Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa

<p>Abstract</p> <p>Background</p> <p>Several lines of evidence indicate that the central cannabinoid receptor 1 (CNR1) as well as the major endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA) and monoglyceride lipase (MGLL) are implicated in mediating the orexigenic effects of cannabinoids. The aim of this study was to analyse whether nucleotide sequence variations in the <it>CNR1</it>, <it>FAAH</it>, <it>NAAA </it>and <it>MGLL </it>genes are associated with anorexia nervosa (AN).</p> <p>Methods</p> <p>We analysed the association of a previously described (AAT)n repeat in the 3' flanking region of CNR1 as well as a total of 15 single nucleotide polymorphisms (SNPs) representative of regions with restricted haplotype diversity in <it>CNR1</it>, <it>FAAH</it>, <it>NAAA </it>or <it>MGLL </it>in up to 91 German AN trios (patient with AN and both biological parents) using the transmission-disequilibrium-test (TDT). One SNP was additionally analysed in an independent case-control study comprising 113 patients with AN and 178 normal weight controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, ARMS-PCR or using 3730xl capillary sequencers.</p> <p>Results</p> <p>The TDT revealed no evidence for association for any of the SNPs or the (AAT)n repeat with AN (all two-sided uncorrected p-values > 0.05). The lowest p-value of 0.11 was detected for the A-allele of the <it>CNR1 </it>SNP rs1049353 for which the transmission rate was 59% (95% confidence interval 47%...70%). Further genotyping of rs1049353 in 113 additional independent patients with AN and 178 normal weight controls could not substantiate the initial trend for association (p = 1.00).</p> <p>Conclusion</p> <p>As we found no evidence for an association of genetic variation in <it>CNR1</it>, <it>FAAH, NAAA and MGLL </it>with AN, we conclude that genetic variations in these genes do not play a major role in the etiology of AN in our study groups.</p

Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants

Background. Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. Methodology/Principal Findings. a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency $10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13610 27, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95 % confidence interval (CI) 1.22–2.27; OR TT 2.76, 95 % CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p,0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium

Технические особенности эксплуатации магистральных нефтепроводов в условиях Крайнего Севера

Объект исследования – магистральные нефтепроводы, расположенные в условиях Крайнего Севера. Целью работы является исследование особенностей эксплуатации и разработка рекомендаций для обеспечения надежности магистральных нефтепроводов в условиях Крайнего СевераThe object of the research is the main oil pipelines located in the Far North. The aim of the work is to study the features of operation and development of recommendations to ensure the reliability of the maintec main oil pipelines in the Far North

The Association of a SNP Upstream of INSIG2 with Body Mass Index is Reproduced in Several but Not All Cohorts

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples

Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent control of Dorsal

Transcriptional control of the Drosophila terminal gap gene huckebein (hkb) depends on Torso (Tor) receptor tyrosine kinase (RTK) signaling and the Rel/NFB homolog Dorsal (Dl) . Dl acts as an intrinsic transcriptional activator in the ventral region of the embryo, but under certain conditions, such as when it is associated with the non-DNA-binding co-repressor Groucho (Gro), it is converted into a repressor . Gro is recruited to the enhancer element in the vicinity of Dl by sequence-specific transcription factors such as Dead Ringer (Dri) . We examined the interplay between Dl, Gro and Dri on the hkb enhancer and show that when acting over a distance, Gro abolishes rather than converts Dl activator function. Reducing the distance between Dl- and Dri-binding sites, however, switches Dl into a Gro-dependent repressor that overrides activation of transcription. Both of the distance-dependent regulatory options of Gro - quenching and silencing of transcription- are inhibited by RTK signaling. These data describe a newly identified mode of function for Gro when acting in concert with Dl. RTK signaling provides a way of modulating Dl function by interfering either with Gro activity or with Dri-dependent recruitment of Gro to the enhancer.Häder T, Wainwright D, Shandala T, Saint R, Taubert H, Brönner G and Jäckle H

Control of triglyceride storage by a WD40/TPR-domain protein

Obesity is a metabolic disorder related to improper control of energy uptake and expenditure, which results in excessive accumulation of body fat. Initial insights into the genetic pathways that regulate energy metabolism have been provided by a discrete number of obesity-related genes that have been identified in mammals. Here, we report the identification of the adipose (adp) gene, the mutation of which causes obesity in Drosophila. Loss of adp activity promotes increased fat storage, which extends the lifespan of mutant flies under starvation conditions. By contrast, adp gain-of-function causes a specific reduction of the fat body in Drosophila. adp encodes an evolutionarily conserved WD40/tetratricopeptide-repeat-domain protein that is likely to represent an intermediate in a novel signalling pathway

Expression Patterns of Genes that Cause a Gain-of-Function Muscle Phenotype

<p>Lateral views of embryos at stage 11 (M), stage 13 (A, C, E, G, I, K, and N), and stage 16 (B, D, F, H, J, and L) that were stained with transcript-specific anti-sense RNA probes or with anti-Toll antibodies (A and B). Note the expression of Toll (A and B) in segment border cells, <i>sdc</i> (LD08230) (C and D) in trachea, segment border cells, and the differentiated apodemes, CG3563 (LD15689) (E and F) in the apodeme precusor cells at the segment border, CG13913 (RE53394) (G and H) and CG5008/<i>gnbp3</i> (SD21560) (I and J) in a subset of apodeme precursors and cells of the epidermis, CG14713/14714 transcripts (AT17253) (K and L) in the dorsal and ventral epidermis around the segment border, and <i>pxb</i> (SD26190) (M and N) in intrasegmental epidermal stripes.</p

Muscle Pattern Defects in <i>esg</i> and <i>sdc</i> Mutants

<p>Muscle pattern of three segments of <i>oreR</i> (A, D, and G), <i>esg ^L2</i> (B and H), and <i>sdc ²³</i> mutant embryos (C, E, F, and I) after staining with anti-MHC antibodies or using a <i>delilah</i> transcript-specific anti-sense RNA probe (G–H). Lateral (A–C and G–I) and ventral views (D–F) of embryos at stage 14 (E) and stage 16 (A–D and F–I). <i>esg</i> mutant embryos show variable muscle pattern defects with muscles absent ([B], arrowheads). In <i>sdc</i> mutant embryos few muscles cross the ventral midline in a position dorsal to the central nervous system ([E], arrowheads), and they show disruptions of the pattern in the ventral region ([C], arrowheads). The typical “finger-type pattern” of the ventral muscles of wild-type embryos (D) is unordered in <i>sdc ²³</i> mutant embryos, with ventral muscles aligning in parallel with the anterio-posterior axis, ignoring the segment border attachment ([F], arrowheads). Also shown is the pattern of epidermal muscle attachment sites (<i>delilah</i> marker gene expression) in wild-type (G), <i>esg</i> (H), and <i>sdc</i> (I) mutant embryos. Note that the pattern is unchanged in the mutants.</p

Schematic Representation of the Classification of the 66 Identified Candidate Genes into Functional Groups

<p>The affiliation of the genes products is indicated by the color and the size of the fragments represents the quantitative distribution. cytsk., cytoskeleton; nucl. acid bdg., nucleic acid binding; prot. mod. + degrade., protein modification or degradation; secr. + membrane assoc., secreted or membrane-associated factors; transp. + carrier, transporter or carrier; unknown fct., unknown function.</p