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Article ; Online: Mini-review: Update on the genetics of schizophrenia.

Coelewij, Leda / Curtis, David

2018 Volume 82, Issue 5, Page(s) 239–243

Abstract: A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and ... ...

Abstract	A number of important findings have recently emerged relevant to identifying genetic risk factors for schizophrenia. Findings using common variants point towards gene sets of interest and also demonstrate an overlap with other psychiatric and nonpsychiatric disorders. Imputation of variants of the gene for complement component 4 (C4) from GWAS data has shown that the predicted expression of the C4A product is associated with schizophrenia risk. Very rare variants disrupting SETD1A, RBM12 or NRXN1 have a large effect on risk. Other rare, damaging variants are enriched in genes that are loss of function intolerant and/or whose products localise to the synapse. These and particular copy number variants can result in increased risk of schizophrenia but also of other neurodevelopmental disorders. The findings for C4 and NRXN1 may be especially helpful for elucidating the biological mechanisms that can lead to disease.
MeSH term(s)	Calcium-Binding Proteins ; Cell Adhesion Molecules, Neuronal/genetics ; Complement C4/genetics ; DNA Copy Number Variations ; Genome-Wide Association Study ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Nerve Tissue Proteins/genetics ; Neural Cell Adhesion Molecules ; RNA-Binding Proteins/genetics ; Risk Factors ; Schizophrenia/genetics
Chemical Substances	Calcium-Binding Proteins ; Cell Adhesion Molecules, Neuronal ; Complement C4 ; NRXN1 protein, human ; Nerve Tissue Proteins ; Neural Cell Adhesion Molecules ; RBM12 protein, human ; RNA-Binding Proteins ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Setd1A protein, human (EC 2.1.1.43)
Language	English
Publishing date	2018-06-20
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	333-5
ISSN	1469-1809 ; 0003-4800
ISSN (online)	1469-1809
ISSN	0003-4800
DOI	10.1111/ahg.12259
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Article ; Online: Blood metabolomic and transcriptomic signatures stratify patient subgroups in multiple sclerosis according to disease severity.

Oppong, Alexandra E / Coelewij, Leda / Robertson, Georgia / Martin-Gutierrez, Lucia / Waddington, Kirsty E / Dönnes, Pierre / Nytrova, Petra / Farrell, Rachel / Pineda-Torra, Inés / Jury, Elizabeth C

iScience

2024 Volume 27, Issue 3, Page(s) 109225

Abstract: There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning ... ...

Abstract	There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning analysis of serum metabolomic data stratified patients with RRMS from SPMS with high accuracy and a putative score was developed that stratified MS patient subsets. The top differentially expressed metabolites between SPMS versus patients with RRMS included lipids and fatty acids, metabolites enriched in pathways related to cellular respiration, notably, elevated lactate and glutamine (gluconeogenesis-related) and acetoacetate and bOHbutyrate (ketone bodies), and reduced alanine and pyruvate (glycolysis-related). Serum metabolomic changes were recapitulated in the whole blood transcriptome, whereby differentially expressed genes were also enriched in cellular respiration pathways in patients with SPMS. The final gene-metabolite interaction network demonstrated a potential metabolic shift from glycolysis toward increased gluconeogenesis and ketogenesis in SPMS, indicating metabolic stress which may trigger stress response pathways and subsequent neurodegeneration.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109225
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Article ; Online: Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis.

Martin-Gutierrez, Lucia / Waddington, Kirsty E / Maggio, Annalisa / Coelewij, Leda / Oppong, Alexandra / Yang, Nina / Adriani, Marsilio / Nytrova, Petra / Farrell, Rachel / Pineda-Torra, Inés / Jury, Elizabeth C

Clinical and experimental immunology

2024

Abstract: Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment ... ...

Abstract	Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
Language	English
Publishing date	2024-04-16
Publishing country	England
Document type	Journal Article
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxae032
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Article: Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults.

Parikh, Chinar R / Ponnampalam, Jaya K / Seligmann, George / Coelewij, Leda / Pineda-Torra, Ines / Jury, Elizabeth C / Ciurtin, Coziana

Therapeutic advances in musculoskeletal disease

2021 Volume 13, Page(s) 1759720X211002685

Abstract: The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved ... ...

