|
1
|
Ates I, Terzi U, Suzen S, Irham LM. An overview on Sjögren's syndrome and systemic lupus erythematosus' genetics. Toxicol Res (Camb) 2025; 14:tfae194. [PMID: 39991010 PMCID: PMC11847510 DOI: 10.1093/toxres/tfae194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/13/2024] [Accepted: 02/14/2025] [Indexed: 02/25/2025] Open
Abstract
Major autoimmune rheumatic disorders, such as systemic lupus erythematosus and Sjögren's syndrome, are defined by the presence of autoantibodies. These diseases are brought on by immune system dysregulation, which can present clinically in a wide range of ways. The etiologies of these illnesses are complex and heavily impacted by a variety of genetic and environmental variables. The most powerful susceptibility element for each of these disorders is still the human leukocyte antigen (HLA) area, that was the initial locus found to be associated. This region is primarily responsible for the HLA class II genes, such as DQA1, DQB1, and DRB1, however class I genes have also been linked. Numerous genetic variants that do not pose a risk to HLA have been found as a result of intensive research into the genetic component of these diseases conducted over the last 20 years. Furthermore, it is generally acknowledged that autoimmune rheumatic illnesses have similar genetic backgrounds and share molecular pathways of disease, including the interferon (IFN) type I routes. Pleiotropic sites for autoimmune rheumatic illnesses comprise TNIP1, DNASEL13, IRF5, the HLA region, and others. It remains a challenge to determine the causative biological mechanisms beneath the genetic connections. Nonetheless, functional analyses of the loci and mouse models have produced recent advancements. With an emphasis on the HLA region, we present an updated summary of the structure of genes underpinning both of these autoimmune rheumatic illnesses here.
Collapse
Affiliation(s)
- Ilker Ates
- Department of Toxicology, Ankara University, Faculty of Pharmacy, Emniyet Distr, Degol Str, No. 4, 06560 Yenimahalle, Ankara, Turkey
| | - Ulku Terzi
- Department of Toxicology, Ankara University, Faculty of Pharmacy, Emniyet Distr, Degol Str, No. 4, 06560 Yenimahalle, Ankara, Turkey
| | - Sinan Suzen
- Department of Toxicology, Ankara University, Faculty of Pharmacy, Emniyet Distr, Degol Str, No. 4, 06560 Yenimahalle, Ankara, Turkey
| | - Lalu Muhammad Irham
- Department of Toxicology, Ahmad Dahlan University, Faculty of Pharmacy, Prof. Dr. Soepomo, S.H., Street, Warungboto, 55164, Yogyakarta, Indonesia
| |
Collapse
|
|
2
|
Janssen LM, Lemaire F, Sanchez-Calero CL, Huaux F, Ronsmans S, Hoet PH, Ghosh M. External and internal exposome as triggers of biological signalling in systemic sclerosis - A narrative synthesis. J Autoimmun 2025; 150:103342. [PMID: 39643962 DOI: 10.1016/j.jaut.2024.103342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/20/2024] [Accepted: 11/25/2024] [Indexed: 12/09/2024]
Abstract
Systemic sclerosis (SSc) is an autoimmune chronic connective tissue disorder with a complex pathogenesis and a strong gene-environment interaction. Despite the low prevalence of SSc, with around 100-250 cases per million, the morbidity and mortality are high and disproportionately affecting women. In this context, we review the influence of the external and internal exposome on the "immunome" in SSc. While several studies have addressed aspects of exposure-induced autoimmunity in general, very few have focused on SSc-specific phenotypes. In epidemiological studies, targeted characterization of the external exposome component in relation to SSc has often been limited to a single exposure. Despite the selective characterization of exposure, such studies play an important role in providing evidence that can be used towards reduction of exposure of modifiable factors, and can lead to proper management and prevention of SSc. Additionally, there is an effort towards integration of external exposome data with health data (health records, medical imaging, diagnostic results, etc.), to significantly improve our understanding of the environmental and occupational causes of SSc. A limited number of studies have identified biological processes related to the vascular homeostasis, fibrotic processes and the immune system. The key findings of the current review show advances in our understanding of the SSc disease phenotype and associated biomarkers in relation to specific pathophysiological features, however most often such studies are not supplemented with external exposome data.
Collapse
Affiliation(s)
- Lisa Mf Janssen
- Environment and Health, Department of Public Health and Primary Care, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Frauke Lemaire
- Environment and Health, Department of Public Health and Primary Care, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | | | - François Huaux
- Louvain Center for Toxicology and Applied Pharmacology, UCLouvain, Brussels, Belgium
| | - Steven Ronsmans
- Environment and Health, Department of Public Health and Primary Care, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Peter Hm Hoet
- Environment and Health, Department of Public Health and Primary Care, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
| | - Manosij Ghosh
- Environment and Health, Department of Public Health and Primary Care, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
| |
Collapse
|
|
3
|
Alghamdi AG, Alanazi AM, Nourelden AZ, Alhamidi HA, Al Ibrahim BK, Alshowair MA, Tawfik MM, Bawazir AH, Nagadi OS, Alshehri HM, Alahmari MS. Coexisting autoimmune disorders among patients with inflammatory bowel disease at a tertiary center in Saudi Arabia: A cross-sectional study. Saudi J Gastroenterol 2025; 31:41-49. [PMID: 39757766 PMCID: PMC11804963 DOI: 10.4103/sjg.sjg_259_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/17/2024] [Accepted: 11/18/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Approximately 25% of individuals with inflammatory bowel disease (IBD) concurrently experience immune-mediated inflammatory diseases (IMIDs), while the overall prevalence of these conditions in the general population is 5-7%. Individuals with IBD and concurrent IMIDs tend to have a more aggressive disease profile. We aimed to assess the prevalence of coexisting autoimmune disorders among patients with IBD and their association with inflammatory bowel disease type. METHODS In this cross-sectional study at a tertiary care center in Riyadh, Saudi Arabia, we examined 875 patients with IBD (530 with Crohn's disease and 345 with ulcerative colitis). Patient demographics, disease types, treatment modalities, and co-occurring autoimmune conditions were analyzed using statistical and regression analyses. RESULTS Overall, 21.7%, 19.4%, and 25.2% of the patients had IMIDs, Crohn's disease, and ulcerative colitis, respectively. Patients with ulcerative colitis had higher rates of hepatic autoimmune conditions (9.6%) and endocrine autoimmune diseases (4.1% vs 1.3%; P = 0.010) than those with Crohn's disease (4.5%; P = 0.003). Regression analysis revealed significant associations between hepatic (P = 0.012) and endocrine autoimmune diseases (P = 0.018) with ulcerative colitis diagnosis, although the model's predictive accuracy was moderate (overall, 63%; specificity, 95%; sensitivity, 14%). CONCLUSIONS Our study highlights the significant co-occurrence of autoimmune diseases with IBD, particularly the distinct autoimmune profiles of Crohn's disease and ulcerative colitis. Identifying the specific ulcerative colitis-associated autoimmune comorbidities could guide personalized therapeutic strategies and inform future research on the pathophysiological relationship between these conditions.
Collapse
Affiliation(s)
- Ahmed G. Alghamdi
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
- Department of Internal Medicine, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia
| | - Aisha M. Alanazi
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| | | | - Hussam A. Alhamidi
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Bashaar K. Al Ibrahim
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mishal A. Alshowair
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Marwa M. Tawfik
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
- Internal Medicine Department, Hepatobiliary Unit, Alexandria Faculty of Medicine, Alexandria, Egypt
| | - Abdullah H. Bawazir
- Department of Internal Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Omar S. Nagadi
- Department of Internal Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Hameed M. Alshehri
- Department of Internal Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mohammed S. Alahmari
- Department of Gastroenterology and Hepatology, King Fahad Medical City, Riyadh, Saudi Arabia
| |
Collapse
|
|
4
|
Buianova A, Yukina M, Cheranev V, Suchalko O, Shmitko A, Samitova A, Nuralieva N, Kulagina E, Savvateeva E, Troshina E, Rebrikov D, Gryadunov D, Korostin D. Trio-based exome sequencing and high-resolution HLA typing in families of patients with autoimmune adrenal insufficiency and autoimmune polyglandular syndrome. PLoS One 2024; 19:e0312335. [PMID: 39423205 PMCID: PMC11488712 DOI: 10.1371/journal.pone.0312335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 10/01/2024] [Indexed: 10/21/2024] Open
Abstract
Autoimmune adrenal insufficiency (AAI) is a rare disease. This research evaluates three patients with AAI, including autoimmune polyglandular syndrome (APS) type 2. Two patients had APS or AAI during childhood, and one had a history of endocrine autoimmune disease, indicating a possible hereditary basis of the condition. Trio-based exome sequencing and high-resolution HLA typing were employed to analyze patients and their parents. Benign or likely benign variants of the AIRE gene were identified in all participants of the study. These variants, coupled with clinical data and the results of antibody studies to type I interferons, helped to exclude APS-1. Patients with APS-2, in contrast to patient with AAI, inherited distinct variants of unknown significance in the CLEC16A gene, which is associated with autoimmune diseases, including AAI. Various risk alleles in other genes associated with autoimmunity were identified in all patients. HLA typing of class II loci revealed alleles related to APS. Nevertheless, the frequencies of the haplotypes identified are substantial in the healthy Russian population. Immunological tests can detect antibody carriers and assess the risk of autoimmune disease development. In the future, to identify genetic predictors of autoimmune endocrinopathies, it is recommended to analyze the whole genome of patients and their relatives, examining clinically relevant variants in non-coding regions.
