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Article ; Online: Examination of the shared genetic architecture between multiple sclerosis and systemic lupus erythematosus facilitates discovery of novel lupus risk loci.

Kerns, Sophia / Owen, Katherine A / Schwalbe, Dana / Grammer, Amrie C / Lipsky, Peter E

2024

Abstract: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared ... ...

Abstract	Systemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared to many other diseases. Multiple Sclerosis (MS) is a chronic relapsing autoimmune disease of the central nervous system (CNS) that also manifests neurological and immunological features. Here, we identify a method of leveraging large-scale genome wide association studies (GWAS) in MS to identify novel genetic risk loci in SLE. Statistical genetic comparison methods including linkage disequilibrium score regression (LDSC) and cross-phenotype association analysis (CPASSOC) to identify genetic overlap in disease pathophysiology, traditional 2-sample and novel PPI-based mendelian randomization to identify causal associations and Bayesian colocalization were applied to association studies conducted in MS to facilitate discovery in the smaller, more limited datasets available for SLE. Pathway analysis using SNP-to-gene mapping identified biological networks composed of molecular pathways with causal implications for CNS disease in SLE specifically, as well as pathways likely causal of both pathologies, providing key insights for therapeutic selection.
Language	English
Publishing date	2024-04-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-024-02672-3
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Article ; Online: Deconvoluting the heterogeneity of SLE: The contribution of ancestry.

Owen, Katherine A / Grammer, Amrie C / Lipsky, Peter E

The Journal of allergy and clinical immunology

2021 Volume 149, Issue 1, Page(s) 12–23

Abstract: Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disorder with a prominent genetic component. Evidence has shown that individuals of non-European ancestry experience the disease more severely, exhibiting an increased incidence of ... ...

Abstract	Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disorder with a prominent genetic component. Evidence has shown that individuals of non-European ancestry experience the disease more severely, exhibiting an increased incidence of cardiovascular disease, renal involvement, and tissue damage compared with European ancestry populations. Furthermore, there seems to be variability in the response of individuals within different ancestral groups to standard medications, including cyclophosphamide, mycophenolate, rituximab, and belimumab. Although the widespread application of candidate gene, Immunochip, and genome-wide association studies has contributed to our understanding of the link between genetic variation (typically single nucleotide polymorphisms) and SLE, despite decades of research it is still unclear why ancestry remains a key determinant of poorer outcome in non-European-ancestry patients with SLE. Here, we will discuss the impact of ancestry on SLE disease burden in patients from diverse backgrounds and highlight how research efforts using novel bioinformatic and pathway-based approaches have begun to disentangle the complex genetic architecture linking ancestry to SLE susceptibility. Finally, we will illustrate how genomic and gene expression analyses can be combined to help identify novel molecular pathways and drug candidates that might uniquely impact SLE among different ancestral populations.
MeSH term(s)	Animals ; Environment ; Epigenesis, Genetic ; Genetic Predisposition to Disease ; Genomics ; Humans ; Lupus Erythematosus, Systemic/genetics ; Lupus Erythematosus, Systemic/therapy
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2021.11.005
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Article ; Online: Salmonella Typhimurium manipulates macrophage cholesterol homeostasis through the SseJ-mediated suppression of the host cholesterol transport protein ABCA1.

Greene, Adam R / Owen, Katherine A / Casanova, James E

Cellular microbiology

2021 Volume 23, Issue 8, Page(s) e13329

Abstract: Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified-endosomal compartment referred to as the Salmonella-containing vacuole (SCV). SCV biogenesis is driven by multiple effector proteins translocated through two type ...

Abstract	Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified-endosomal compartment referred to as the Salmonella-containing vacuole (SCV). SCV biogenesis is driven by multiple effector proteins translocated through two type III secretion systems (T3SS-1 and T3SS-2). While many host proteins targeted by these effector proteins have been characterised, the role of host lipids in SCV dynamics remains poorly understood. Previous studies have shown that S. Typhimurium infection in macrophages leads to accumulation of intracellular cholesterol, some of which concentrates in and around SCVs; however, the underlying mechanisms remain unknown. Here, we show that S. Typhimurium utilises the T3SS-2 effector SseJ to downregulate expression of the host cholesterol transporter ABCA1 in macrophages, leading to a ~45% increase in cellular cholesterol. Mechanistically, SseJ activates a signalling cascade involving the host kinases FAK and Akt to suppress Abca1 expression. Mutational inactivation of SseJ acyltransferase activity, silencing FAK, or inhibiting Akt prevents Abca1 downregulation and the corresponding accumulation of cholesterol during infection. Importantly, RNAi-mediated silencing of ABCA1 rescued bacterial survival in FAK-deficient macrophages, suggesting that Abca1 downregulation and cholesterol accumulation are important for intracellular survival.
MeSH term(s)	Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Carrier Proteins ; Cholesterol ; Homeostasis ; Macrophages/metabolism ; Salmonella typhimurium/metabolism
Chemical Substances	Bacterial Proteins ; Carrier Proteins ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2021-04-22
Publishing country	India
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/cmi.13329
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Article ; Online: Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry.

