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

Macrophage migration inhibitory factor, infection, the brain, and corticosteroids

Bacterial meningitis is a complex disorder in which injury is caused, in part, by the causative organism and, in part, by the host's own inflammatory response. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and a neuro-endocrine mediator that might play a role in pneumococcal meningitis. Here, we discuss the role of MIF in infection, the brain, and corticosteroids and conclude that experimental meningitis studies have to determine whether MIF is a potential target for adjunctive therapy in pneumococcal meningitis

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

A tangled start:The link between childhood maltreatment, psychopathology, and relationships in adulthood

Background: Adults with a history of childhood maltreatment are more likely to experience distrust, feel distant from others, and develop an insecure attachment style which may also affect relationship quality. Furthermore, childhood maltreatment has been linked to several mental health problems; including, depression, anxiety, and alcohol dependance severity, that are also known to relationship quality. Objective: The current study was designed to investigate to what extent childhood maltreatment is associated with adult insecure attachment and intimate relationships and whether this association is mediated by psychopathology. Participants and Method: In a study comprised of 2035 adults aged 18-65, we investigated whether childhood maltreatment was associated with insecure adult attachment styles and the quality of intimate relationships and whether this was mediated by depression, anxiety, and alcohol dependence severity (based on repeated assessments of the Inventory of Depressive Symptomatology-Self Report, Beck Anxiety Index, and Alcohol Use Disorders Identification Test respectively). Results: The path model showed an acceptable fit, RMSEA = 0.05, and suggested full mediation of the association of childhood maltreatment with quality of intimate relationships by depression severity and a) anxious attachment (13 = -4.0 * 10-2; 95% CI = -5.5 * 10-2, -2.7 * 10-2) and b) avoidant attachment (13 = -7.2 * 10-2; 95% CI = -9.6 * 10-2, -4.9 * 10-2). Anxiety and alcohol dependence severity were not significant mediators. Conclusions: Childhood maltreatment is associated with a lower quality of intimate relationships, which is fully mediated by depression severity and insecure attachment styles.Prevention, Population and Disease management (PrePoD)Public Health and primary car

Fetal and infant growth and the risk of obesity during early childhood: the Generation R Study.

OBJECTIVE: To examine whether infant growth rates are influenced by fetal growth characteristics and are associated with the risks of overweight and obesity in early childhood. DESIGN: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward. METHODS: Fetal growth characteristics (femur length (FL) and estimated fetal weight (EFW)) were assessed in the second and third trimesters and at birth (length and weight). Infant peak weight velocity (PWV), peak height velocity (PHV), and body mass index at adiposity peak (BMIAP) were derived for 6267 infants with multiple height and weight measurements. RESULTS: EFW measured during the second trimester was positively associated with PWV and BMIAP during infancy. Subjects with a smaller weight gain between the third trimester and birth had a higher PWV. FL measured during the second trimester was positively associated with PHV. Gradual length gain between the second and third trimesters and between the third trimester and birth were associated with higher PHV. Compared with infants in the lowest quintile, the infants in the highest quintile of PWV had strongly increased risks of overweight/obesity at the age of 4 years (odds ratio (95% confidence interval): 15.01 (9.63, 23.38)). CONCLUSION: Fetal growth characteristics strongly influence infant growth rates. A higher PWV, which generally occurs in the first month after birth, was associated with an increased risk of overweight and obesity at 4 years of age. Longer follow-up studies are necessary to determine how fetal and infant growth patterns affect the risk of disease in later life

Endothelial cells present antigens in vivo

BACKGROUND: Immune recognition of vascular endothelial cells (EC) has been implicated in allograft rejection, protection against pathogens, and lymphocyte recruitment. However, EC pervade nearly all tissues and predominate in none, complicating any direct test of immune recognition. Here, we examined antigen presentation by EC in vivo by testing immune responses against E. coli β-galactosidase (β-gal) in two lines of transgenic mice that express β-gal exclusively in their EC. TIE2-lacZ mice express β-gal in all EC and VWF-lacZ mice express β-gal in heart and brain microvascular EC. RESULTS: Transgenic and congenic wild type FVB mice immunized with β-gal expression vector DNA or β-gal protein generated high titer, high affinity antisera containing comparable levels of antigen-specific IgG1 and IgG2a isotypes, suggesting equivalent activation of T helper cell subsets. The immunized transgenic mice remained healthy, their EC continued to express β-gal, and their blood vessels showed no histological abnormalities. In response to β-gal in vitro, CD4(+ )and CD8(+ )T cells from immunized transgenic and FVB mice proliferated, expressed CD25, and secreted IFN-γ. Infection with recombinant vaccinia virus encoding β-gal raised equivalent responses in transgenic and FVB mice. Hearts transplanted from transgenic mice into FVB mice continued to beat and the graft EC continued to express β-gal. These results suggested immunological ignorance of the transgene encoded EC protein. However, skin transplanted from TIE2-lacZ onto FVB mice lost β-gal(+ )EC and the hosts developed β-gal-specific antisera, demonstrating activation of host immune effector mechanisms. In contrast, skin grafted from TIE2-lacZ onto VWF-lacZ mice retained β-gal(+ )EC and no antisera developed, suggesting a tolerant host immune system. CONCLUSION: Resting, β-gal(+ )EC in transgenic mice tolerize specific lymphocytes that would otherwise respond against β-gal expressed by EC within transplanted skin. We conclude that EC effectively present intracellular "self" proteins to the immune system. However, antigen presentation by EC does not delete or anergize a large population of specific lymphocytes that respond to the same protein following conventional immunization with protein or expression vector DNA. These results clearly demonstrate striking context sensitivity in the immune recognition of EC, a subtlety that must be better understood in order to treat immune diseases and complications involving the vasculature

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

Breast-Feeding Modifies the Association of PPARγ2 Polymorphism Pro12Ala With Growth in Early Life: The Generation R Study

OBJECTIVE-We examined whether the PPARyγ2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. RESEARCH DESIGN AND METHODS-This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARy2 was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. RESULTS-Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction nths, PPARy2 Pro12Ala was not associated with growth rate. When breast-feeding duration was <2 months or 2-4 months, growth rate was higher in Ala12Ala than Pro12Pro carriers (differences 9.80 g/week [3.97-15.63] and 6.32 g/week [-1.04 to 13.68], respectively). CONCLUSIONS-The PPAR7gamma;2 Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life

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