Collapse
Affiliation(s)
- Anastasiia Buianova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Marina Yukina
- Endocrinology Research Centre, Ministry of Health of Russia, Moscow, Russia
| | - Valery Cheranev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Oleg Suchalko
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
- Abu Dhabi Stem Cells Center, Abu Dhabi, United Arab Emirates
| | - Anna Shmitko
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Alina Samitova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Nurana Nuralieva
- Endocrinology Research Centre, Ministry of Health of Russia, Moscow, Russia
| | - Elena Kulagina
- Engelhardt Institute of Molecular Biology (EIMB), Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Russian Academy of Sciences, Moscow, Russia
| | - Elena Savvateeva
- Engelhardt Institute of Molecular Biology (EIMB), Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Russian Academy of Sciences, Moscow, Russia
| | - Ekaterina Troshina
- Endocrinology Research Centre, Ministry of Health of Russia, Moscow, Russia
| | - Denis Rebrikov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Dmitry Gryadunov
- Engelhardt Institute of Molecular Biology (EIMB), Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Russian Academy of Sciences, Moscow, Russia
| | - Dmitriy Korostin
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| |
Collapse
|
|
5
|
Sadeghi P, Karimi H, Lavafian A, Rashedi R, Samieefar N, Shafiekhani S, Rezaei N. Machine learning and artificial intelligence within pediatric autoimmune diseases: applications, challenges, future perspective. Expert Rev Clin Immunol 2024; 20:1219-1236. [PMID: 38771915 DOI: 10.1080/1744666x.2024.2359019] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 05/20/2024] [Indexed: 05/23/2024]
Abstract
INTRODUCTION Autoimmune disorders affect 4.5% to 9.4% of children, significantly reducing their quality of life. The diagnosis and prognosis of autoimmune diseases are uncertain because of the variety of onset and development. Machine learning can identify clinically relevant patterns from vast amounts of data. Hence, its introduction has been beneficial in the diagnosis and management of patients. AREAS COVERED This narrative review was conducted through searching various electronic databases, including PubMed, Scopus, and Web of Science. This study thoroughly explores the current knowledge and identifies the remaining gaps in the applications of machine learning specifically in the context of pediatric autoimmune and related diseases. EXPERT OPINION Machine learning algorithms have the potential to completely change how pediatric autoimmune disorders are identified, treated, and managed. Machine learning can assist physicians in making more precise and fast judgments, identifying new biomarkers and therapeutic targets, and personalizing treatment strategies for each patient by utilizing massive datasets and powerful analytics.
Collapse
Affiliation(s)
- Parniyan Sadeghi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hanie Karimi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Atiye Lavafian
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Semnan University of Medical Science, Semnan, Iran
| | - Ronak Rashedi
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Noosha Samieefar
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- USERN Office, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Shafiekhani
- Department of Biomedical Engineering, Buein Zahra Technical University, Qazvin, Iran
| | - Nima Rezaei
- Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
6
|
Holt EA, Tyler A, Lakusta-Wong T, Lahue KG, Hankes KC, Teuscher C, Lynch RM, Ferris MT, Mahoney JM, Krementsov DN. Probing the basis of disease heterogeneity in multiple sclerosis using genetically diverse mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.03.597205. [PMID: 38895248 PMCID: PMC11185616 DOI: 10.1101/2024.06.03.597205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The thirty-two CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary (AR)-EAE, accompanied by distinct immunopathology. Sex differences in EAE severity were observed in six strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity ( Abcc4 and Gpc6 ) and AR-EAE ( Yap1 and Dync2h1 ). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation. Summary The genetic basis of disease heterogeneity in multiple sclerosis (MS) remains elusive. We leveraged the Collaborative Cross to expand the phenotypic repertoire of the experimental autoimmune encephalomyelitis (EAE) model of MS and identify loci controlling EAE severity, trajectory, and presentation.
Collapse
|
|
7
|
Kars ME, Wu Y, Stenson PD, Cooper DN, Burisch J, Peter I, Itan Y. The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity. Genome Med 2024; 16:66. [PMID: 38741190 PMCID: PMC11092054 DOI: 10.1186/s13073-024-01335-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/16/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. METHODS We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. RESULTS The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein-protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. CONCLUSIONS Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.
Collapse
Affiliation(s)
- Meltem Ece Kars
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yiming Wu
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- College of Life Science, China West Normal University, Nan Chong, Si Chuan, 637009, China
| | - Peter D Stenson
- Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK
| | - David N Cooper
- Institute of Medical Genetics, Cardiff University, Cardiff, CF14 4XN, UK
| | - Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital - Amager and Hvidovre, Kettegård Alle 30, Hvidovre, Copenhagen, 2650, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Copenhagen University Hospital - Amager and Hvidovre, Kettegård Alle 30, Hvidovre, Copenhagen, 2650, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, 2200, Denmark
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Yuval Itan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| |
Collapse
|
|
8
|
Kerns S, Owen KA, Schwalbe D, Grammer AC, Lipsky PE. Examination of the shared genetic architecture between multiple sclerosis and systemic lupus erythematosus facilitates discovery of novel lupus risk loci. Hum Genet 2024; 143:703-719. [PMID: 38609570 DOI: 10.1007/s00439-024-02672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 03/24/2024] [Indexed: 04/14/2024]
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 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.
Collapse
Affiliation(s)
- Sophia Kerns
- AMPEL BioSolutions, LLC, Charlottesville, VA, 22902, USA.
- The RILITE Research Institute, Charlottesville, VA, 22902, USA.
| | - Katherine A Owen
- AMPEL BioSolutions, LLC, Charlottesville, VA, 22902, USA
- The RILITE Research Institute, Charlottesville, VA, 22902, USA
| | - Dana Schwalbe
- AMPEL BioSolutions, LLC, Charlottesville, VA, 22902, USA
- The RILITE Research Institute, Charlottesville, VA, 22902, USA
| | - Amrie C Grammer
- AMPEL BioSolutions, LLC, Charlottesville, VA, 22902, USA
- The RILITE Research Institute, Charlottesville, VA, 22902, USA
| | - Peter E Lipsky
- AMPEL BioSolutions, LLC, Charlottesville, VA, 22902, USA
- The RILITE Research Institute, Charlottesville, VA, 22902, USA
| |
Collapse
|
|
9
|
Huang HYR, Wireko AA, Miteu GD, Khan A, Roy S, Ferreira T, Garg T, Aji N, Haroon F, Zakariya F, Alshareefy Y, Pujari AG, Madani D, Papadakis M. Advancements and progress in juvenile idiopathic arthritis: A Review of pathophysiology and treatment. Medicine (Baltimore) 2024; 103:e37567. [PMID: 38552102 PMCID: PMC10977530 DOI: 10.1097/md.0000000000037567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 02/20/2024] [Indexed: 04/02/2024] Open
Abstract
Juvenile idiopathic arthritis (JIA) is a chronic clinical condition characterized by arthritic features in children under the age of 16, with at least 6 weeks of active symptoms. The etiology of JIA remains unknown, and it is associated with prolonged synovial inflammation and structural joint damage influenced by environmental and genetic factors. This review aims to enhance the understanding of JIA by comprehensively analyzing relevant literature. The focus lies on current diagnostic and therapeutic approaches and investigations into the pathoaetiologies using diverse research modalities, including in vivo animal models and large-scale genome-wide studies. We aim to elucidate the multifactorial nature of JIA with a strong focus towards genetic predilection, while proposing potential strategies to improve therapeutic outcomes and enhance diagnostic risk stratification in light of recent advancements. This review underscores the need for further research due to the idiopathic nature of JIA, its heterogeneous phenotype, and the challenges associated with biomarkers and diagnostic criteria. Ultimately, this contribution seeks to advance the knowledge and promote effective management strategies in JIA.