Abstract	The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications.
Language	English
Publishing date	2021-06-16
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2516075-8
ISSN	1759-7218 ; 1759-720X
ISSN (online)	1759-7218
ISSN	1759-720X
DOI	10.1177/1759720X211002685
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Article ; Online: Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology.

Curtis, David / Coelewij, Leda / Liu, Shou-Hwa / Humphrey, Jack / Mott, Richard

Behavior genetics

2018 Volume 48, Issue 3, Page(s) 198–208

Abstract: A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish ... ...

Abstract	A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the "FMRP targets" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a "prioritized candidate gene". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP = 1.7) and GRIN2B (SLP = 2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, three were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.
MeSH term(s)	Case-Control Studies ; Databases, Genetic ; Gene Ontology ; Genetic Predisposition to Disease ; Humans ; Schizophrenia/genetics ; Sweden ; Synapses/genetics ; Whole Exome Sequencing
Language	English
Publishing date	2018-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280238-7
ISSN	1573-3297 ; 0005-7851 ; 0001-8244
ISSN (online)	1573-3297
ISSN	0005-7851 ; 0001-8244
DOI	10.1007/s10519-018-9893-3
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Article ; Online: Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.

Robinson, George A / Waddington, Kirsty E / Coelewij, Leda / Peng, Junjie / Naja, Meena / Wincup, Chris / Radziszewska, Anna / Peckham, Hannah / Isenberg, David A / Ioannou, Yiannis / Ciurtin, Coziana / Pineda-Torra, Ines / Jury, Elizabeth C

EBioMedicine

2021 Volume 65, Page(s) 103243

Abstract: Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR ... ...

Abstract	Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE. Methods: Serum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples. Findings: Hierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up. Interpretation: Multi-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes. Funding: Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.
MeSH term(s)	Adolescent ; Adult ; Age of Onset ; Apolipoprotein A-I/blood ; Apolipoproteins B/blood ; Atherosclerosis/diagnosis ; Atherosclerosis/etiology ; Biomarkers/blood ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cluster Analysis ; Cohort Studies ; Female ; Humans ; Lipids/blood ; Logistic Models ; Lupus Erythematosus, Systemic/complications ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/pathology ; Male ; Risk Factors ; Severity of Illness Index ; Young Adult
Chemical Substances	Apolipoprotein A-I ; Apolipoproteins B ; Biomarkers ; Lipids
Language	English
Publishing date	2021-02-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2021.103243
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Article ; Online: Using Serum Metabolomics to Predict Development of Anti-drug Antibodies in Multiple Sclerosis Patients Treated With IFNβ.

Waddington, Kirsty E / Papadaki, Artemis / Coelewij, Leda / Adriani, Marsilio / Nytrova, Petra / Kubala Havrdova, Eva / Fogdell-Hahn, Anna / Farrell, Rachel / Dönnes, Pierre / Pineda-Torra, Inés / Jury, Elizabeth C

Frontiers in immunology

2020 Volume 11, Page(s) 1527

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Antibodies/blood ; Antibodies/immunology ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; Biomarkers/blood ; Female ; Humans ; Interferon-beta/adverse effects ; Interferon-beta/therapeutic use ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Male ; Membrane Lipids/metabolism ; Membrane Microdomains ; Metabolome ; Metabolomics/methods ; Multiple Sclerosis/blood ; Multiple Sclerosis/diagnosis ; Multiple Sclerosis/drug therapy ; Prognosis
Chemical Substances	Antibodies ; Antibodies, Neutralizing ; Biomarkers ; Membrane Lipids ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2020-07-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01527
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Article ; Online: Disease-associated and patient-specific immune cell signatures in juvenile-onset systemic lupus erythematosus: patient stratification using a machine-learning approach.

Robinson, George A / Peng, Junjie / Dönnes, Pierre / Coelewij, Leda / Naja, Meena / Radziszewska, Anna / Wincup, Chris / Peckham, Hannah / Isenberg, David A / Ioannou, Yiannis / Pineda-Torra, Ines / Ciurtin, Coziana / Jury, Elizabeth C

The Lancet. Rheumatology

2020 Volume 2, Issue 8, Page(s) e485–e496

Abstract: Background: Juvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine- ... ...

