DNA methylation patterns in cord blood DNA and body size in childhood.

Background: Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood.

Principal Findings: A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood.

Identification of imine or enamine drug metabolites using online hydrogen/deuterium exchange and exact mass measurements.

Rationale: Drug metabolites that have imine or enamine partial structures cause extra mass-to-charge (m/z) increases in online hydrogen/deuterium exchange (HDX) in addition to hydroxyl or amine protons. Online HDX and exact mass measurement were used herein to characterize this extra increase property, and to further confirm proposed metabolite structures.

Methods: Metabolites of two proprietary compounds as well as two commercially available compounds were analyzed using aqueous and HDX liquid chromatography coupled with an LTQ-Orbitrap.

Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position.

Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features.

Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies.

Postnatal growth and DNA methylation are associated with differential gene expression of the TACSTD2 gene and childhood fat mass.

Rapid postnatal growth is associated with increased risk of childhood adiposity. The aim of this study was to establish whether this pathway is mediated by altered DNA methylation and gene expression. Two distinct cohorts, one preterm (n=121) and one term born (n=6,990), were studied.

Regulatory T cells stimulate B7-H1 expression in myeloid-derived suppressor cells in ret melanomas.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells, and they promote an immunosuppressive environment in tumor-bearing hosts. To characterize MDSCs in melanoma, we examined the expression of inhibitory B7 molecules by CD11b(+)Gr1(+) cells isolated from mice with transplantable ret tumors. B7 molecules were expressed on CD11b(+)Gr1(+) cells, which also expressed CD124 and inducible nitric oxide synthase, thus verifying their relation to MDSCs.

New gene functions in megakaryopoiesis and platelet formation.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment.

Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis.

A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis.

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.

Requirement of alveolar bone formation for eruption of rat molars.

Tooth eruption is a localized event that requires a dental follicle (DF) to regulate the resorption of alveolar bone to form an eruption pathway. During the intra-osseous phase of eruption, the tooth moves through this pathway. The mechanism or motive force that propels the tooth through this pathway is controversial but many studies have shown that alveolar bone growth at the base of the crypt occurs during eruption.

Adult height variants affect birth length and growth rate in children.

Previous studies identified 180 single nucleotide polymorphisms (SNPs) associated with adult height, explaining ∼10% of the variance. The age at which these begin to affect growth is unclear. We modelled the effect of these SNPs on birth length and childhood growth.

Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3.

Introduction: Tumors may shift the phenotype and function of dendritic cells (DC) toward the induction of tolerance. In the status of full maturity, DC express a multitude of T cell costimulatory molecules enabling them to induce immune reactions, whereas nonactivated resident DC lack these T cell stimulating capacities. Therefore, we investigated the changes in DC phenotype and expression of B7-H molecules induced by non-small cell lung cancer (NSCLC).

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index.

Background: Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers.

ACTN3 genotype, athletic status, and life course physical capability: meta-analysis of the published literature and findings from nine studies.

The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes.

Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.

Objective: To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents.

Research Design And Methods: A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose.

Regulatory T cells from IL-10-deficient mice fail to suppress contact hypersensitivity reactions due to lack of adenosine production.

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) produce immunosuppressive adenosine by degradation of adenosine triphosphate (ATP) by the ectonucleotidases CD39 and CD73. In this sequence of events, ATP is not only the substrate for generation of adenosine but it also activates the immunosuppressive functions of Tregs. To compare the effects of ATP on IL-10-deficient (IL-10(-/-)) Tregs with wild-type (wt) Tregs, we incubated both types of Tregs with ATP and assessed their phenotype and function.

Vitamin d status is not associated with outcomes of experimentally-induced muscle weakness and pain in young, healthy volunteers.

Vitamin D receptors have been identified in skeletal muscle; and symptoms of vitamin D deficiency include muscle weakness and pain. Moreover, increased serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with improved muscle function. To further clarify the importance of vitamin D to muscle, we examined the association between vitamin D status and exercise-induced muscle pain and weakness in healthy people.

Electroporation to deliver plasmid DNA into rat dental tissues.

Background: Delivery of DNA into the target tissues is an important technique in gene function studies and gene therapy. Surgical treatment of tooth eruption disorders, such as impacted third molars, is a major healthcare cost. Because the dental follicle (DF) is essential for regulating tooth eruption, establishment of local gene transfer protocols is needed to determine the effect of various genes on eruption and to develop gene therapy approaches for inducing the eruption of impacted molars.

Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone.

Previous genome-wide association (GWA) studies have identified SNPs associated with areal bone mineral density (aBMD). However, this measure is influenced by several different skeletal parameters, such as periosteal expansion, cortical bone mineral density (BMD(C)) cortical thickness, trabecular number, and trabecular thickness, which may be under distinct biological and genetic control. We have carried out a GWA and replication study of BMD(C), as measured by peripheral quantitative computed tomography (pQCT), a more homogenous and valid measure of actual volumetric bone density.

Association of COMT Val(108/158)Met genotype and cigarette smoking in pregnant women.

Introduction: Smoking behaviors, including heaviness of smoking and smoking cessation, are known to be under a degree of genetic influence. The enzyme catechol O-methyltransferase (COMT) is of relevance in studies of smoking behavior and smoking cessation due to its presence in dopaminergic brain regions. While the COMT gene is therefore one of the more promising candidate genes for smoking behavior, some inconsistencies have begun to emerge.

Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.

PCSK6 is associated with handedness in individuals with dyslexia.

Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)].

Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma.

Background: Prenatal and infant acetaminophen exposure has been associated with an increased risk of childhood asthma phenotypes. Demonstration of biologically plausible interactions between these exposures and maternal and child antioxidant gene polymorphisms would strengthen causal inference.

Objective: To explore potential interactions between prenatal and infant acetaminophen exposure and antioxidant genotypes on childhood asthma.

Maternal Nrf2 and gluthathione-S-transferase polymorphisms do not modify associations of prenatal tobacco smoke exposure with asthma and lung function in school-aged children.

Background: Maternal smoking during pregnancy has detrimental effects on the respiratory health of infants and children. Polymorphisms of antioxidant genes including glutathione-S-transferases (GSTs) have been proposed as candidates for asthma and reduced lung function in children.

Methods: Women enrolled in the Avon Longitudinal Study of Parents and Children reported smoking habits during pregnancy.

Association between a high-risk autism locus on 5p14 and social communication spectrum phenotypes in the general population.

Objective: Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.