Collapse
Affiliation(s)
- Helen Ye Rim Huang
- Faculty of Medicine and Health Science, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Goshen David Miteu
- School of Biosciences, Biotechnology, University of Nottingham, Nottingham, UK
- Department of Biochemistry, Caleb University Lagos, Lagos, Nigeria
| | - Adan Khan
- Kent and Medway Medical School, Canterbury, Kent, UK
| | - Sakshi Roy
- School of Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UK
| | - Tomas Ferreira
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Tulika Garg
- Government Medical College and Hospital Chandigarh, Chandigarh, India
| | - Narjiss Aji
- Faculty of Medicine and Pharmacy of Rabat, Rabat, Morocco
| | - Faaraea Haroon
- Faculty of Public Health, Health Services Academy, Islamabad, Pakistan
| | - Farida Zakariya
- Faculty of Pharmaceutical Sciences, Ahmadu Bello University Zaria, Zaria, Nigeria
| | - Yasir Alshareefy
- School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Anushka Gurunath Pujari
- Faculty of Medicine and Health Science, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Kinesiology, Faculty of Science, McMaster University, Hamilton, Ontario, Canada
| | - Djabir Madani
- UCD Lochlann Quinn School of Business and Sutherland School of Law, University College Dublin, Dublin, Ireland
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Wuppertal, Germany
| |
Collapse
|
|
10
|
Tian R, Ghosh S. Mechanisms and functions of lncRNAs linked to autoimmune disease risk alleles. Adv Immunol 2024; 161:1-15. [PMID: 38763698 DOI: 10.1016/bs.ai.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
Recent advances in human genomics technologies have helped uncover genetic risk alleles for many complex autoimmune diseases. Intriguingly, over 90% of genome-wide association study (GWAS) risk alleles reside within the non-coding regions of the genome. An emerging new frontier of functional and mechanistic studies have shed light on the functional relevance of risk alleles that lie within long noncoding RNAs (lncRNAs). Here, we review the mechanisms and functional implications of five evolutionarily conserved lncRNAs that display risk allele association with highly prevalent autoimmune diseases.
Collapse
Affiliation(s)
- Ruxiao Tian
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States
| | - Sankar Ghosh
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, United States.
| |
Collapse
|
|
11
|
Dressman D, Tasaki S, Yu L, Schneider J, Bennett DA, Elyaman W, Vardarajan B. Polygenic risk associated with Alzheimer's disease and other traits influences genes involved in T cell signaling and activation. Front Immunol 2024; 15:1337831. [PMID: 38590520 PMCID: PMC10999606 DOI: 10.3389/fimmu.2024.1337831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 02/22/2024] [Indexed: 04/10/2024] Open
Abstract
Introduction T cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants. Methods We first compute a polygenic risk score (PRS) for Alzheimer's disease (AD) using genomic sequencing data from a cohort of Alzheimer's disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes. Results Several genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes. Discussion Our findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions.
Collapse
Affiliation(s)
- Dallin Dressman
- Department of Neurology, Columbia University, New York, NY, United States
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States
| | - Shinya Tasaki
- Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL, United States
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
| | - Lei Yu
- Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL, United States
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
| | - Julie Schneider
- Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL, United States
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
- Department of Pathology, Rush University Medical Center, Chicago, IL, United States
| | - David A Bennett
- Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL, United States
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
| | - Wassim Elyaman
- Department of Neurology, Columbia University, New York, NY, United States
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States
| | - Badri Vardarajan
- Department of Neurology, Columbia University, New York, NY, United States
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States
- College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, The Gertrude H. Sergievsky Center, New York, NY, United States
| |
Collapse
|
|
12
|
Yaqubi K, Kostev K, Klein I, Schüssler S, May P, Luedde T, Roderburg C, Loosen SH. Inflammatory bowel disease is associated with an increase in the incidence of multiple sclerosis: a retrospective cohort study of 24,934 patients. Eur J Med Res 2024; 29:186. [PMID: 38504334 PMCID: PMC10953134 DOI: 10.1186/s40001-024-01776-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 03/08/2024] [Indexed: 03/21/2024] Open
Abstract
BACKGROUND Recent data suggest a potential pathophysiological link between inflammatory bowel disease (IBD) and multiple sclerosis (MS), two immune-mediated diseases both of which can have a significant impact on patients' quality of life. In the present manuscript, we investigate the association between IBD and MS in a German cohort of general practice patients. These results may have important implications for the screening and management of patients with IBD, as well as for further research into the pathophysiological mechanisms underlying both disorders. METHODS 4,934 individuals with IBD (11,140 with Crohn's disease (CD) and 13,794 with ulcerative colitis (UC)) as well as 24,934 propensity score matched individuals without IBD were identified from the Disease Analyzer database (IQVIA). A subsequent diagnosis of MS was analyzed as a function of IBD using Cox regression models. RESULTS After 10 years of follow-up, 0.9% and 0.7% of CD and UC patients but only 0.5% and 0.3% of matched non-IBD pairs were diagnosed with MS, respectively (pCD = 0.002 and pUC < 0.001). Both CD (HR: 2.09; 95% CI 1.28-3.39) and UC (HR: 2.35; 95% CI 1.47-3.78) were significantly associated with a subsequent MS diagnosis. Subgroup analysis revealed that the association between both CD and UC and MS was more pronounced among male patients. CONCLUSION The results of our analysis suggest a notable association between IBD and a subsequent MS diagnosis. These findings warrant further pathophysiological investigation and may have clinical implications for the screening of IBD patients in the future.
Collapse
Affiliation(s)
- Kaneschka Yaqubi
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | | | | | | | - Petra May
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Christoph Roderburg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sven H Loosen
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
| |
Collapse
|
|
13
|
Zhang J, Qi J, Li Y, Wang J, Jiang H, Sun Q, Gu Q, Ying Z. Association between type 1 diabetes mellitus and ankylosing spondylitis: a two-sample Mendelian randomization study. Front Immunol 2023; 14:1289104. [PMID: 38173714 PMCID: PMC10762686 DOI: 10.3389/fimmu.2023.1289104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/01/2023] [Indexed: 01/05/2024] Open
Abstract
Objective The development of ankylosing spondylitis (AS) is closely related to autoimmune system dysfunction. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that is a risk factor for many diseases. This study aimed to investigate the causal relationship between T1DM mellitus and AS genetically. Methods A genome-wide association study (GWAS) of causal relationships between exposure (T1DM) and outcome (AS) was performed using summary data from the GWAS database. We conducted a two-sample Mendelian randomization (MR) study of these two diseases. Inverse variance weighting (IVW) was used as the primary analysis method, with MR Egger, weighted median, and weighted mode used as supplementary methods. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-Pleiotropy RESidual Sum and outlier methods, leave-one-out analysis, and funnel plots. Results A total of 11 single nucleotide polymorphisms (SNPs)were identified for instrumental variables(IVs) for MR analysis.IVW found that T1DM was causally associated with AS ((IVW: OR = 1.0006 (95% CI 1.0001, 1.0011), p = 0.0057; MR-Egger: OR = 1.0003 (95% CI 0.9995, 1.0012), p = 0.4147; weighted median: OR = 1.0006 (95% CI 1.0003, 1.0008), p = 0.0001; weighted mode: OR = 1.0007 (95% CI 1.0005, 1.0009), p = 0.0001). No horizontal pleiotropy was found for the MR-Egger intercept, and leave -one-out analysis found that the results remained stable after the removal of individual SNPs. Conclusion The results of the two-sample MR analysis supported a causal relationship between T1DM and AS risk.