Abstract	Background: Juvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine-learning approaches to characterise the immune cell profile of patients with juvenile-onset SLE and investigate links with the disease trajectory over time. Methods: This study included patients who attended the University College London Hospital (London, UK) adolescent rheumatology service, had juvenile-onset SLE according to the 1997 American College of Rheumatology revised classification criteria for lupus or the 2012 Systemic Lupus International Collaborating Clinics criteria, and were diagnosed before 18 years of age. Blood donated by healthy age-matched and sex-matched volunteers who were taking part in educational events in the Centre for Adolescent Rheumatology Versus Arthritis at University College London (London, UK) was used as a control. Immunophenotyping profiles (28 immune cell subsets) of peripheral blood mononuclear cells from patients with juvenile-onset SLE and healthy controls were determined by flow cytometry. We used balanced random forest (BRF) and sparse partial least squares-discriminant analysis (sPLS-DA) to assess classification and parameter selection, and validation was by ten-fold cross-validation. We used logistic regression to test the association between immune phenotypes and k-means clustering to determine patient stratification. Retrospective longitudinal clinical data, including disease activity and medication, were related to the immunological features identified. Findings: Between Sept 5, 2012, and March 7, 2018, peripheral blood was collected from 67 patients with juvenile-onset SLE and 39 healthy controls. The median age was 19 years (IQR 13-25) for patients with juvenile-onset SLE and 18 years (16-25) for healthy controls. The BRF model discriminated patients with juvenile-onset SLE from healthy controls with 90·9% prediction accuracy. The top-ranked immunological features from the BRF model were confirmed using sPLS-DA and logistic regression, and included total CD4, total CD8, CD8 effector memory, and CD8 naive T cells, Bm1, and unswitched memory B cells, total CD14 monocytes, and invariant natural killer T cells. Using these markers patients were clustered into four distinct groups. Notably, CD8 T-cell subsets were important in driving patient stratification, whereas B-cell markers were similarly expressed across the cohort of patients with juvenile-onset SLE. Patients with juvenile-onset SLE and elevated CD8 effector memory T-cell frequencies had more persistently active disease over time, as assessed by the SLE disease activity index 2000, and this was associated with increased treatment with mycophenolate mofetil and an increased prevalence of lupus nephritis. Finally, network analysis confirmed the strong association between immune phenotype and differential clinical features. Interpretation: Machine-learning models can define potential disease-associated and patient-specific immune characteristics in rare disease patient populations. Immunological association studies are warranted to develop data-driven personalised medicine approaches for treatment of patients with juvenile-onset SLE. Funding: Lupus UK, The Rosetrees Trust, Versus Arthritis, and UK National Institute for Health Research University College London Hospital Biomedical Research Centre.
Language	English
Publishing date	2020-07-29
Publishing country	England
Document type	Journal Article
ISSN	2665-9913
ISSN (online)	2665-9913
DOI	10.1016/S2665-9913(20)30168-5
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Article ; Online: Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

Coelewij, Leda / Waddington, Kirsty E / Robinson, George A / Chocano, Elvira / McDonnell, Thomas / Farinha, Filipa / Peng, Junjie / Dönnes, Pierre / Smith, Edward / Croca, Sara / Bakshi, Jyoti / Griffin, Maura / Nicolaides, Andrew / Rahman, Anisur / Jury, Elizabeth C / Pineda-Torra, Ines

Arteriosclerosis, thrombosis, and vascular biology

2021 Volume 41, Issue 4, Page(s) 1446–1458

Abstract: Figure: see text]. ...

Abstract	[Figure: see text].
MeSH term(s)	Adult ; Aged ; Asymptomatic Diseases ; Biomarkers/blood ; Carotid Artery Diseases/blood ; Carotid Artery Diseases/diagnostic imaging ; Carotid Artery Diseases/drug therapy ; Carotid Artery Diseases/etiology ; Case-Control Studies ; Female ; Humans ; Lipidomics ; Lipoproteins/blood ; Lupus Erythematosus, Systemic/blood ; Lupus Erythematosus, Systemic/complications ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/drug therapy ; Machine Learning ; Magnetic Resonance Spectroscopy ; Metabolome ; Middle Aged ; Peripheral Arterial Disease/blood ; Peripheral Arterial Disease/diagnostic imaging ; Peripheral Arterial Disease/drug therapy ; Peripheral Arterial Disease/etiology ; Predictive Value of Tests ; Risk Factors ; Young Adult
Chemical Substances	Biomarkers ; Lipoproteins
Language	English
Publishing date	2021-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.120.315321
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