Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Domains of disgust sensitivity: revisited factor structure of the questionnaire for the assessment of disgust sensitivity (QADS) in a cross-sectional, representative german survey

<p>Abstract</p> <p>Background</p> <p>Disgust sensitivity is defined as a predisposition to experiencing disgust, which can be measured on the basis of the Disgust Scale and its German version, the Questionnaire for the Assessment of Disgust Sensitivity (QADS). In various studies, different factor structures were reported for either instrument. The differences may most likely be due to the selected factor analysis estimation methods and the small non-representative samples. Consequently, the aims of this study were to explore and confirm a theory-driven and statistically coherent QADS factor structure in a large representative sample and to present its standard values.</p> <p>Methods</p> <p>The QADS was answered by N = 2473 healthy subjects. The respective households and participants were selected using the random-route sampling method. Afterwards, the collected sample was compared to the information from the Federal Statistical Office to ensure that it was representative for the German residential population. With these data, an exploratory Promax-rotated Principal Axis Factor Analysis as well as comparative confirmatory factor analyses with robust Maximum Likelihood estimations were computed. Any possible socio-demographic influences were quantified as effect sizes.</p> <p>Results</p> <p>The data-driven and theoretically sound solution with the three highly interrelated factors Animal Reminder Disgust, Core Disgust, and Contamination Disgust led to a moderate model fit. All QADS scales had very good reliabilities (Cronbach's alpha) from .90 to .95. There were no age-differences found among the participants, however, the female participants showed remarkably higher disgust ratings.</p> <p>Conclusions</p> <p>Based on the representative sample, the QADS factor structure was revised. Gender-specific standard percentages permit a population-based assessment of individual disgust sensitivity. The differences of the original QADS, the new solution, and the Disgust Scale - Revised will be discussed.</p

Genetic Factors Influence the Clustering of Depression among Individuals with Lower Socioeconomic Status

Objective: To investigate the extent to which shared genetic factors can explain the clustering of depression among individuals with lower socioeconomic status, and to examine if neuroticism or intelligence are involved in these pathways. Methods: In total 2,383 participants (1,028 men and 1,355 women) of the Erasmus Rucphen Family Study were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADSD). Socioeconomic status was assessed as the highest level of education obtained. The role of shared genetic factors was quantified by estimating genetic correlations (rG) between symptoms of depression and education level, with and without adjustment for premorbid intelligence and neuroticism scores. Results: Higher level of education was associated with lower depression scores (partial correlation coefficient 20.09 for CESD and 20.17 for HADS-D). Significant genetic correlations were found between education and bo

Problems and needs for improving primary care of osteoarthritis patients: the views of patients, general practitioners and practice nurses

BACKGROUND: Osteoarthritis (OA) is highly prevalent and has substantial impact on quality of life as well as on healthcare costs. The general practitioner (GP) often is the first care provider for patients with this chronic disease. The aim of this study was to identify health care needs of patients with OA and to reveal possible obstacles for improvements in primary care management of OA patients. METHODS: We performed semi-structured interviews with a stratified sample of 20 patients, 20 GPs and 20 practice nurses. RESULTS: Diagnosing OA posed no major problem, but during the course of OA, GPs found it difficult to distinguish between complaints resulting from the affection of the joints and complaints related to a concomitant depression. Patients felt to be well informed about the degenerative nature of the disease and possible side effects of medications, but they lacked information on individual consequences of the disease. Therefore, the most important concerns of many patients were pain and fear of disability which they felt to be addressed by GPs only marginally. Regarding pain treatment, physicians and patients had an ambivalent attitude towards NSAIDs and opiates. Therefore, pain treatment was not performed according to prevailing guidelines. GPs felt frustrated about the impact of counselling regarding life style changes but on the other hand admitted to have no systematic approach to it. Patients stated to be aware of the impact of life style on OA but lacked detailed information e.g. on how to exercise. Several suggestions were made concerning improvement. CONCLUSION: GPs should focus more on disability and pain and on giving information about treatment since these topics are inadequately addressed. Advanced approaches are needed to increase GPs impact on patients' life style. Being aware of the problem of labelling patients as chronically ill, a more proactive, patient-centred care is needed

Age-Dependent TLR3 Expression of the Intestinal Epithelium Contributes to Rotavirus Susceptibility

Rotavirus is a major cause of diarrhea worldwide and exhibits a pronounced small intestinal epithelial cell (IEC) tropism. Both human infants and neonatal mice are highly susceptible, whereas adult individuals remain asymptomatic and shed only low numbers of viral particles. Here we investigated age-dependent mechanisms of the intestinal epithelial innate immune response to rotavirus infection in an oral mouse infection model. Expression of the innate immune receptor for viral dsRNA, Toll-like receptor (Tlr) 3 was low in the epithelium of suckling mice but strongly increased during the postnatal period inversely correlating with rotavirus susceptibility, viral shedding and histological damage. Adult mice deficient in Tlr3 (Tlr3−/−) or the adaptor molecule Trif (TrifLps2/Lps2) exerted significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild-type animals. In contrast, neonatal mice deficient in Tlr3 or Trif did not display impaired cell stimulation or enhanced rotavirus susceptibility. Using chimeric mice, a major contribution of the non-hematopoietic cell compartment in the Trif-mediated antiviral host response was detected in adult animals. Finally, a significant age-dependent increase of TLR3 expression was also detected in human small intestinal biopsies. Thus, upregulation of epithelial TLR3 expression during infancy might contribute to the age-dependent susceptibility to rotavirus infection