Collapse
Affiliation(s)
- Ju Zhang
- Jinzhou Medical University Graduate Training Base Zhejiang Provincial People's Hospital, Center for General Practice Medicine, Department of Rheumatology and Immunology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Jiaping Qi
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Yixuan Li
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Jing Wang
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Huan Jiang
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Qiong Sun
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Qinchen Gu
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| | - Zhenhua Ying
- Jinzhou Medical University Graduate Training Base Zhejiang Provincial People's Hospital, Center for General Practice Medicine, Department of Rheumatology and Immunology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine Cultivation for Arthritis Diagnosis and Treatment, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hang zhou Medical College, Hangzhou, Zhejiang, China
| |
Collapse
|
|
14
|
Bogers L, Kuiper KL, Smolders J, Rip J, van Luijn MM. Epstein-Barr virus and genetic risk variants as determinants of T-bet + B cell-driven autoimmune diseases. Immunol Lett 2023; 261:66-74. [PMID: 37451321 DOI: 10.1016/j.imlet.2023.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 06/07/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such 'atypical' memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet+ B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein-Barr virus (EBV). The impact of EBV on T-bet+ B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet+ B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet+ B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet+ B-cell formation.
Collapse
Affiliation(s)
- Laurens Bogers
- MS Center ErasMS, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Kirsten L Kuiper
- MS Center ErasMS, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Joost Smolders
- MS Center ErasMS, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands; MS Center ErasMS, Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 CN, The Netherlands; Netherlands Institute for Neuroscience, Neuroimmunology research group, Amsterdam 1105 BA, The Netherlands
| | - Jasper Rip
- MS Center ErasMS, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands
| | - Marvin M van Luijn
- MS Center ErasMS, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Wytemaweg 80, Rotterdam 3015 CN, The Netherlands.
| |
Collapse
|
|
15
|
Afrasiabi A, Ahlenstiel C, Swaminathan S, Parnell GP. The interaction between Epstein-Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities. Clin Transl Immunology 2023; 12:e1454. [PMID: 37337612 PMCID: PMC10276892 DOI: 10.1002/cti2.1454] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/30/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease, characterised by the demyelination of neurons in the central nervous system. Whilst it is unclear what precisely leads to MS, it is believed that genetic predisposition combined with environmental factors plays a pivotal role. It is estimated that close to half the disease risk is determined by genetic factors. However, the risk of developing MS cannot be attributed to genetic factors alone, and environmental factors are likely to play a significant role by themselves or in concert with host genetics. Epstein-Barr virus (EBV) infection is the strongest known environmental risk factor for MS. There has been increasing evidence that leaves little doubt that EBV is necessary, but not sufficient, for developing MS. One plausible explanation is EBV may alter the host immune response in the presence of MS risk alleles and this contributes to the pathogenesis of MS. In this review, we discuss recent findings regarding how EBV infection may contribute to MS pathogenesis via interactions with genetic risk loci and discuss possible therapeutic interventions.
Collapse
Affiliation(s)
- Ali Afrasiabi
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- The Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyNSWAustralia
| | - Chantelle Ahlenstiel
- Kirby InstituteUniversity of New South WalesSydneyNSWAustralia
- RNA InstituteUniversity of New South WalesSydneyNSWAustralia
| | - Sanjay Swaminathan
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- Department of MedicineWestern Sydney UniversitySydneyNSWAustralia
| | - Grant P Parnell
- EBV Molecular Lab, Centre for Immunology and Allergy Research, Westmead Institute for Medical ResearchUniversity of SydneySydneyNSWAustralia
- Biomedical Informatics and Digital Health, School of Medical Sciences, Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia
| |
Collapse
|
|
16
|
Wen YP, Yu ZG. Identifying shared genetic loci and common risk genes of rheumatoid arthritis associated with three autoimmune diseases based on large-scale cross-trait genome-wide association studies. Front Immunol 2023; 14:1160397. [PMID: 37377963 PMCID: PMC10291128 DOI: 10.3389/fimmu.2023.1160397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Introduction Substantial links between autoimmune diseases have been shown by an increasing number of studies, and one hypothesis for this comorbidity is that there is a common genetic cause. Methods In this paper, a large-scale cross-trait Genome-wide Association Studies (GWAS) was conducted to investigate the genetic overlap among rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes. Results and discussion Through the local genetic correlation analysis, 2 regions with locally significant genetic associations between rheumatoid arthritis and multiple sclerosis, and 4 regions with locally significant genetic associations between rheumatoid arthritis and type 1 diabetes were discovered. By cross-trait meta-analysis, 58 independent loci associated with rheumatoid arthritis and multiple sclerosis, 86 independent loci associated with rheumatoid arthritis and inflammatory bowel disease, and 107 independent loci associated with rheumatoid arthritis and type 1 diabetes were identified with genome-wide significance. In addition, 82 common risk genes were found through genetic identification. Based on gene set enrichment analysis, it was found that shared genes are enriched in exposed dermal system, calf, musculoskeletal, subcutaneous fat, thyroid and other tissues, and are also significantly enriched in 35 biological pathways. To verify the association between diseases, Mendelian randomized analysis was performed, which shows possible causal associations between rheumatoid arthritis and multiple sclerosis, and between rheumatoid arthritis and type 1 diabetes. The common genetic structure of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes was explored by these studies, and it is believed that this important discovery will lead to new ideas for clinical treatment.
Collapse
Affiliation(s)
- Ya-Ping Wen
- National Center for Applied Mathematics in Hunan, Xiangtan University, Hunan, China
- Key Laboratory of Intelligent Computing and Information Processing of Ministry of Education, Xiangtan University, Hunan, China
| | - Zu-Guo Yu
- National Center for Applied Mathematics in Hunan, Xiangtan University, Hunan, China
- Key Laboratory of Intelligent Computing and Information Processing of Ministry of Education, Xiangtan University, Hunan, China
| |
Collapse
|
|
17
|
Baglaenko Y, Wagner C, Bhoj VG, Brodin P, Gershwin ME, Graham D, Invernizzi P, Kidd KK, Korsunsky I, Levy M, Mammen AL, Nizet V, Ramirez-Valle F, Stites EC, Williams MS, Wilson M, Rose NR, Ladd V, Sirota M. Making inroads to precision medicine for the treatment of autoimmune diseases: Harnessing genomic studies to better diagnose and treat complex disorders. CAMBRIDGE PRISMS. PRECISION MEDICINE 2023; 1:e25. [PMID: 38550937 PMCID: PMC10953750 DOI: 10.1017/pcm.2023.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 06/13/2024]
Abstract
Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.
Collapse
Affiliation(s)
| | | | | | | | | | - Daniel Graham
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
| | - Kenneth K. Kidd
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Michael Levy
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andrew L. Mammen
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, USA
| | - Victor Nizet
- School of Medicine, University of California San Diego, San Diego, CA, USA
| | | | - Edward C. Stites
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
| | | | - Michael Wilson
- Weill Institute for Neurosciences, Department of Neurology, UCSF, San Francisco, CA, USA
| | - Noel R. Rose
- Autoimmune Association, Clinton Township, MI, USA
| | | | - Marina Sirota
- Bakar Computational Health Sciences Institute, UCSF, San Francisco, CA, USA
- Department of Pediatrics, UCSF, San Francisco, CA, USA
| |
Collapse
|
|
18
|
Lee HJ, Lee SW, Cha HR, Ha EK, Kim JH, Shin SY, Lee KC, Leung PSC, Han MY, Choi JJ, Gershwin ME. Acquired susceptibility to autoimmune diseases in pediatric patients with Escherichia coli infection: A population-matched retrospective cohort study. J Autoimmun 2023; 137:102997. [PMID: 36737299 DOI: 10.1016/j.jaut.2023.102997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/26/2022] [Accepted: 01/07/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND Escherichia coli (E.coli) infection has been proposed to play an important role as an initial trigger in the development of autoimmunity via molecular mimicry. However, there has been no preliminary cohort study to establish the association of E.coli infection with autoimmune diseases. Therefore, we conducted a large scale, population-matched cohort study to determine the risk of autoimmune disease among patients with exposure to E.coli. METHODS Utilizing the National Health Insurance Service database, we retrospectively analyzed a total of 259,875 Korean children that consisted of 23,625 exposed and 236,250 unexposed persons from January 1, 2002 to December 31, 2017. The exposed cohort was defined as patients diagnosed with E.coli infection. Unexposed controls were matched by birth year and sex at a 1:10 ratio for each exposed patient, using incidence density sampling. The primary outcome was autoimmune disease development. We used the Cox model to estimate the risks of autoimmune diseases among patients diagnosed with E.coli infection. RESULTS Over a mean follow-up of 10 years, there were 1455 autoimmune disease cases among exposed patients (incidence rate, 63.6 per 10,000 person-years) and 11,646 autoimmune disease cases among unexposed persons (incidence rate, 50.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.254 (95% CI 1.187-1.325). E.coli infection was associated with increased risks of autoimmune diseases; Reactive arthritis, HR 1.487, 95% CI 1.131-1.956; Henoch Schönlein purpura, HR 1.265, 95% CI 1.050-1.524; Systemic lupus erythematosus, HR 1.838, 95% CI 1.165-2.898; Sjögren's syndrome, HR 2.002, 95% CI 1.342-2.987; IgA nephropathy, HR 1.613, 95% CI 1.388-1.874. Kaplan-Meier cumulative incidence curves also showed a significant association between E.coli infection and incident autoimmune disease (p < 0.0001). This relationship was not only independent of demographic variables, but also remained consistent across various sensitivity analyses. On the other hand, patients with longer hospital stay for E.coli infection were at a higher risk of autoimmune disease (p = 0.0003), and the risk of autoimmune disease also tended to increase, as the frequency of E.coli infection was higher. Moreover, the relative risk of autoimmune disease seemed to be attenuated by use of antibiotics and a history of intestinal infectious disease, but elevated by coexistence of other autoimmune diseases. CONCLUSIONS Our cohort study indicates that E.coli infection was significantly associated with increased susceptibility to autoimmune diseases, even after adjusting for different factors. Thus, among environmental factors, a previous history of E.coli infection could be a predisposing risk factor in the development of autoimmune diseases.