Rector, Ian / Owen, Katherine A / Bachali, Prathyusha / Hubbard, Erika / Yazdany, Jinoos / Dall'era, Maria / Grammer, Amrie C / Lipsky, Peter E

RMD open

2023 Volume 9, Issue 3

Abstract: Objectives: Type I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations. Here, we explored the expression ... ...

Abstract	Objectives: Type I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations. Here, we explored the expression of the interferon gene signatures (IGSs) in SLE patients of European ancestry (EA) and Asian ancestry (AsA). Methods: We used gene set variation analysis with multiple IGS encompassing the response to both type 1 and type 2 IFN in isolated CD14+ monocytes, CD19+B cells, CD4+T cells and Natural Killer (NK) cells from patients with SLE stratified by self-identified ancestry. The expression of genes upstream of the IGS and influenced by lupus-associated risk alleles was also examined. Lastly, we employed machine learning (ML) models to assess the most important features classifying patients by disease activity. Results: AsA patients with SLE exhibited greater enrichment in the IFN core and IFNA2 IGS compared with EA patients in all cell types examined and, in the presence and absence of autoantibodies. Overall, AsA patients with SLE demonstrated higher expression of genes upstream of the IGS than EA counterparts. ML with feature importance analysis indicated that IGS expression in NK cells, anti-dsDNA, complement levels and AsA status contributed to disease activity. Conclusions: AsA patients with SLE exhibited higher IGS than EA patients in all cell types regardless of autoantibody status, with enhanced expression of genetically associated genes upstream of the IGS potentially contributing. AsA, along with the IGS in NK cells, anti-dsDNA and complement, independently influenced SLE disease activity.
MeSH term(s)	Humans ; Interferon Type I/genetics ; Alleles ; Autoantibodies ; Killer Cells, Natural ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/genetics
Chemical Substances	Interferon Type I ; Autoantibodies
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2812592-7
ISSN	2056-5933 ; 2056-5933
ISSN (online)	2056-5933
ISSN	2056-5933
DOI	10.1136/rmdopen-2023-003475
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Article ; Online: Mendelian randomization and pathway analysis demonstrate shared genetic associations between lupus and coronary artery disease.

Kain, Jessica / Owen, Katherine A / Marion, Miranda C / Langefeld, Carl D / Grammer, Amrie C / Lipsky, Peter E

Cell reports. Medicine

2022 Volume 3, Issue 11, Page(s) 100805

Abstract: Coronary artery disease (CAD) is a leading cause of death in patients with systemic lupus erythematosus (SLE). Despite clinical evidence supporting an association between SLE and CAD, pleiotropy-adjusted genetic association studies are limited and focus ... ...

Abstract	Coronary artery disease (CAD) is a leading cause of death in patients with systemic lupus erythematosus (SLE). Despite clinical evidence supporting an association between SLE and CAD, pleiotropy-adjusted genetic association studies are limited and focus on only a few common risk loci. Here, we identify a net positive causal estimate of SLE-associated non-HLA SNPs on CAD by traditional Mendelian randomization (MR) approaches. Pathway analysis using SNP-to-gene mapping followed by unsupervised clustering based on protein-protein interactions (PPIs) identifies biological networks composed of positive and negative causal sets of genes. In addition, we confirm the casual effects of specific SNP-to-gene modules on CAD using only SNP mapping to each PPI-defined functional gene set as instrumental variables. This PPI-based MR approach elucidates various molecular pathways with causal implications between SLE and CAD and identifies biological pathways likely causative of both pathologies, revealing known and novel therapeutic interventions for managing CAD in SLE.
MeSH term(s)	Humans ; Mendelian Randomization Analysis ; Coronary Artery Disease/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Lupus Erythematosus, Systemic/epidemiology
Language	English
Publishing date	2022-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100805
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Article ; Online: Salmonella Manipulates Autophagy to "Serve and Protect".

Owen, Katherine A / Casanova, James E

Cell host & microbe

2015 Volume 18, Issue 5, Page(s) 517–519

Abstract: Many intracellular pathogens, including Salmonella typhimurium, trigger autophagy in host cells, which is widely thought to restrict intracellular growth and survival. In this issue of Cell Host & Microbe, Kreibich et al. (2015) demonstrate a role for ... ...

