Hereditäre Defekte hepatobiliärer Transportproteine

Zusammenfassung: Eine gestörte Funktion hepatobiliärer Transportproteine kann zu schweren hereditären cholestatischen Leberkrankheiten führen. Die progressive familiäre intrahepatische Cholestase (PFIC) manifestiert sich im frühen Kindesalter. Varianten des FIC1-Aminophospholipidtransporters (ATP8B1-Gen) verursachen sowohl die PFIC1 als auch die benigne rekurrente intrahepatische Cholestase vom Typ1 (BRIC1). Ein Funktionsverlust der Gallensäuren-Effluxpumpe BSEP (ABCB11) führt zu PFIC2 oder BRIC2. Eine häufige BSEP-Variante, der V444A-Polymorphismus, wird häufig bei verschiedenen Arten von Cholestase gefunden, u.a. bei medikamentös induzierten Leberschäden. Schließlich führt die Dysfunktion des "multidrug resistance gene product 3" (MDR3, ABCB4) zu PFIC3, die mit niedrigen biliären Phospholipiden und - aufgrund von Gallengangsschädigungen - hohen GGT-Konzentrationen im Serum einhergeht. Alle drei Transportergene sind auch mit gewissen Formen der intrahepatischen Schwangerschaftscholestase assoziiert. Die Behandlungsoptionen umfassen die Gabe von Ursodeoxycholsäure (UDCA) bei milderen Verlaufsformen bis hin zur Lebertransplantation bei schweren pädiatrischen cholestatischen Leberkrankheite

The phylogenetic position of Acoela as revealed by the complete mitochondrial genome of Symsagittifera roscoffensis

<p>Abstract</p> <p>Background</p> <p>Acoels are simply organized unsegmented worms, lacking hindgut and anus. Several publications over recent years challenge the long-held view that acoels are early offshoots of the flatworms. Instead a basal position as sister group to all other bilaterian animals was suggested, mainly based on molecular evidence. This led to the view that features of acoels might reflect those of the last common ancestor of Bilateria, and resulted in several evo-devo studies trying to interpret bilaterian evolution using acoels as a proxy model for the "Urbilateria".</p> <p>Results</p> <p>We describe the first complete mitochondrial genome sequence of a member of the Acoela, <it>Symsagittifera roscoffensis</it>. Gene content and circular organization of the mitochondrial genome does not significantly differ from other bilaterian animals. However, gene order shows no similarity to any other mitochondrial genome within the Metazoa. Phylogenetic analyses of concatenated alignments of amino acid sequences from protein coding genes support a position of Acoela and Nemertodermatida as the sister group to all other Bilateria. Our data provided no support for a sister group relationship between Xenoturbellida and Acoela or Acoelomorpha. The phylogenetic position of <it>Xenoturbella bocki </it>as sister group to or part of the deuterostomes was also unstable.</p> <p>Conclusions</p> <p>Our phylogenetic analysis supports the view that acoels and nemertodermatids are the earliest divergent extant lineage of Bilateria. As such they remain a valid source for seeking primitive characters present in the last common ancestor of Bilateria. Gene order of mitochondrial genomes seems to be very variable among Acoela and Nemertodermatida and the groundplan for the metazoan mitochondrial genome remains elusive. More data are needed to interpret mitochondrial genome evolution at the base of Bilateria.</p

Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension

Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p &lt; 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p &lt; 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension

Migraine and gastrointestinal disorders in middle and old age: A UK Biobank study

Introduction: Migraine is a prevalent condition causing a substantial level of disability worldwide. Despite this, the pathophysiological mechanisms are not fully understood. Migraine often co-occurs with gastrointestinal disorders, but the direction of a potential causal link is unclear. The aim of this project was to investigate the associations between migraine and several gastrointestinal disorders in the same cohort in order to determine the relative strengths of these associations. Methods: This cross-sectional study examined whether migraine is associated with irritable bowel syndrome (IBS), peptic ulcers, Helicobacter pylori (HP) infections, celiac disease, Crohn's disease and ulcerative colitis. Baseline data covering 489,753 UK Biobank participants (migraine group: n = 14,180) were analyzed using Pearson's chi-square tests and adjusted binary logistic regression models. Results: Migraine was significantly associated with IBS (odds ratio [OR] 2.24, 95% confidence interval [CI] 2.08–2.40, p &lt;.001) and peptic ulcers (OR 1.55, 95% CI 1.35–1.77, p &lt;.001). Migraine was not associated with HP infection (OR 1.34, 95% CI 1.04–1.73, p =.024), celiac disease (OR 1.29, 95% CI 1.04–1.60, p =.023), Crohn's disease (OR 1.08, 95% CI 0.80–1.45, p =.617) or ulcerative colitis (OR 1.00, 95% CI 0.79–1.27, p =.979) after adjusting for multiple testing. Conclusions: Migraine was associated with IBS and peptic ulcers in this large population-based cohort. The associations with HP infection, celiac disease, Crohn's disease, and ulcerative colitis did not reach significance, suggesting a weaker link between migraine and autoimmune gastrointestinal conditions or HP infection

High leptin levels are associated with migraine with aura.