Collapse
Affiliation(s)
- Hyun Joo Lee
- Division of Rheumatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea
| | - Seung Won Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, 16416, South Korea
| | - Hye Ryeong Cha
- Department of Computer Science and Engineering, Sungkyunkwan University, Suwon, Republic of Korea
| | - Eun Kyo Ha
- Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University, 1 Singil-ro, Yeongdeungpo-gu, Seoul, 07441, South Korea
| | - Ju Hee Kim
- Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University, 150 Seongan-ro, Gangdong-gu, Seoul, 05355, South Korea
| | - Seung Yong Shin
- CHA University School of Medicine, 120 Haeryong-ro, Pocheon, 11160, South Korea
| | - Ki Cheon Lee
- Department of Computer Science and Engineering, College of Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California Davis, Davis, CA, 95616, USA
| | - Man Yong Han
- Division of Allergy & Respiratory Medicine, Department of Pediatrics, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
| | - Jin Jung Choi
- Division of Rheumatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, South Korea.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California Davis, Davis, CA, 95616, USA
| |
Collapse
|
|
19
|
Räisänen LK, Kääriäinen SE, Sund R, Engberg E, Viljakainen HT, Kolho KL. Antibiotic exposures and the development of pediatric autoimmune diseases: a register-based case-control study. Pediatr Res 2023; 93:1096-1104. [PMID: 35854091 PMCID: PMC10033398 DOI: 10.1038/s41390-022-02188-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/27/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Antibiotics have been associated with several individual autoimmune diseases (ADs). This study aims to discover whether pre-diagnostic antibiotics are associated with the onset of ADs in general. METHODS From a cohort of 11,407 children, 242 developed ADs (type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis (JIA), or inflammatory bowel diseases) by a median age of 16 years. Antibiotic purchases from birth until the date of diagnosis (or respective date in the matched controls n = 708) were traced from national registers. RESULTS Total number of antibiotic purchases was not related to the onset of ADs when studied as a group. Of specific diagnoses, JIA was associated with the total number of antibiotics throughout the childhood and with broad-spectrum antibiotics before the age of 3 years. Intriguingly, recent and frequent antibiotic use (within 2 years before diagnosis and ≥3 purchases) was associated with the onset of ADs (OR 1.72, 95% CI 1.08-2.74). Regardless of frequent use in childhood (40% of all antibiotics), penicillin group antibiotics were not related to any ADs. CONCLUSIONS Use of antibiotics was relatively safe regarding the overall development of ADs. However, broad-spectrum antibiotics should be used considerately as they may associate with an increased likelihood of JIA. IMPACT Increasing numbers of antibiotic purchases before the age of 3 years or throughout childhood were not associated with the development of pediatric autoimmune diseases. Broad-spectrum antibiotics were related to the development of autoimmune diseases, especially juvenile idiopathic arthritis in children, while penicillin group antibiotics were not. The use of broad-spectrum antibiotics in children should be cautious as they may carry along a risk for autoimmune disease development.
Collapse
Affiliation(s)
- Laura K Räisänen
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | | | - Reijo Sund
- Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Elina Engberg
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Heli T Viljakainen
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kaija-Leena Kolho
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland.
- Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
| |
Collapse
|
|
20
|
Khunsriraksakul C, Li Q, Markus H, Patrick MT, Sauteraud R, McGuire D, Wang X, Wang C, Wang L, Chen S, Shenoy G, Li B, Zhong X, Olsen NJ, Carrel L, Tsoi LC, Jiang B, Liu DJ. Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus. Nat Commun 2023; 14:668. [PMID: 36750564 PMCID: PMC9905560 DOI: 10.1038/s41467-023-36306-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 01/25/2023] [Indexed: 02/09/2023] Open
Abstract
Systemic lupus erythematosus is a heritable autoimmune disease that predominantly affects young women. To improve our understanding of genetic etiology, we conduct multi-ancestry and multi-trait meta-analysis of genome-wide association studies, encompassing 12 systemic lupus erythematosus cohorts from 3 different ancestries and 10 genetically correlated autoimmune diseases, and identify 16 novel loci. We also perform transcriptome-wide association studies, computational drug repurposing analysis, and cell type enrichment analysis. We discover putative drug classes, including a histone deacetylase inhibitor that could be repurposed to treat lupus. We also identify multiple cell types enriched with putative target genes, such as non-classical monocytes and B cells, which may be targeted for future therapeutics. Using this newly assembled result, we further construct polygenic risk score models and demonstrate that integrating polygenic risk score with clinical lab biomarkers improves the diagnostic accuracy of systemic lupus erythematosus using the Vanderbilt BioVU and Michigan Genomics Initiative biobanks.
Collapse
Affiliation(s)
- Chachrit Khunsriraksakul
- Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Qinmengge Li
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Havell Markus
- Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Matthew T Patrick
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Renan Sauteraud
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Daniel McGuire
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Xingyan Wang
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Chen Wang
- Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Lida Wang
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Siyuan Chen
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Ganesh Shenoy
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Bingshan Li
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN, 37235, USA
| | - Xue Zhong
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Nancy J Olsen
- Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Laura Carrel
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Lam C Tsoi
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Bibo Jiang
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Dajiang J Liu
- Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
| |
Collapse
|
|
21
|
Innate and adaptive immune abnormalities underlying autoimmune diseases: the genetic connections. SCIENCE CHINA. LIFE SCIENCES 2023:10.1007/s11427-021-2187-3. [PMID: 36738430 PMCID: PMC9898710 DOI: 10.1007/s11427-021-2187-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/10/2022] [Indexed: 02/05/2023]
Abstract
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
Collapse
|
|
22
|
Ayala-Ramirez M, MacNell N, McNamee LE, McGrath JA, Akhtari FS, Curry MD, Dunnon AK, Fessler MB, Garantziotis S, Parks CG, Fargo DC, Schmitt CP, Motsinger-Reif AA, Hall JE, Miller FW, Schurman SH. Association of distance to swine concentrated animal feeding operations with immune-mediated diseases: An exploratory gene-environment study. ENVIRONMENT INTERNATIONAL 2023; 171:107687. [PMID: 36527873 PMCID: PMC10962257 DOI: 10.1016/j.envint.2022.107687] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/03/2022] [Accepted: 12/07/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Concentrated animal feeding operations (CAFOs) are a source of environmental pollution and have been associated with a variety of health outcomes. Immune-mediated diseases (IMD) are characterized by dysregulation of the normal immune response and, while they may be affected by gene and environmental factors, their association with living in proximity to a CAFO is unknown. OBJECTIVES We explored gene, environment, and gene-environment (GxE) relationships between IMD, CAFOs, and single nucleotide polymorphisms (SNPs) of prototypical xenobiotic response genes AHR, ARNT, and AHRR and prototypical immune response gene PTPN22. METHODS The exposure analysis cohort consisted of 6,464 participants who completed the Personalized Environment and Genes Study Health and Exposure Survey and a subset of 1,541 participants who were genotyped. We assessed the association between participants' residential proximity to a CAFO in gene, environment, and GxE models. We recombined individual associations in a transethnic model using METAL meta-analysis. RESULTS In White participants, ARNT SNP rs11204735 was associated with autoimmune diseases and rheumatoid arthritis (RA), and ARNT SNP rs1889740 was associated with RA. In a transethnic genetic analysis, ARNT SNPs rs11204735 and rs1889740 and PTPN22 SNP rs2476601 were associated with autoimmune diseases and RA. In participants living closer than one mile to a CAFO, the log-distance to a CAFO was associated with autoimmune diseases and RA. In a GxE interaction model, White participants with ARNT SNPs rs11204735 and rs1889740 living closer than eight miles to a CAFO had increased odds of RA and autoimmune diseases, respectively. The transethnic model revealed similar GxE interactions. CONCLUSIONS Our results suggest increased risk of autoimmune diseases and RA in those living in proximity to a CAFO and a potential role of the AHR-ARNT pathway in conferring risk. We also report the first association of ARNT SNPs rs11204735 and rs1889740 with RA. Our findings, if confirmed, could allow for novel genetically-targeted or other preventive approaches for certain IMD.
