Genetic and Environmental Influences on Early Growth: The Generation R Study

Epidemiological studies have demonstrated an inverse relationship between birth weight and the risk of adult disease, such as type 2 diabetes (T2D) and cardiovascular disease. These fi ndings have led to the developmental origins of health and disease hypothesis or ‘DOHaD-hypothesis’. Initially, publications reporting these associations were received with some skepticism. Recently, however, these relationships have been found to be quite robust, though the eff ect size might not be as large as originally estimated. The main proposed causal pathway underlying the association between low birth weight and metabolic phenotype is a suboptimal fetal environment which leads to fetal undernutrition (Figure 1).4,5 This undernutrition subsequently causes developmental adaptations that permanently alter fetal growth, physiology and metabolism, also referred to as fetal programming.4 Though this programming might lead to an increased survival rate in early life, the developmental adaptations can have long-lasting eff ects on disease in adulthood

Risk factors and outcomes associated with first-trimester fetal growth restriction

Context: Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. Objective: To determine the risk factors and outcomes associated with firsttrimester growth restriction. Design, Setting, and Participants: Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of first-trimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, the Netherlands. Mothers were enrolled between 2001 and 2005. Main Outcome Measures: First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age <37 weeks), low birth weight (<2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. Results In the multivariate analysis, maternal age was positively associated with firsttrimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, -0.40 mm; 95% CI, -0.74 to -0.06 and -0.52 mm; 95% CI, -0.90 to -0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, -3.84 mm; 95% CI, -5.71 to -1.98). Compared with normal first-trimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in firsttrimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). Conclusions Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood

Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta [SE] -0.23 [0.03], P = 2.15 x 10(-19)). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: beta [SE] 0.17 [0.03], P = 5.76 x 10(-10); XXLVLDL cholesterol ester: beta [SE] 0.17 [0.03], P = 9.74 x 10(-10)), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 x 10(-8)). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-beta, Matsuda insulin sensitivity index, and HbA(1c) in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes.Functional Genomics of Systemic Disorder

Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers

Background: Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high-throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high-throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins.Objective: The aim of this study was to evaluate the viability of the aptamer-based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods.Methods: We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity-based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values.Results: SomaScan measurements exhibited overall poor agreement, particularly for D-dimer (average fit, 492.7 ng/mL; 95% PI, 110.0-1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0-4.7).Conclusion: Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome-wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies.Diabetes mellitus: pathophysiological changes and therap

Insulin VNTR and IGF-1 promoter region polymorphisms are not associated with body composition in early childhood: The generation R study

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood. Copyrigh

Association of mental health and negative life events with weight change in patients with overweight: a cohort study

Background: It is unclear to what extent mental health and negative life events (NLEs) contribute to weight change in patients with overweight. This study aimed to evaluate the association of anxiety, depression, NLEs and quality of life (QoL) with weight change over ten years in middle-aged individuals with overweight.Methods: Population-based cohort study of 2889 middle-aged men and women with a body mass index ≥27 kg/m2. Relative weight change over ten years was defined as weight loss (≤- 5 %), stable weight (between >- 5 % and Results: In 51 % participants weight was stable, 33 % participants lost weight and 17 % gained weight. Mild (odds ratio 1.36; 95 % confidence interval 1.05-1.75), and moderate to very severe depressive symptoms (1.43; 0.97-2.12) and four or more distant NLEs (1.35; 1.10-1.67) were associated with weight gain. Anxiety symptoms, the mental component summary of QoL were not associated with either weight gain or weight loss.Limitations: Due to the observational design residual confounding cannot be excluded.Conclusion: Our study suggests that depressive symptoms or having experienced distant NLEs are associated with weight gain over time in middle-aged individuals with overweight. These subgroups might benefit from proactive attention from their health care providers.Keywords: Body weight changes; Life change events; Longitudinal study; Mental health; Overweight.</p

Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts

Background and aims: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics.Methods and results: Cross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (beta (SE) = 0.064 (0.018) SD per 5 degrees C, p = 5.03e(-4)) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e(-05)) and leucine (0.111 (0.018) SD, p = 1.25e(-09)). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (-0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e(-6))). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB.Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V.Prevention, Population and Disease management (PrePoD)Public Health and primary car

The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity

Aims To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL).Methods To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (H-1-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON).Results We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 +/- 3.0% pre-exercise to 8.1 +/- 2.0% post exercise, p < 0.05) and CON (from 2.4 +/- 0.6% pre-exercise to 1.6 +/- 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by similar to 23% (p < 0.05).Conclusions The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels.Clinical epidemiolog

Association of measures of body fat with serum alpha-tocopherol and its metabolites in middle-aged individuals

Background and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary a-TOH metab-olites in middle-aged individuals. Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N Z 511, 53% women; mean [SD] age of 55 [6.1] years), serum a-TOH and a-TOH metab-olites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (a-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (a-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were as-sessed using magnetic resonance imaging. Using multivariable-adjusted linear regression ana -lyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary a-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum a-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized a-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Diabetes mellitus: pathophysiological changes and therap

Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index

Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (Metabolic health: pathophysiological trajectories and therap