Abstract	Many intracellular pathogens, including Salmonella typhimurium, trigger autophagy in host cells, which is widely thought to restrict intracellular growth and survival. In this issue of Cell Host & Microbe, Kreibich et al. (2015) demonstrate a role for the autophagic machinery in the repair of damaged Salmonella-containing vacuoles (SCVs).
MeSH term(s)	Autophagy ; Cytoplasm ; Humans ; Salmonella Infections ; Salmonella typhimurium ; Vacuoles
Language	English
Publishing date	2015-11-16
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2015.10.020
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Article ; Online: Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry.

Owen, Katherine A / Bell, Kristy A / Price, Andrew / Bachali, Prathyusha / Ainsworth, Hannah / Marion, Miranda C / Howard, Timothy D / Langefeld, Carl D / Shen, Nan / Yazdany, Jinoos / Dall'era, Maria / Grammer, Amrie C / Lipsky, Peter E

Scientific reports

2023 Volume 13, Issue 1, Page(s) 5339

Abstract: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including ... ...

Abstract	Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.
MeSH term(s)	Humans ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Lupus Erythematosus, Systemic/genetics ; Genotype ; Case-Control Studies
Language	English
Publishing date	2023-04-01
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-32569-6
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Article ; Online: Patient-Reported Outcome Information Collected from Lupus Patients Using a Mobile Application: Compliance and Validation.

Bell, Kristy / Dykas, Claire / Muckian, Bridget / Williams, Brooke / Rainey, Hope / Comberg, Maggy / Mora, Mary / Owen, Katherine A / Lipsky, Peter E

ACR open rheumatology

2021 Volume 4, Issue 2, Page(s) 99–109

Abstract: Objective: Patient-reported outcomes (PROs) can provide critical information concerning the impact of a disease on an individual. Mobile technology to collect PRO data in an electronic format (ePRO) allows for frequent assessment in the person's regular ...

Abstract	Objective: Patient-reported outcomes (PROs) can provide critical information concerning the impact of a disease on an individual. Mobile technology to collect PRO data in an electronic format (ePRO) allows for frequent assessment in the person's regular environment. The goal of this study was to assess the compliance with a phone application (app) and validate ePRO information in individuals with systemic lupus erythematosus (SLE). Methods: A smartphone app that collects ePRO data from various clinical instruments was developed. Information was collected by both an ePRO and a paper-administered instrument as part of a multicenter randomized interventional clinical trial of patients meeting American College of Rheumatology (ACR) criteria for the classification of SLE. To determine agreement between PRO information collected in the different formats, intraclass correlation coefficients (ICCs), paired Student's t tests, and Bland-Altman plots were evaluated. Compliance and Cronbach's alpha were also assessed as a measure of survey reliability. Results: For the 62 subjects from diverse ancestral backgrounds, compliance with ePRO completion was high (more than 75%). Cronbach alpha values for PROs indicated moderate to high survey reliability. The vast majority (73.4%) of ICC values were indicative of good to excellent reliability between measurement methods. Bland-Altman plots verified method agreement, and 87% of pairwise t tests yielded an insignificant difference between information collected with the different administration methods. Conclusion: The excellent compliance and the high level of consistency between data collected by paper and that collected by electronic methods indicate that the app provides a reliable means of cataloging real-time changes in PROs in SLE patients.
Language	English
Publishing date	2021-11-10
Publishing country	United States
Document type	Journal Article
ISSN	2578-5745
ISSN (online)	2578-5745
DOI	10.1002/acr2.11370
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Article ; Online: Salmonella Suppresses the TRIF-Dependent Type I Interferon Response in Macrophages.

Owen, Katherine A / Anderson, C J / Casanova, James E

mBio

2016 Volume 7, Issue 1, Page(s) e02051–15

Abstract: Unlabelled: Salmonella enterica is an intracellular pathogen that causes diseases ranging from gastroenteritis to typhoid fever. Salmonella bacteria trigger an autophagic response in host cells upon infection but have evolved mechanisms for suppressing ... ...

