s-ICAM-1 and s-VCAM-1 in healthy men are strongly associated with traits of the metabolic syndrome, becoming evident in the postprandial response to a lipid-rich meal

<p>Abstract</p> <p>Background</p> <p>The importance of the postprandial state for the early stages of atherogenesis is increasingly acknowledged. We conducted assessment of association between postprandial triglycerides, insulin and glucose after ingestion of a standardized lipid-rich test meal, and soluble cellular adhesion molecules (sCAM) in young healthy subjects.</p> <p>Methods</p> <p>Metabolic parameters and sICAM-1, sVCAM-1 and E-selectin were measured before and hourly until 6 hours after ingestion of a lipid-rich meal in 30 healthy young men with fasting triglycerides <150 mg/dl and normal fasting glucose levels. Subjects were classified as either normal responders (NR) (postprandial triglyceride maxima < 260 mg/dl) or high responders (HR) (postprandial triglyceride maxima > 260 mg/dl). Levels of CAM were compared in HR and NR, and correlation with postprandial triglyceride, insulin and glucose response was assessed.</p> <p>Results</p> <p>Fasting sICAM-1 and sVCAM-1 levels were significantly higher in HR as compared to NR (p = 0.046, p = 0.03). For sE-selectin there was such a trend (p = 0.05). There was a strong positive and independent correlation between sICAM-1 and postprandial insulin maxima (r = 0.70, p < 0.001). sVCAM-1 showed significant correlation with postprandial triglycerides (AUC) (r = 0.37, p = 0.047). We found no correlation between sCAMs and fasting insulin or triglyceride concentrations.</p> <p>Conclusion</p> <p>This independent association of postprandial triglycerides with sICAM-1 may indicate a particular impact of postprandial lipid metabolism on endothelial reaction.</p

Efficacy assessment of SNP sets for genome-wide disease association studies

The power of a genome-wide disease association study depends critically upon the properties of the marker set used, particularly the number and physical spacing of markers, and the level of inter-marker association due to linkage disequilibrium. Extending our previously devised theoretical framework for the entropy-based selection of genetic markers, we have developed a local measure of the efficacy of a marker set, relative to including a maximally polymorphic single nucleotide polymorphism (SNP) at the map position of interest. Using this quantitative criterion, we evaluated five currently available SNP sets, namely Affymetrix 100K and 500K, and Illumina 100K, 300K and 550K in the CEU, YRI and JPT + CHB HapMap populations. At 50% relative efficacy, the commercial marker sets cover between 19 and 68% of the human genome, depending upon the population under study. An optimal technology-independent 500K marker set constructed from HapMap for Caucasians, in contrast, would achieve 73% coverage at the same relative efficacy

Role of NOD2/CARD15 in coronary heart disease

<p>Abstract</p> <p>Background:</p> <p>Bacterial DNA has been repeatedly detected in atheromatous lesions of coronary heart disease (CHD) patients. Phylogenetic signatures in the atheroma lesions that are similar to those of bacterial biofilms on human barrier organs, including the respiratory or gastrointestinal tract, raise the question of a defective barrier function in CHD. NOD2 plays a major role in defense against bacterial invasion. Genetic variation in the <it>CARD15 </it>gene, which encodes NOD2, was previously shown to result in a barrier defect that causes chronic inflammatory disorders (e.g. Crohn disease). In the present study, we investigated the possible involvement of NOD2/<it>CARD15 </it>in the pathology of CHD by <it>i) </it>analyzing the local expression of NOD2 in atherectomy versus healthy tissue (n = 5 each) using histochemical immunofluorescence and <it>ii) </it>by testing the three major functional <it>CARD15 </it>variants (R702W, G908R and 1007fs) for association with early-onset CHD in 900 German patients and 632 healthy controls.</p> <p>Results:</p> <p>In atherectomy tissue of CHD patients, NOD2 was detected in inflammatory cells at the luminal sides of the lesions. However, the allele and genotype frequencies of the three major <it>CARD15 </it>polymorphisms did not differ between CHD patients and controls.</p> <p>Conclusion:</p> <p>The NOD2 up-regulation in atheroma lesions indicates an involvement of this protein in the pathology of CHD. Although NOD2 could be important in local immune response mechanisms, none of the analyzed <it>CARD15 </it>variants seem to play a significant role in the etiology of CHD.</p

The impact of correlations between pigmentation phenotypes and underlying genotypes on genetic prediction of pigmentation traits