Background Migraine is a prevalent disorder characterised by recurrent headache attacks preceded or accompanied by aura in a subgroup of patients. Migraine often occurs together with major depressive disorder (MDD). Alterations of adipokine levels have been reported both in migraine and in MDD. In this cross-sectional study, we aimed to assess the associations between serum leptin and adiponectin levels and migraine or migraine subtypes. Analyses were adjusted for a lifetime history of MDD in order to investigate the association between adipokines and migraine under consideration of depression status. Methods We included 3025 participants from the CoLaus/PsyCoLaus study. The impact of leptin and adiponectin levels on a diagnosis of migraine was analysed by binary regression analyses, adjusting for variables known to influence adipokine levels. Subgroup analyses were conducted based on the presence of aura. Results Crude leptin levels were significantly higher in subjects with migraine than controls (Mann-Whitney U = 515,102, p = 6 × 10-7). When performing adjusted analyses, leptin levels were found to be significantly higher in subjects with migraine (odds ratio = 1.22, p = 0.024) and migraine with aura (odds ratio = 1.34, p = 0.004). Conclusion High leptin levels might play a role in the pathogenesis of migraine and migraine with aura

Roux-En Y Gastric Bypass Surgery Induces Genome-Wide Promoter-Specific Changes in DNA Methylation in Whole Blood of Obese Patients

Context DNA methylation has been proposed to play a critical role in many cellular and biological processes. Objective To examine the influence of Roux-en-Y gastric bypass (RYGB) surgery on genome-wide promoter-specific DNA methylation in obese patients. Promoters are involved in the initiation and regulation of gene transcription. Methods Promoter-specific DNA methylation in whole blood was measured in 11 obese patients (presurgery BMI &gt;35 kg/m2, 4 females), both before and 6 months after RYGB surgery, as well as once only in a control group of 16 normal-weight men. In addition, body weight and fasting plasma glucose were measured after an overnight fast. Results The mean genome-wide distance between promoter-specific DNA methylation of obese patients at six months after RYGB surgery and controls was shorter, as compared to that at baseline (p&lt;0.001). Moreover, postsurgically, the DNA methylation of 51 promoters was significantly different from corresponding values that had been measured at baseline (28 upregulated and 23 downregulated, P&lt;0.05 for all promoters, Bonferroni corrected). Among these promoters, an enrichment for genes involved in metabolic processes was found (n = 36, P&lt;0.05). In addition, the mean DNA methylation of these 51 promoters was more similar after surgery to that of controls, than it had been at baseline (P&lt;0.0001). When controlling for the RYGB surgery-induced drop in weight (-24% of respective baseline value) and fasting plasma glucose concentration (-16% of respective baseline value), the DNA methylation of only one out of 51 promoters (~2%) remained significantly different between the pre-and postsurgery time points. Conclusions Epigenetic modifications are proposed to play an important role in the development of and predisposition to metabolic diseases, including type II diabetes and obesity. Thus, our findings may form the basis for further investigations to unravel the molecular effects of gastric bypass surgery. Clinical Trial ClinicalTrials.gov NCT0173074

Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression

Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw&lt;1e-4) and susceptibility for suicidal symptoms (padj.&lt;0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.&lt;0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region

A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score

Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases

A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants

The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p =.02) and ln CES-D score (p =.001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p =.02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p =.03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs

Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus.

1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids, which are formed in a side reaction during sphingolipid de-novo synthesis. Recently, we demonstrated that 1-deoxySLs are biomarkers for the prediction of T2DM in obese, non-diabetic patients. Here we investigated the relevance of 1-deoxySLs as long-term predictive biomarkers for the incidence of T2DM in an asymptomatic population. Here, we analyzed the plasma sphingoid base profile in a nested group of non-diabetic individuals (N = 605) selected from a population-based study including 5 year follow-up data (CoLaus study). 1-DeoxySLs at baseline were significantly elevated in individuals who developed T2DM during the follow-up (p&lt;0.001), together with increased glucose (p&lt;5.11E-14), triglycerides (p&lt;0.001) and HOMA-IR indices (p&lt;0.001). 1-Deoxy-sphinganine (1-deoxySA) and 1-deoxy-sphingosine (1-deoxySO) were predictive for T2DM, even after adjusting for fasting glucose levels in the binary regression analyses. The predictive value of the combined markers 1-deoxySA+glucose were superior to glucose alone in normal-weight subjects (p&lt;0.001) but decreased substantially with increasing BMI. Instead, plasma adiponectin and waist-to-hip ratio appeared to be better risk predictors for obese individuals (BMI&gt;30kg/m2). In conclusion, elevated plasma 1-deoxySL levels are strong and independent risk predictors of future T2DM, especially for non-obese individuals in the general population