Abstract	Unlabelled: Salmonella enterica is an intracellular pathogen that causes diseases ranging from gastroenteritis to typhoid fever. Salmonella bacteria trigger an autophagic response in host cells upon infection but have evolved mechanisms for suppressing this response, thereby enhancing intracellular survival. We recently reported that S. enterica serovar Typhimurium actively recruits the host tyrosine kinase focal adhesion kinase (FAK) to the surface of the Salmonella-containing vacuole (SCV) (K. A. Owen et al., PLoS Pathog 10:e1004159, 2014). FAK then suppresses autophagy through activation of the Akt/mTORC1 signaling pathway. In FAK(-/-) macrophages, bacteria are captured in autophagosomes and intracellular survival is attenuated. Here we show that the cell-autonomous bacterial suppression of autophagy also suppresses the broader innate immune response by inhibiting production of beta interferon (IFN-β). Induction of bacterial autophagy (xenophagy), but not autophagy alone, triggers IFN-β production through a pathway involving the adapter TRIF and endosomal Toll-like receptor 3 (TLR3) and TLR4. Selective FAK knockout in macrophages resulted in rapid bacterial clearance from mucosal tissues after oral infection. Clearance correlated with increased IFN-β production by intestinal macrophages and with IFN-β-dependent induction of IFN-γ by intestinal NK cells. Blockade of either IFN-β or IFN-γ increased host susceptibility to infection, whereas experimental induction of IFN-β was protective. Thus, bacterial suppression of autophagy not only enhances cell-autonomous survival but also suppresses more-systemic innate immune responses by limiting type I and type II interferons. Importance: Salmonella enterica serovar Typhimurium represents one of the most commonly identified bacterial causes of foodborne illness worldwide. S. Typhimurium has developed numerous strategies to evade detection by the host immune system. Autophagy is a cellular process that involves the recognition and degradation of defective proteins and organelles. More recently, autophagy has been described as an important means by which host cells recognize and eliminate invading intracellular pathogens and plays a key role in the production of cytokines. Previously, we determined that Salmonella bacteria are able to suppress their own autophagic capture and elimination by macrophages. Building on that study, we show here that the inhibition of autophagy by Salmonella also prevents the induction of a protective cytokine response mediated by beta interferon (IFN-β) and IFN-γ. Together, these findings identify a novel virulence strategy whereby Salmonella bacteria prevent cell autonomous elimination via autophagy and suppress the activation of innate immune responses.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/metabolism ; Animals ; Autophagy ; Focal Adhesion Protein-Tyrosine Kinases/genetics ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Immunity, Innate ; Interferon-beta/biosynthesis ; Interferon-beta/immunology ; Interferon-gamma/biosynthesis ; Interferon-gamma/immunology ; Intestines/cytology ; Killer Cells, Natural/immunology ; Macrophages/immunology ; Macrophages/microbiology ; Mice ; Mice, Knockout ; Salmonella Infections, Animal/immunology ; Salmonella Infections, Animal/microbiology ; Salmonella typhimurium/immunology ; Salmonella typhimurium/pathogenicity ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 4/metabolism
Chemical Substances	Adaptor Proteins, Vesicular Transport ; TICAM-1 protein, mouse ; Toll-Like Receptor 3 ; Toll-Like Receptor 4 ; Interferon-beta (77238-31-4) ; Interferon-gamma (82115-62-6) ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2)
Language	English
Publishing date	2016-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.02051-15
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Article ; Online: The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus.

Catalina, Michelle D / Owen, Katherine A / Labonte, Adam C / Grammer, Amrie C / Lipsky, Peter E

Journal of autoimmunity

2019 Volume 110, Page(s) 102359

Abstract: Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that causes damage to multiple organ systems. Despite decades of research and available murine models that capture some aspects of the human disease, new treatments for SLE lag ... ...

Abstract	Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that causes damage to multiple organ systems. Despite decades of research and available murine models that capture some aspects of the human disease, new treatments for SLE lag behind other autoimmune diseases such as Rheumatoid Arthritis and Crohn's disease. Big data genomic assays have transformed our understanding of SLE by providing important insights into the molecular heterogeneity of this multigenic disease. Gene wide association studies have demonstrated more than 100 risk loci, supporting a model of multiple genetic hits increasing SLE risk in a non-linear fashion, and providing evidence of ancestral diversity in susceptibility loci. Epigenetic studies to determine the role of methylation, acetylation and non-coding RNAs have provided new understanding of the modulation of gene expression in SLE patients and identified new drug targets and biomarkers for SLE. Gene expression profiling has led to a greater understanding of the role of myeloid cells in the pathogenesis of SLE, confirmed roles for T and B cells in SLE, promoted clinical trials based on the prominent interferon signature found in SLE patients, and identified candidate biomarkers and cellular signatures to further drug development and drug repurposing. Gene expression studies are advancing our understanding of the underlying molecular heterogeneity in SLE and providing hope that patient stratification will expedite new therapies based on personal molecular signatures. Although big data analyses present unique interpretation challenges, both computationally and biologically, advances in machine learning applications may facilitate the ability to predict changes in SLE disease activity and optimize therapeutic strategies.
MeSH term(s)	Alleles ; Animals ; Big Data ; Biomarkers ; Data Mining ; Disease Susceptibility/immunology ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/etiology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/therapy ; Machine Learning ; Precision Medicine/methods
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-12-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2019.102359
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