Collapse
Affiliation(s)
- Montserrat Ayala-Ramirez
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - Nathaniel MacNell
- Social and Scientific Systems, 505 Emperor Blvd Suite 400, Durham, NC 27703, USA.
| | - Lucy E McNamee
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - John A McGrath
- Social and Scientific Systems, 505 Emperor Blvd Suite 400, Durham, NC 27703, USA.
| | - Farida S Akhtari
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - Matthew D Curry
- Social and Scientific Systems, 505 Emperor Blvd Suite 400, Durham, NC 27703, USA.
| | - Askia K Dunnon
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - Michael B Fessler
- Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop D2-01, Durham, NC 27709, USA.
| | - Stavros Garantziotis
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, BG 109 RM 109 MSC CU-01, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - Christine G Parks
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop A3-05, Durham, NC 27709, USA.
| | - David C Fargo
- Office of Scientific Computing, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop B3-01, Durham, NC 27709, USA.
| | - Charles P Schmitt
- Office of Data Science, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Mail Drop K2-02, Durham, NC 27709, USA.
| | - Alison A Motsinger-Reif
- PEGS Co-PI, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, RTP 101, Research Triangle Park, NC 27709, USA.
| | - Janet E Hall
- PEGS Co-PI, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, BG 101 RM A222 MSC A2-03. 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| | - Frederick W Miller
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, RTP 101 David P. Rall Building, Research Triangle Park, NC 27709, USA.
| | - Shepherd H Schurman
- Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
| |
Collapse
|
|
23
|
Melamud MM, Ermakov EA, Boiko AS, Kamaeva DA, Sizikov AE, Ivanova SA, Baulina NM, Favorova OO, Nevinsky GA, Buneva VN. Multiplex Analysis of Serum Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis. Int J Mol Sci 2022; 23:ijms232213829. [PMID: 36430309 PMCID: PMC9695219 DOI: 10.3390/ijms232213829] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 10/27/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
Changes in cytokine profiles and cytokine networks are known to be a hallmark of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). However, cytokine profiles research studies are usually based on the analysis of a small number of cytokines and give conflicting results. In this work, we analyzed cytokine profiles of 41 analytes in patients with SLE and MS compared with healthy donors using multiplex immunoassay. The SLE group included treated patients, while the MS patients were drug-free. Levels of 11 cytokines, IL-1b, IL-1RA, IL-6, IL-9, IL-10, IL-15, MCP-1/CCL2, Fractalkine/CX3CL1, MIP-1a/CCL3, MIP-1b/CCL4, and TNFa, were increased, but sCD40L, PDGF-AA, and MDC/CCL22 levels were decreased in SLE patients. Thus, changes in the cytokine profile in SLE have been associated with the dysregulation of interleukins, TNF superfamily members, and chemokines. In the case of MS, levels of 10 cytokines, sCD40L, CCL2, CCL3, CCL22, PDGF-AA, PDGF-AB/BB, EGF, IL-8, TGF-a, and VEGF, decreased significantly compared to the control group. Therefore, cytokine network dysregulation in MS is characterized by abnormal levels of growth factors and chemokines. Cross-disorder analysis of cytokine levels in MS and SLE showed significant differences between 22 cytokines. Protein interaction network analysis showed that all significantly altered cytokines in both SLE and MS are functionally interconnected. Thus, MS and SLE may be associated with impaired functional relationships in the cytokine network. A cytokine correlation networks analysis revealed changes in correlation clusters in SLE and MS. These data expand the understanding of abnormal regulatory interactions in cytokine profiles associated with autoimmune diseases.
Collapse
Affiliation(s)
- Mark M. Melamud
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Evgeny A. Ermakov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Anastasiia S. Boiko
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia
| | - Daria A. Kamaeva
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia
| | - Alexey E. Sizikov
- Institute of Clinical Immunology, Siberian Branch of the Russian Academy of Sciences, 630099 Novosibirsk, Russia
| | - Svetlana A. Ivanova
- Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 634014 Tomsk, Russia
| | - Natalia M. Baulina
- Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Olga O. Favorova
- Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Georgy A. Nevinsky
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Valentina N. Buneva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Correspondence: ; Tel.: +7-383-363-51-27
| |
Collapse
|
|
24
|
Nociti V, Romozzi M. Multiple Sclerosis and Autoimmune Comorbidities. J Pers Med 2022; 12:jpm12111828. [PMID: 36579555 PMCID: PMC9698878 DOI: 10.3390/jpm12111828] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/17/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by broad inter- and intraindividual heterogeneity and different prognoses. Multisystem comorbidities are frequent features in people with MS (PwMS) and can affect treatment choices, quality of life, disability and mortality. In this scenario, autoimmune comorbidities play a cardinal role for several reasons, such as the implication on MS pathogenesis, diagnostic delay, disease activity, disability progression, brain atrophy, and treatment choice. However, the impact of an autoimmune comorbid condition on MS is not fully elucidated. This review aims to summarize the currently available data on the incidence and prevalence of autoimmune diseases in PwMS, the possible effect of this association on clinical and neuroradiological MS course and its impact on treatment choice.
Collapse
Affiliation(s)
- Viviana Nociti
- Centro Sclerosi Multipla, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00168 Rome, Italy
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
| | - Marina Romozzi
- Centro Sclerosi Multipla, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00168 Rome, Italy
| |
Collapse
|
|
25
|
Abstract
Macroautophagy/autophagy, a fundamental cell process for nutrient recycling and defense against pathogens (termed xenophagy), is crucial to human health. ATG16L2 (autophagy related 16 like 2) is an autophagic protein and a paralog of ATG16L1. Both proteins are implicated in similar diseases such as cancer and other chronic diseases; however, most autophagy studies to date have primarily focused on the function of ATG16L1, with ATG16L2 remaining uncharacterized and understudied. Overexpression of ATG16L2 has been reported in various cancers including colorectal, gastric, and prostate carcinomas, whereas altered methylation of ATG16L2 has been associated with lung cancer formation and poorer response to therapy in leukemia. In addition, ATG16L2 polymorphisms have been implicated in a range of other diseases including inflammatory bowel diseases and neurodegenerative disorders. Despite this likely role in human health, the function of this enigmatic protein in autophagy remains unknown. Here, we review current studies on ATG16L2 and collate evidence that suggests that this protein is a potential modulator of autophagy as well as the implications this has on pathogenesis.Abbreviations: ATG5: autophagy related 5; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG16L2: autophagy related 16 like 2; CD: Crohn disease; IBD: inflammatory bowel diseases; IRGM: immunity related GTPase M; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PE: phosphatidylethanolamine; RB1CC1: RB1 inducible coiled-coil 1; SLE: systemic lupus erythematosus; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.