Semi-supervised prediction of protein subcellular localization using abstraction augmented Markov models

<p>Abstract</p> <p>Background</p> <p>Determination of protein subcellular localization plays an important role in understanding protein function. Knowledge of the subcellular localization is also essential for genome annotation and drug discovery. Supervised machine learning methods for predicting the localization of a protein in a cell rely on the availability of large amounts of labeled data. However, because of the high cost and effort involved in labeling the data, the amount of labeled data is quite small compared to the amount of unlabeled data. Hence, there is a growing interest in developing <it>semi-supervised methods</it> for predicting protein subcellular localization from large amounts of unlabeled data together with small amounts of labeled data.</p> <p>Results</p> <p>In this paper, we present an Abstraction Augmented Markov Model (AAMM) based approach to semi-supervised protein subcellular localization prediction problem. We investigate the effectiveness of AAMMs in exploiting <it>unlabeled</it> data. We compare semi-supervised AAMMs with: (i) Markov models (MMs) (which do not take advantage of unlabeled data); (ii) an expectation maximization (EM); and (iii) a co-training based approaches to semi-supervised training of MMs (that make use of unlabeled data).</p> <p>Conclusions</p> <p>The results of our experiments on three protein subcellular localization data sets show that semi-supervised AAMMs: (i) can effectively exploit unlabeled data; (ii) are more accurate than both the MMs and the EM based semi-supervised MMs; and (iii) are comparable in performance, and in some cases outperform, the co-training based semi-supervised MMs.</p

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study

The therapeutic effect of clinical trials: understanding placebo response rates in clinical trials – A secondary analysis

BACKGROUND AND PURPOSE: Placebo response rates in clinical trials vary considerably and are observed frequently. For new drugs it can be difficult to prove effectiveness superior to placebo. It is unclear what contributes to improvement in the placebo groups. We wanted to clarify, what elements of clinical trials determine placebo variability. METHODS: We analysed a representative sample of 141 published long-term trials (randomized, double-blind, placebo-controlled; duration > 12 weeks) to find out what study characteristics predict placebo response rates in various diseases. Correlational and regression analyses with study characteristics and placebo response rates were carried out. RESULTS: We found a high and significant correlation between placebo and treatment response rate across diseases (r = .78; p < .001). A multiple regression model explained 79% of the variance in placebo variability (F = 59.7; p < 0.0001). Significant predictors are, among others, the duration of the study (beta = .31), the quality of the study (beta = .18), the fact whether a study is a prevention trial (beta = .44), whether dropouts have been documented (beta = -.20), or whether additional treatments have been documented (beta = -.17). Healing rates with placebo are lower in the following diagnoses; neoplasms (beta = -.21), nervous diseases (beta = -.10), substance abuse (beta = -.14). Without prevention trials the amount of variance explained is 42%. CONCLUSION: Medication response rates and placebo response rates in clinical trials are highly correlated. Trial characteristics can explain some portion of the variance in placebo healing rates in RCTs. Placebo response in trials is only partially due to methodological artefacts and only partially dependent on the diagnoses treated

Contributions to the phylogeny of Ixodes (Pholeoixodes) canisuga, I. (Ph.) kaiseri, I. (Ph.) hexagonus and a simple pictorial key for the identification of their females

Background: In Europe, hard ticks of the subgenus Pholeoixodes (Ixodidae: Ixodes) are usually associated with burrow-dwelling mammals and terrestrial birds. Reports of Pholeoixodes spp. from carnivores are frequently contradictory, and their identification is not based on key diagnostic characters. Therefore, the aims of the present study were to identify ticks collected from dogs, foxes and badgers in several European countries, and to reassess their systematic status with molecular analyses using two mitochondrial markers. Results: Between 2003 and 2017, 144 Pholeoixodes spp. ticks were collected in nine European countries. From accurate descriptions and comparison with type-materials, a simple illustrated identification key was compiled for adult females, by focusing on the shape of the anterior surface of basis capituli. Based on this key, 71 female ticks were identified as I. canisuga, 21 as I. kaiseri and 21 as I. hexagonus. DNA was extracted from these 113 female ticks, and from further 31 specimens. Fragments of two mitochondrial genes, cox1 (cytochrome c oxidase subunit 1) and 16S rRNA, were amplified and sequenced. Ixodes kaiseri had nine unique cox1 haplotypes, which showed 99.2-100% sequence identity, whereas I. canisuga and I. hexagonus had eleven and five cox1 haplotypes, respectively, with 99.5-100% sequence identity. The distribution of cox1 haplotypes reflected a geographical pattern. Pholeoixodes spp. ticks had fewer 16S rRNA haplotypes, with a lower degree of intraspecific divergence (99.5-100% sequence identity) and no geographical clustering. Phylogenetic analyses were in agreement with morphology: I. kaiseri and I. hexagonus (with the similar shape of the anterior surface of basis capituli) were genetically more closely related to each other than to I. canisuga. Phylogenetic analyses also showed that the subgenus Eschatocephalus (bat ticks) clustered within the subgenus Pholeoixodes. Conclusions: A simple, illustrated identification key is provided for female Pholeoixodes ticks of carnivores (including I. hexagonus and I. rugicollis) to prevent future misidentification of these species. It is also shown that I. kaiseri is more widespread in Europe than previously thought. Phylogenetic analyses suggest that the subgenus Pholeoixodes is not monophyletic: either the subgenus Eschatocephalus should be included in Pholeoixodes, or the latter subgenus should be divided, which is a task for future studies