROUND:Skinfold thickness enables the measurement of overall and regional subcutaneous fatness in infancy and may be associated with total and abdominal body fat in later childhood. We examined the associations of subcutaneous fat in infancy with total and abdominal fat at school-age. METHODS:In a population-based prospective cohort study among 821 children, we calculated total subcutaneous fat (sum of biceps, triceps, suprailiacal, and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat) at 1.5 and 24 months. At 6 years, we measured fat mass index (total fat/height(3) ), central-to-total fat ratio (trunk fat/total fat), and android-to-gynoid fat ratio (android fat/gynoid fat) by dual-energy X-ray absorptiometry and preperitoneal fat mass area by abdominal ultrasound. RESULTS:Central-to-total subcutaneous fat ratio at 1.5 months was positively associated with fat mass index and central-to-total fat ratio at 6 years, whereas both total and central-to-total subcutaneous fat ratio at 24 months were positively associated with all childhood adiposity measures. A 1-standard-deviation scores higher total subcutaneous fat at 24 months was associated with an increased risk of childhood overweight (odds ratio 1.70, 95% confidence interval 1.36, 2.12). These associations were weaker than those for body mass index and stronger among girls than boys. CONCLUSIONS:Subcutaneous fat in infancy is positively associated with total and abdominal fat at school-age. Our results also suggest that skinfold thicknesses add little value to estimate later body fat, as compared with body mass index

Explaining Ethnic Differences in Late Antenatal Care Entry by Predisposing, Enabling and Need Factors in the Netherlands. The Generation R Study

Despite compulsory health insurance in Europe, ethnic differences in access to health care exist. The objective of this study is to investigate how ethnic differences between Dutch and non-Dutch women with respect to late entry into antenatal care provided by community midwifes can be explained by need, predisposing and enabling factors. Data were obtained from the Generation R Study. The Generation R Study is a multi-ethnic population-based prospective cohort study conducted in the city of Rotterdam. In total, 2,093 pregnant women with a Dutch, Moroccan, Turkish, Cape Verdean, Antillean, Surinamese Creole and Surinamese Hindustani background were included in this study. We examined whether ethnic differences in late antenatal care entry could be explained by need, predisposing and enabling factors. Subsequently, logistic regression analysis was used to assess the independent role of explanatory variables in the timing of antenatal care entry. The main outcome measure was late entry into antenatal care (gestational age at first visit after 14 weeks). With the exception of Surinamese-Hindustani women, the percentage of mothers entering antenatal care late was higher in all non-Dutch compared to Dutch mothers. We could explain differences between Turkish (OR = 0.95, CI: 0.57–1.58), Cape Verdean (OR = 1.65. CI: 0.96–2.82) and Dutch women. Other differences diminished but remained significant (Moroccan: OR = 1,74, CI: 1.07–2.85; Dutch Antillean OR 1.80, CI: 1.04–3.13). We found that non-Dutch mothers were more likely to enter antenatal care later than Dutch mothers. Because we are unable to explain fully the differences regarding Moroccan, Surinamese-Creole and Antillean women, future research should focus on differences between 1st and 2nd generation migrants, as well as on language barriers that may hinder access to adequate information about the Dutch obstetric system

When do myopia genes have their effect? Comparison of genetic risks between children and adults

Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged 25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10–25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated; and in adults 20 loci were associated. Association with GRS increased with age; β = 0.0016 per risk allele (P = 2 × 10–8) in <10 years, 0.0033 (P = 5 × 10–15) in 10- to 25-year-olds, and 0.0048 (P = 1 × 10–72) in adults. Genes with strongest effects (LAMA2, GJD2) had an early effect that increased with age. Our results provide insights on the age span during which myopia genes exert their effect. These insights form the basis for understanding the mechanisms underlying high and pathological myopia