Collapse
Affiliation(s)
- Laurence Don Wai Luu
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia,CONTACT Laurence Don Wai Luu School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Nadeem O. Kaakoush
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia,Natalia Castaño-Rodríguez School of Biotechnology and Biomolecular Sciences, Faculty of Science, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| |
Collapse
|
|
26
|
Hackett J, Gibson H, Frelinger J, Buntzman A. Using the Collaborative Cross and Diversity Outbred Mice in Immunology. Curr Protoc 2022; 2:e547. [PMID: 36066328 PMCID: PMC9612550 DOI: 10.1002/cpz1.547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The Collaborative Cross (CC) and the Diversity Outbred (DO) stock mouse panels are the most powerful murine genetics tools available to the genetics community. Together, they combine the strength of inbred animal models with the diversity of outbred populations. Using the 63 CC strains or a panel of DO mice, each derived from the same 8 parental mouse strains, researchers can map genetic contributions to exceptionally complex immunological and infectious disease traits that would require far greater powering if performed by genome-wide association studies (GWAS) in human populations. These tools allow genes to be studied in heterozygous and homozygous states and provide a platform to study epistasis between interacting loci. Most importantly, once a quantitative phenotype is investigated and quantitative trait loci are identified, confirmatory genetic studies can be performed, which is often problematic using the GWAS approach. In addition, novel stable mouse models for immune phenotypes are often derived from studies utilizing the DO and CC mice that can serve as stronger model systems than existing ones in the field. The CC/DO systems have contributed to the fields of cancer immunology, autoimmunity, vaccinology, infectious disease, allergy, tissue rejection, and tolerance but have thus far been greatly underutilized. In this article, we present a recent review of the field and point out key areas of immunology that are ripe for further investigation and awaiting new CC/DO research projects. We also highlight some of the strong computational tools that have been developed for analyzing CC/DO genetic and phenotypic data. Additionally, we have formed a centralized community on the CyVerse infrastructure where immunogeneticists can utilize those software tools, collaborate with groups across the world, and expand the use of the CC and DO systems for investigating immunogenetic phenomena. © 2022 Wiley Periodicals LLC.
Collapse
Affiliation(s)
- Justin Hackett
- Barbara Ann Karmanos Cancer Institute, Hudson-Webber Cancer Research Center, Detroit, Michigan
| | - Heather Gibson
- Barbara Ann Karmanos Cancer Institute, Hudson-Webber Cancer Research Center, Detroit, Michigan
| | - Jeffrey Frelinger
- University of Arizona, Valley Fever Center for Excellence, Tucson, Arizona
- Department of Microbiology and Immunology, University of North Carolina System, Chapel Hill, North Carolina
| | - Adam Buntzman
- University of Arizona, BIO5 Institute, Valley Fever Center for Excellence, Tucson, Arizona
| |
Collapse
|
|
27
|
Khunsriraksakul C, Markus H, Olsen NJ, Carrel L, Jiang B, Liu DJ. Construction and Application of Polygenic Risk Scores in Autoimmune Diseases. Front Immunol 2022; 13:889296. [PMID: 35833142 PMCID: PMC9271862 DOI: 10.3389/fimmu.2022.889296] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with autoimmune diseases and provided unique mechanistic insights and informed novel treatments. These individual genetic variants on their own typically confer a small effect of disease risk with limited predictive power; however, when aggregated (e.g., via polygenic risk score method), they could provide meaningful risk predictions for a myriad of diseases. In this review, we describe the recent advances in GWAS for autoimmune diseases and the practical application of this knowledge to predict an individual’s susceptibility/severity for autoimmune diseases such as systemic lupus erythematosus (SLE) via the polygenic risk score method. We provide an overview of methods for deriving different polygenic risk scores and discuss the strategies to integrate additional information from correlated traits and diverse ancestries. We further advocate for the need to integrate clinical features (e.g., anti-nuclear antibody status) with genetic profiling to better identify patients at high risk of disease susceptibility/severity even before clinical signs or symptoms develop. We conclude by discussing future challenges and opportunities of applying polygenic risk score methods in clinical care.
Collapse
Affiliation(s)
- Chachrit Khunsriraksakul
- Graduate Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, United States
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Havell Markus
- Graduate Program in Bioinformatics and Genomics, Pennsylvania State University College of Medicine, Hershey, PA, United States
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Nancy J. Olsen
- Department of Medicine, Division of Rheumatology, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Laura Carrel
- Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Bibo Jiang
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Dajiang J. Liu
- Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, United States
- Department of Public Health Sciences, Pennsylvania State University College of Medicine, Hershey, PA, United States
- *Correspondence: Dajiang J. Liu,
| |
Collapse
|
|
28
|
Ortíz-Fernández L, Martín J, Alarcón-Riquelme ME. A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren's Syndrome. Clin Rev Allergy Immunol 2022; 64:392-411. [PMID: 35749015 DOI: 10.1007/s12016-022-08951-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 11/03/2022]
Abstract
Systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and Sjögren's syndrome are four major autoimmune rheumatic diseases characterized by the presence of autoantibodies, caused by a dysregulation of the immune system that leads to a wide variety of clinical manifestations. These conditions present complex etiologies strongly influenced by multiple environmental and genetic factors. The human leukocyte antigen (HLA) region was the first locus identified to be associated and still represents the strongest susceptibility factor for each of these conditions, particularly the HLA class II genes, including DQA1, DQB1, and DRB1, but class I genes have also been associated. Over the last two decades, the genetic component of these disorders has been extensively investigated and hundreds of non-HLA risk genetic variants have been uncovered. Furthermore, it is widely accepted that autoimmune rheumatic diseases share molecular disease pathways, such as the interferon (IFN) type I pathways, which are reflected in a common genetic background. Some examples of well-known pleiotropic loci for autoimmune rheumatic diseases are the HLA region, DNASEL13, TNIP1, and IRF5, among others. The identification of the causal molecular mechanisms behind the genetic associations is still a challenge. However, recent advances have been achieved through mouse models and functional studies of the loci. Here, we provide an updated overview of the genetic architecture underlying these four autoimmune rheumatic diseases, with a special focus on the HLA region.
Collapse
Affiliation(s)
- Lourdes Ortíz-Fernández
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Parque Tecnológico de La Salud, 18016, Granada, Spain
| | - Javier Martín
- Institute of Parasitology and Biomedicine López-Neyra, CSIC, Parque Tecnológico de La Salud, 18016, Granada, Spain
| | - Marta E Alarcón-Riquelme
- GENYO. Center for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Av de la Ilustración 114, Parque Tecnológico de La Salud, 18016, Granada, Spain. .,Institute for Environmental Medicine, Karolinska Institutet, 171 77, Solna, Sweden.
| |
Collapse
|
|
29
|
Hackett JB, Glassbrook JE, Muñiz MC, Bross M, Fielder A, Dyson G, Movahhedin N, McCasland J, McCarthy-Leo C, Gibson HM. A diversity outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors. Oncoimmunology 2022; 11:2064958. [PMID: 35481286 PMCID: PMC9037414 DOI: 10.1080/2162402x.2022.2064958] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) have improved outcomes for a variety of malignancies; however, many patients fail to benefit. While tumor-intrinsic mechanisms are likely involved in therapy resistance, it is unclear to what extent host genetic background influences response. To investigate this, we utilized the Diversity Outbred (DO) and Collaborative Cross (CC) mouse models. DO mice are an outbred stock generated by crossbreeding eight inbred founder strains, and CC mice are recombinant inbred mice generated from the same eight founders. We generated 207 DOB6F1 mice representing 48 DO dams and demonstrated that these mice reliably accept the C57BL/6-syngeneic B16F0 tumor and that host genetic background influences response to ICI. Genetic linkage analysis from 142 mice identified multiple regions including one within chromosome 13 that associated with therapeutic response. We utilized 6 CC strains bearing the positive (NZO) or negative (C57BL/6) driver genotype in this locus. We found that 2/3 of predicted responder CCB6F1 crosses show reproducible ICI response. The chromosome 13 locus contains the murine prolactin family, which is a known immunomodulating cytokine associated with various autoimmune disorders. To directly test whether prolactin influences ICI response rates, we implanted inbred C57BL/6 mice with subcutaneous slow-release prolactin pellets to induce mild hyperprolactinemia. Prolactin augmented ICI response against B16F0, with increased CD8 infiltration and 5/8 mice exhibiting slowed tumor growth relative to controls. This study highlights the role of host genetics in ICI response and supports the use of F1 crosses in the DO and CC mouse populations as powerful cancer immunotherapy models.