Predicting appearance phenotypes from genotypes is relevant for various areas of human genetic research and applications such as genetic epidemiology, human history, anthropology, and particularly in forensics. Many appearance phenotypes, and thus their underlying genotypes, are highly correlated, with pigmentation traits serving as primary examples. However, all available genetic prediction models, including those for pigmentation traits currently used in forensic DNA phenotyping, ignore phenotype correlations. Here, we investigated the impact of appearance phenotype correlations on genetic appearance prediction in the exemplary case of three pigmentation traits. We used data for categorical eye, hair and skin colour as well as 41 DNA markers utilized in the recently established HIrisPlex-S system from 762 individuals with complete phenotype and genotype information. Based on these data, we performed genetic prediction modelling of eye, hair and skin colour via three different strategies, namely the established approach of predicting phenotypes solely based on genotypes while not considering phenotype correlations, and two novel approaches that considered phenotype correlations, either incorporating truly observed correlated phenotypes or DNA-predicted correlated phenotypes in addition to the DNA predictors. We found that using truly observed correlated pigmentation phenotypes as additional predictors increased the DNA-based prediction accuracies for almost all eye, hair and skin colour categories, with the largest increase for intermediate eye colour, brown hair colour, dark to black skin colour, and particularly for dark skin colour. Outcomes of dedicated computer simulations suggest that this prediction accuracy increase is due to the additional genetic information that is implicitly provided by the truly observed correlated pigmentation phenotypes used, yet not covered by the DNA predictors applied. In contrast, considering DNA-predicted correlated pigmentation phenotypes as additional predictors did not improve the performance of the genetic prediction of eye, hair and skin colour, which was in line with the results from our computer simulations. Hence, in practical applications of DNA-based appearance prediction where no phenotype knowledge is available, such as in forensic DNA phenotyping, it is not advised to use DNA-predicted correlated phenotypes as predictors in addition to the DNA predictors. In the very least, this is not recommended for the pigmentation traits and the established pigmentation DNA predictors tested here

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.</p

CDKN2BAS is associated with periodontitis in different European populations and is activated by bacterial infection

Epidemiological studies have indicated a relationship between coronary heart disease (CHD) and periodontitis. Recently, CDKN2BAS was reported as a shared genetic risk factor of CHD and aggressive periodontitis (AgP), but the causative variant has remained unknown. To identify and validate risk variants in different European populations, we first explored 150 kb of the genetic region of CDKN2BAS including the adjacent genes CDKN2A and CDKN2B, covering 51 tagging single nucleotide polymorphisms (tagSNPs) in AgP and chronic periodontitis (CP) in individuals of Dutch origin (n=313). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1264). For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP before and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (OR 1.48, 95% CI 1.19 to 1.85; p=0.0004). We further showed in vivo gene expression of CDKN2BAS, CDKN2A, CDKN2B, and CDK4 in healthy and inflamed gingival epithelium (GE) and connective tissue (CT), and detected a significantly higher expression of CDKN2BAS in healthy CT compared to GE (p=0.004). After 24 h of stimulation with Porphyromonas gingivalis in Streptococcus gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed a 25-fold and fourfold increase of CDKN2BAS gene expression in HGFs (p=0.003) and GECs (p=0.004), respectively. Considering the global importance of CDKN2BAS in the disease risk of CHD, this observation supports the theory of inflammatory components in the disease physiology of CHD

Reassessment Of Lesion-Associated Gene And Variant Pathogenicity In Focal Human Epilepsies

Purpose: Increasing availability of surgically resected brain tissue from Focal Cortical Dysplasia and low-grade epilepsy-associated tumor patients fostered large-scale genetic examination. However, assessment of germline and somatic variant pathogenicity remains difficult. Methods: Here, we critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 12 disease-related genes and 88 neuropathology-associated missense variants. We (1) assessed evolutionary gene constraint using the pLI and missense z scores, (2) applied guidelines by the American College of Medical Genetics and Genomics (ACMG), and (3) predicted pathogenicity by using PolyPhen-2, CADD, and GERP. Results: Constraint analysis classified only seven out of 12 genes to be likely disease-associated, while 35 (40\%) of those 88 variants were classified as being variants of unknown significance (VUS) and 53 (60\%) as being likely pathogenic (LPII). Pathogenicity prediction yielded discrimination between neuropathology-associated variants (LPII and VUS) and rare variant scores obtained from individuals present in the Genome Aggregation Database (gnomAD). Conclusion: We conclude that several VUS are likely disease-associated and will be reclassified by future molecular evidence. In summary, interpretation of lesion-associated gene variants remains complex while the application of current ACMG guidelines including bioinformatic pathogenicity prediction will help improving interpretation and prediction

Pre-resonance Raman spectra of adriamycin

Pre-resonance Raman spectra have been obtained for aqueous solutions of adriamycin. All bands are attributable to the anthracycline chromophore and are vibrations coupled to the first (20,800 cm-1) electronic transition of the molecule. Both ring modes and vibrations of the carbonyl, hydroxy and methoxy substituents are observed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21699/1/0000090.pd

Testing the impact of trait prevalence priors in Bayesian-based genetic prediction modeling of human appearance traits

The prediction of appearance traits by use of solely genetic information has become an established approach and a number of statistical prediction models have already been developed for this purpose. However, given limited knowledge on appearance genetics, currently available models are incomplete and do not include all causal genetic variants as predictors. Therefore such prediction models may benefit from the inclusion of additional information that acts as a proxy for this unknown genetic background. Use of priors, possibly informed by trait category prevalence values in biogeographic ancestry groups, in a Bayesian framework may thus improve the prediction accuracy of previously predicted externally visible characteristics, but has not been investigated as of yet. In this study, we assessed the impact of using trait prevalence-informed priors on the prediction p