Project description:Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti-aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers.
Project description:The inflammatory bowel diseases (IBD), which include mainly Crohn's disease (CD) and ulcerative colitis (UC), are common chronic inflammatory conditions of the digestive system. The diagnosis of IBD relies on the use of a combination of factors including symptoms, endoscopy and levels of serum proteins such as C-reactive protein (CRP) or faecal calprotectin. Currently there is no single reliable biomarker to determine IBD. Galectins are a family of galactoside-binding proteins that are commonly altered in the circulation of disease conditions such as cancer and inflammation. This study investigated serum galectin levels as possible biomarkers in determining IBD and IBD disease activity. Levels of galectins-1, -2, -3, -4, -7 and -8 were analysed in 208 samples from ambulant IBD patients (97 CD, 71 UC) patients and 40 from healthy people. Disease activity was assessed using Harvey-Bradshaw Index for CD and simple clinical colitis activity index for UC. The relationship of each galectin in determining IBD and IBD disease activity were analysed and compared with current IBD biomarker CRP. It was found that serum level of galectin-1 and -3, but not galectins-2, -4, -7 and -8, were significantly higher in IBD patients than in healthy people. At cut-off of 4.1ng/ml, galectin-1 differentiated IBD from healthy controls with 71% sensitivity and 87% specificity. At cut-off of 38.5ng/ml, galectin-3 separated IBD from healthy controls with 53% sensitivity and 87% specificity. None of the galectins however were able to distinguish active disease from remission in UC or CD. Thus, levels of galectins-1 and -3 are significantly elevated in both UC and CD patients compared to healthy people. Although the increased galectin levels are not able to separate active and inactive UC and CD, they may have the potential to be developed as useful biomarkers for IBD diagnosis either alone or in combination with other biomarkers.
Project description:There are inconsistent findings in the literature about the directionality and magnitude of the association between inflammation and depressive symptoms. This analysis separates predictors into between-person and within-person components to gain greater clarity about this relationship. Blood samples were collected and depressive symptoms assessed in 140 adolescents (54% female, 59% Black, Mage = 16.1 years) with at least three blood draws and a total of 394 follow-up observations. Multi-level modeling indicated that the within-person effect of tumor necrosis factor alpha (TNF-α) predicted change in total depressive symptoms, suggesting a potential causal relationship. There were no significant within-person effects of total depressive symptoms on change in biomarkers. Exploratory analyses examined associations between inflammatory biomarkers and subsets of depressive symptoms. These findings inform modeling decisions that may explain inconsistencies in the extant literature as well as suggest potential causal relationships between certain proteins with significant within-person effects on depressive symptoms, and vice-versa.
Project description:Recent advances in data analysis methods based on principles of Mendelian Randomisation, such as Egger regression and the weighted median estimator, add to the researcher's ability to infer cause-effect links from observational data. Now is the time to gauge the potential of these methods within specific areas of biomedical research. In this paper, we choose a study in metabolomics as an illustrative testbed. We apply Mendelian Randomisation methods in the analysis of data from the DILGOM (Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome) study, in the context of an effort to identify molecular pathways of cardiovascular disease. In particular, our illustrative analysis addresses the question whether body mass, as measured by body mass index (BMI), exerts a causal effect on the concentrations of a collection of 137 cardiometabolic markers with different degrees of atherogenic power, such as the (highly atherogenic) lipoprotein metabolites with very low density (VLDLs) and the (protective) high density lipoprotein metabolites.We found strongest evidence of a positive BMI effect (that is, evidence that an increase in BMI causes an increase in the metabolite concentration) on those metabolites known to represent strong risk factors for coronary artery disease, such as the VLDLs, and evidence of a negative effect on protective biomarkers.The methods discussed represent a useful scientific tool, although they assume the validity of conditions that are (at best) only partially verifiable. This paper provides a rigorous account of such conditions. The results of our analysis provide a proof-of-concept illustration of the potential usefulness of Mendelian Randomisation in genomic biobank studies aiming to dissect the molecular causes of disease, and to identify candidate pharmacological targets.
Project description:Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn's disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-? and -?, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, T?? and T CD8(+) cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4(+) T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the ?2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells' function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-? and -? also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-? inhibitors. Additionally, polymorphisms of TNF-? gene are known to affect the gene expression level and particular TNF-? genotypes may influence the response of IBD patients treated with TNF-? inhibitors.
Project description:Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology which mostly involves the intestine and requires a personalized approach for treatment. IBD represents a heterogeneous group of patients with inherently variable disease courses. Hence, the heterogeneity of patient populations may delay the diagnosis, clinical practice and initiation of appropriate treatment. Use of biomarkers for diagnosis and management of IBD is still necessary. Descriptions of the immunological pathway abnormalities in IBD improve assessment to identify the patient's disease status, and relative risk of progression to complicated disease behaviors, and this information may ultimately influence therapeutic decisions. In this study, we try to explain the role of biomarkers in early diagnosis, estimating prognosis, and target agents for correct managements of IBD's patients. This information might be important to provide insight into emerging panels of multiple IBD biomarkers and highlighting the essential role of personalizes panel for each patient.
