scholarly journals Disease Heterogeneity in Na+/Citrate Cotransporter Deficiency

2016 ◽  
pp. 107-111 ◽  
Author(s):  
Irina Anselm ◽  
Morgan MacCuaig ◽  
Sanjay B. Prabhu ◽  
Gerard T. Berry
Keyword(s):  
Disease Heterogeneity

scholarly journals Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323906
Author(s):  
Jue-Sheng Ong ◽  
Jiyuan An ◽  
Xikun Han ◽  
Matthew H Law ◽  
Priyanka Nandakumar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Testing ◽  
Association Studies ◽  
Barrett’S Oesophagus ◽  
Oesophageal Reflux ◽  
Oesophageal Adenocarcinoma ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Disease Heterogeneity ◽  
Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

scholarly journals Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ellen F. Mosleth ◽  
Christian Alexander Vedeler ◽  
Kristian Hovde Liland ◽  
Anette McLeod ◽  
Gerd Haga Bringeland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neural Development ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Retinol Binding Protein ◽  
Proteomics Data ◽  
Disease Heterogeneity ◽  
Low Levels

AbstractDespite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.

scholarly journals HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Ziyu Jiang ◽  
Wenqian Ren ◽  
Hua Liang ◽  
Jinhua Yan ◽  
Daizhi Yang ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Risk ◽  
Hla Class I ◽  
Class I ◽  
Chinese Patients ◽  
Onset Age ◽  
Disease Heterogeneity ◽  
Negatively Associated ◽  
Healthy Control

Abstract Aims/hypothesis The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. Methods A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. Results The susceptible DR3 (β = −0.09, p = 0.0009) and DR4-DQ8 (β = −0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (β = 0.21, p = 0.0314) and DR12 (β = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (β = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (β = −0.21, p = 0.0050). The unit for β was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. Conclusions/interpretation In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies. Graphical abstract

scholarly journals Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis

2020 ◽  
Author(s):  
Keane Lim ◽  
Jason Smucny ◽  
Deanna M Barch ◽  
Max Lam ◽  
Richard S E Keefe ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Latent Profile Analysis ◽  
Reference Group ◽  
Profile Analysis ◽  
Cognitive Profiles ◽  
Discovery Cohort ◽  
Longitudinal Stability ◽  
Disease Heterogeneity ◽  
Independent Cohort ◽  
Latent Profile

Abstract Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a “less-impaired” cognitive subtype, 2 subtypes with “intermediate cognitive impairment” differentiated by executive function performance, and a “globally impaired” cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.

Effects of high and low doses of methimazole in patients with Graves' thyrotoxicosis

1987 ◽  
Vol 116 (1_Suppl) ◽  
pp. S312-S317 ◽  
Author(s):  
G. Benker ◽  
D. Reinwein ◽  
H. Creutzig ◽  
H. Hirche ◽  
W. D. Alexander ◽  
...  
Keyword(s):  
Antithyroid Drug ◽  
Drug Dosage ◽  
Antithyroid Drugs ◽  
Graves Disease ◽  
Duration Of Treatment ◽  
Disease Heterogeneity ◽  
Remission Rates ◽  
Set Up ◽  
The Many ◽  
The Impact

Abstract. In spite of the long-established use of antithyroid drugs, there are many unsettled questions connected with this treatment of Graves' disease. There is a lack of controlled prospective trials studying the results of antithyroid drug therapy while considering the many variables such as disease heterogeneity, regional differences, drug dosage and duration of treatment. Therefore, a multicenter study has been set up in order to compare the effects of two fixed doses of methimazole (10 vs 40 mg) with thyroid hormone supplementation on the clinical, biochemical and immunological course of Graves' disease and on remission rates. Experience accumulated so far suggests that treatment is safe using either 10 or 40 mg of methimazole. While there is a tendency for an advantage of the higher dose within the first weeks (higher effectiveness in controlling hyperthyroidism), this difference is not significant. The impact of dosage on remission rates remains to be shown.

scholarly journals Inference of an Integrative, Executable Network for Rheumatoid Arthritis Combining Data-Driven Machine Learning Approaches and a State-of-the-Art Mechanistic Disease Map

2021 ◽  
Vol 11 (8) ◽  
pp. 785
Author(s):  
Quentin Miagoux ◽  
Vidisha Singh ◽  
Dereck de Mézquita ◽  
Valerie Chaudru ◽  
Mohamed Elati ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Machine Learning ◽  
State Of The Art ◽  
Biological Information ◽  
Response To Treatment ◽  
Patient Specific ◽  
Learning Approaches ◽  
Data Types ◽  
Disease Heterogeneity ◽  
Combining Data

Rheumatoid arthritis (RA) is a multifactorial, complex autoimmune disease that involves various genetic, environmental, and epigenetic factors. Systems biology approaches provide the means to study complex diseases by integrating different layers of biological information. Combining multiple data types can help compensate for missing or conflicting information and limit the possibility of false positives. In this work, we aim to unravel mechanisms governing the regulation of key transcription factors in RA and derive patient-specific models to gain more insights into the disease heterogeneity and the response to treatment. We first use publicly available transcriptomic datasets (peripheral blood) relative to RA and machine learning to create an RA-specific transcription factor (TF) co-regulatory network. The TF cooperativity network is subsequently enriched in signalling cascades and upstream regulators using a state-of-the-art, RA-specific molecular map. Then, the integrative network is used as a template to analyse patients’ data regarding their response to anti-TNF treatment and identify master regulators and upstream cascades affected by the treatment. Finally, we use the Boolean formalism to simulate in silico subparts of the integrated network and identify combinations and conditions that can switch on or off the identified TFs, mimicking the effects of single and combined perturbations.

scholarly journals Blood Neutrophil Counts are Associated with Exacerbation Frequency and Mortality in COPD

2020 ◽  
Author(s):  
Mike Lonergan ◽  
Alison J Dicker ◽  
Megan L Crichton ◽  
Holly R Keir ◽  
Melissa K. Van Dyke ◽  
...  
Keyword(s):  
Large Population ◽  
Real Life ◽  
Population Based ◽  
Blood Eosinophil ◽  
Blood Neutrophil ◽  
Disease Heterogeneity ◽  
Disease Information ◽  
Increased Risk ◽  
Eosinophil Counts

Abstract Background Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC). Methods In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality over up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. Results 178120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/µL (IQR 4000-7000cells/µL). Mortality rates among those 34% with elevated BNCs (defined as 6000-15000cells/µL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P<0.001) than those with BNC in the normal range (2000-6000cells/µL). People with elevated BNC were more likely to be classified as GOLD D (46% v 33% P<0.001), have more exacerbations (mean 2.3 v 1.3/year, P<0.001), and were more likely to have severe exacerbations (13% vs. 5%, P<0.001) in the following year. Eosinophil counts were much less predictive of these outcomes. In a sub-cohort (N=276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity. Conclusion High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients.

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