Cardiovascular and metabolic influences of fetal smoke exposure

Many epidemiological studies showed associations of low birth weight with cardiovascular disease, type 2 diabetes and obesity. The associations seem to be consistent and stronger among subjects with a postnatal catch up growth. It has been suggested that developmental changes in response to adverse fetal exposures might lead to changes in the fetal anatomy and physiology. These adaptations may be beneficial for short term, but may lead to common diseases in adulthood. Maternal smoking during pregnancy is one of the most important adverse fetal exposures in Western countries, and is known to be associated with a 150–200 g lower birth weight. An accumulating body of evidence suggests that maternal smoking during pregnancy might be involved in pathways leading to both low birth weight and common diseases, including cardiovascular disease, type 2 diabetes and obesity, in adulthood. In this review, we discuss epidemiological studies focused on the associations of maternal smoking with fetal growth and development and cardiovascular and metabolic disease in later life. We also discuss potential biological mechanisms, and challenges for future epidemiological studies

Does involvement in a cohort study improve health and affect health inequalities? A natural experiment

Abstract Background Evidence suggests that the process of taking part in health research can improve participants\u2019 health, independent of any intended intervention. However, no research has yet explored whether these effects differ across socioeconomic groups. If the effect of mere participation in health research also has a social gradient this could increase health inequalities and bias research results. This study used the Born in Bradford family cohort (BIB) to explore whether simply taking part in BIB had improved participants\u2019 health and, if so, whether this effect was mediated by socioeconomic status. Methods Survey data on self-reported health behaviours were collected between 2007 and 2010 as part of BIB. These were augmented by clinical data on birth weight. Pregnant women on their second pregnancy, joining BIB for the first time formed the control group. Their health was compared to women on their second pregnancy who had both pregnancies within the study, who formed the exposed group. In order to limit the inherent bias in a non-randomised study, propensity score analysis was used, matching on age, ethnicity, education and date of questionnaire. The results were then compared according to mothers' education. Results Of six outcomes tested, only alcohol consumption showed a statistically significant reduction with exposure to BIB (OR: 0.35, 95% CIs 0.13, 0.92). Although effect estimates were larger for women with higher education compared to lower education, these effects were not statistically significant. Conclusions Despite one significant finding, these results overall are insufficient to conclude that simply taking part in BIB affected participants\u2019 health. We recommend that socioeconomic status is considered in future studies testing effects of research participation, and that randomised studies with larger sample sizes are conducted

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.Acknowledgements We thank all cohort members and researchers who participated in the study. Cohort-specific acknowledgments can be found in Supplementary material online, Text S2. Data used in this study are available to bone fide researchers upon request to each cohort. Details of how to access the data are provided in Supplementary material online, Text S2. Please contact Professor Deborah Lawlor ([email protected]) and Dr Ahmed Elhakeem ([email protected]) if you have relevant data and would like to join the ART-Health Cohort Collaboration and contribute to future collaborations

A genome-wide association study for corneal astigmatism: The CREAM Consortium

Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis was performed of genome-wide association studies (GWAS) of corneal astigmatism undertaken for 14 European ancestry (N = 22,250) and 8 Asian ancestry (N = 9,120) cohorts by the CREAM Consortium. Cases were defined as having >0.75 D of corneal astigmatism. For the meta-analysed results of European ancestry cohorts, subsequent gene-based and gene-set analyses were performed using VEGAS2 and MAGMA software. Additionally, estimates of SNP-based heritability for corneal and refractive astigmatism and spherical equivalent were calculated for Europeans using LD score regression. Results: Meta-analysis of all cohorts identified a genome-wide significant locus near the gene PDGFRA (platelet derived growth factor receptor alpha): top SNP: rs7673984, odds ratio = 1.12 (95% CI: 1.08-1.16), P = 5.55 x 10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified 3 novel candidate genes for corneal astigmatism in Europeans: CLDN7 (claudin-7), ACP2 (acid phosphatase 2, lysosomal) and TNFAIP8L3 (TNF alpha induced protein 8 like 3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified 3 novel candidate genes CLDN7, ACP2 and TNFAIP8L3 that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors to the development of astigmatism