Project description:BackgroundType 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation.ObjectiveAssessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE).MethodsData were extracted from three randomized placebo-controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation-regulated chemokine (TARC), plasma eotaxin-3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count.ResultsDupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin-3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from -24.8% to -88.6% (placebo +2.6% to -53.6%); -38.2% to -51.5% (placebo +8.3% to -0.16%) in eotaxin-3; -24.8% to -76.7% (placebo +8.3% to -4.4%) in total IgE; and -13.6% to -41.1% (placebo +10.1% to -6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: -15.8, 0]); transient increases followed by decreases to below-baseline levels in asthma (-14.6% [-20.0, -7.7]) and CRSwNP (-29.4% [-40.0, -16.3]); and significant decreases in EoE (-50.0% [-50.0, -33.3]).Conclusion and clinical relevanceDupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.
Project description:Background: Previous studies suggested an association of sleep disorders with inflammatory bowel disease (IBD) and indicated that using pharmacological treatments for the modulation of circadian rhythms might prevent IBD pathogenesis or aggravation, but whether the effect of sleep traits on IBD was causal is inconclusive and, therefore, prevents drug repurposing based on the previous studies. We aimed to examine the causal effect of different sleep traits on the pathogenesis of IBD. Methods: Genetic instruments for sleep traits were selected from the largest GWAS studies available in the UK Biobank (n = 449,734) and the 23andMe Research (n = 541,333). A two-sample Mendelian randomization (MR) study was conducted to examine the association of the genetic instruments with IBD (12,882 cases and 21,770 controls), ulcerative colitis (6,968 cases, 20,464 controls), and Crohn's disease (5,956 cases and 14,927 controls). We applied the inverse-variance weighted (IVW) method to estimate causal effects, and we used the weighted median and MR-Egger method for sensitivity analyses. Results: We found that sleep duration (OR, 1.00, 95% CI 1.00-1.01), short sleep duration (OR, 1.07, 95% CI 0.41-2.83), morningness (OR, 1.05, 95% CI 0.87-1.27), daytime napping (OR, 1.64, 95% CI 0.62-4.4), frequent insomnia (OR, 1.17, 95% CI 0.8-1.72), any insomnia (OR, 1.17, 95% CI 0.69-1.97), and snoring (OR, 0.31, 95% CI 0.06-1.54) had no causal effect on IBD, and these sleep traits had no causal effect on ulcerative colitis and Crohn's disease either. Most of the sensitivity analyses showed consistent results with those of the IVW method. Conclusion: Our MR study did not support the causal effect of sleep traits on IBD. Pharmacological modulation of circadian rhythms for the prevention of IBD pathogenesis was unwarranted.
Project description:Observational studies have revealed that dental diseases such as periodontitis and dental caries increase the risk of cardiovascular diseases (CVDs). However, the causality between periodontal disease (PD) and CVDs is still not clarified. In the present study, two-sample Mendelian randomization (MR) studies were carried out to assess the association between genetic liability for periodontal diseases (dental caries and periodontitis) and major CVDs, including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and stroke-including ischemic stroke as well as its three main subtypes-based on large-scale genome-wide association studies (GWASs). Our two-sample MR analyses did not provide evidence for dental caries and periodontitis as the causes of cardiovascular diseases; sensitivity analyses, including MR-Egger analysis and weighted median analysis, also supported this result. Gene functional annotation and pathway enrichment analyses indicated the common pathophysiology between cardiovascular diseases and periodontal diseases. The associations from observational studies may be explained by shared risk factors and comorbidities instead of direct consequences. This also suggests that addressing the common risk factors-such as reducing obesity and improving glucose tolerance-could benefit both conditions.
Project description:BACKGROUND AND AIMS:The study investigates the practical utility of whole-blood gene expression profiling to diagnose inflammatory bowel diseases [IBDs]. METHODS:The discovery cohorts included 102 and 51 paediatric IBD patients and controls, and 95 and 46 adult IBD patients and controls, respectively. The replication cohorts included 447 and 76 paediatric IBD patients and controls, and 271 and 108 adult IBD patients and controls, respectively. In the discovery phase, RNA samples extracted from whole peripheral blood were analysed using RNA-Seq, and the predictive values of selected biomarkers were validated using quantitative polymerase chain reaction [qPCR]. RESULTS:In all, 15 differentially expressed transcripts [adjusted p ?0.05] were selected from the discovery sequencing datasets. The receiver operating characteristic curves and area under the curve [ROC-AUC] in replication analyses showed high discriminative power [AUC range, 0.91-0.98] for 11 mRNAs in paediatric patients with active IBD. By contrast, the AUC-ROC values ranged from 0.63 to 0.75 in comparison among inactive paediatric IBDs and active/inactive adult IBDs, indicating a lack of discriminative power. The best multi-mRNA diagnostic classifier showed moderate discriminative power [AUC = 0.81] for paediatric inactive IBD, but was not able to discriminate active or inactive adult IBD patients from controls. The AUC-ROC values did not confirm an ability of the mRNAs abundances to discriminate between active ulcerative colitis and active Crohn's disease in paediatric or adult populations. CONCLUSIONS:This study identifies and validates blood transcriptional biomarkers that could be used in clinical settings as diagnostic predictors of IBD clinical activity in paediatric, but not adult, IBD patients.