Collapse
Affiliation(s)
- Justin B. Hackett
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - James E. Glassbrook
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
- Department of Biochemistry Microbiology Immunology, Wayne State University, Detroit, MI, USA
| | - Maria C. Muñiz
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Madeline Bross
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Abigail Fielder
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Gregory Dyson
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Nasrin Movahhedin
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Jennifer McCasland
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Claire McCarthy-Leo
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA
| | - Heather M. Gibson
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| |
Collapse
|
|
30
|
He H, Yu Y, Liew Z, Gissler M, László KD, Valdimarsdóttir UA, Zhang J, Li F, Li J. Association of Maternal Autoimmune Diseases With Risk of Mental Disorders in Offspring in Denmark. JAMA Netw Open 2022; 5:e227503. [PMID: 35426923 PMCID: PMC9012963 DOI: 10.1001/jamanetworkopen.2022.7503] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
IMPORTANCE Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood. OBJECTIVE To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood. DESIGN, SETTING, AND PARTICIPANTS This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021. EXPOSURES Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register. MAIN OUTCOMES AND MEASURES The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders. RESULTS Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; >18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; >18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26]). CONCLUSIONS AND RELEVANCE In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.
Collapse
Affiliation(s)
- Hua He
- Developmental and Behavioral Pediatric Department and Child Primary Care Department, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Ministry of Education, Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongfu Yu
- Department of Biostatistics, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Department of Clinical Medicine, Department of Clinical Epidemiology, Aarhus University, Denmark
| | - Zeyan Liew
- Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, Connecticut
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut
| | - Mika Gissler
- Finnish Institute for Health and Welfare, Information Services Department, Helsinki, Finland
- Research Centre for Child Psychiatry, University of Turku, Turku, Finland
- Region Stockholm, Academic Primary Health Care Centre, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | | | - Unnur Anna Valdimarsdóttir
- Center of Public Health Sciences, University of Iceland, Reykjavik, Iceland
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Jun Zhang
- Ministry of Education, Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Developmental and Behavioral Pediatric Department and Child Primary Care Department, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Ministry of Education, Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiong Li
- Department of Clinical Medicine, Department of Clinical Epidemiology, Aarhus University, Denmark
| |
Collapse
|
|
31
|
Räisänen L, Lommi S, Engberg E, Kolho K, Viljakainen H. Central obesity in school-aged children increases the likelihood of developing paediatric autoimmune diseases. Pediatr Obes 2022; 17:e12857. [PMID: 34608761 PMCID: PMC9285017 DOI: 10.1111/ijpo.12857] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The incidences of both paediatric obesity and autoimmune diseases have been increasing, but their relationship with one another is unclear. OBJECTIVE To determine whether obesity or particular dietary patterns in school-aged children are potential risk factors for autoimmune diseases during adolescence. METHODS This matched case-control study included 525 children, followed up from a median age of 11.3 to 16.7 years. Of them, 105 children received primary autoimmune diagnoses (diabetes, thyroiditis, arthritis, or inflammatory bowel diseases) after baseline and generated the case group. Four children with matching age, sex, and residential area generated the control group of 420 children. At baseline, age- and sex-specific body mass index categories were acquired and waist-to-height ratio (WHTR) was calculated. Central obesity was present when WHTR ≥0.5. Dietary patterns were analysed using a food frequency questionnaire (FFQ). RESULTS School-aged children with central obesity were 2.11 (OR, 95% CI 1.11-3.98) times more likely to develop autoimmune diseases before age of 19 years than those without central obesity. Being overweight was not related to the onset of these diseases (OR 1.60, 95% CI 0.89-2.87, nor were dietary patterns. CONCLUSION Central obesity in school-aged children was related to the development of autoimmune diseases, while being overweight and dietary patterns were not.
Collapse
Affiliation(s)
- Laura Räisänen
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Faculty of Medicine and Health Technology (MET)Tampere UniversityTampereFinland,Department of PediatricsTampere University HospitalTampereFinland
| | - Sohvi Lommi
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Department of Public HealthUniversity of HelsinkiHelsinkiFinland
| | - Elina Engberg
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Department of Psychology and LogopedicsUniversity of HelsinkiHelsinkiFinland
| | - Kaija‐Leena Kolho
- Faculty of Medicine and Health Technology (MET)Tampere UniversityTampereFinland,Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Heli Viljakainen
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| |
Collapse
|
|
32
|
Chou YJ, Tai YH, Dai YX, Lee DD, Chang YT, Chen TJ, Chen MH. Obsessive-compulsive disorder and the associated risk of autoimmune skin diseases: a nationwide population-based cohort study. CNS Spectr 2022; 28:1-7. [PMID: 35147076 DOI: 10.1017/s1092852921000973] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND The concurrent incidence of autoimmune comorbidities in obsessive-compulsive disorder (OCD) is known. However, the association between OCD and related autoimmune skin diseases (ASDs) has not been well studied. OBJECTIVE This study aimed to investigate the association between OCD and the risk of ASDs. METHODS To assess the risk of developing ASDs, we recruited 44 324 patients with OCD and 177 296 matched controls from the National Health Insurance Research Database in Taiwan. A Cox regression model was used for the analyses. RESULTS After adjusting for confounders, an increased risk of ASDs among the patients with OCD (adjusted hazard ratio [aHR]: 6.36; 95% confidence interval [CI]: 5.43-7.45) was found when compared to the controls. Statistically significant associations were found between OCD and seven individual ASDs, including psoriasis (aHR: 12.52; 95% CI: 8.78-17.85), lichen planus (aHR: 27.22; 95% CI: 13.09-56.60), alopecia areata (aHR: 13.69; 95% CI: 9.38-19.98), autoimmune bullous diseases (aHR: 4.30; 95% CI: 2.03-9.11), hidradenitis suppurativa (aHR: 29.95; 95% CI: 3.35-267.62), vitiligo (aHR: 9.35; 95% CI: 5.35-16.32), and lupus erythematosus (aHR: 2.10; 95% CI: 1.52-2.91). CONCLUSIONS Patients with OCD had an increased risk of developing ASDs compared to matched controls. Further studies are required to clarify the underlying mechanisms.
Collapse
Affiliation(s)
- Yu-Ju Chou
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ying-Hsuan Tai
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ying-Xiu Dai
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Din-Dar Lee
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yun-Ting Chang
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tzeng-Ji Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mu-Hong Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| |
Collapse
|
|
33
|
Ding Y, Cui M, Qian J, Wang C, Shen Q, Ren H, Li L, Zhang F, Zhang R. Calculation of Similarity Between 26 Autoimmune Diseases Based on Three Measurements Including Network, Function, and Semantics. Front Genet 2021; 12:758041. [PMID: 34858474 PMCID: PMC8632457 DOI: 10.3389/fgene.2021.758041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/27/2021] [Indexed: 11/13/2022] Open
Abstract
Autoimmune diseases (ADs) are a broad range of diseases in which the immune response to self-antigens causes damage or disorder of tissues, and the genetic susceptibility is regarded as the key etiology of ADs. Accumulating evidence has suggested that there are certain commonalities among different ADs. However, the theoretical research about similarity between ADs is still limited. In this work, we first computed the genetic similarity between 26 ADs based on three measurements: network similarity (NetSim), functional similarity (FunSim), and semantic similarity (SemSim), and systematically identified three significant pairs of similar ADs: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), myasthenia gravis (MG) and autoimmune thyroiditis (AIT), and autoimmune polyendocrinopathies (AP) and uveomeningoencephalitic syndrome (Vogt-Koyanagi-Harada syndrome, VKH). Then we investigated the gene ontology terms and pathways enriched by the three significant AD pairs through functional analysis. By the cluster analysis on the similarity matrix of 26 ADs, we embedded the three significant AD pairs in three different disease clusters respectively, and the ADs of each disease cluster might have high genetic similarity. We also detected the risk genes in common among the ADs which belonged to the same disease cluster. Overall, our findings will provide significant insight in the commonalities of different ADs in genetics, and contribute to the discovery of novel biomarkers and the development of new therapeutic methods for ADs.
Collapse
Affiliation(s)
- Yanjun Ding
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.,Department of Microbiology, WU Lien-Teh Institute, Harbin Medical University, Harbin, China
| | - Mintian Cui
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Jun Qian
- Department of Microbiology, WU Lien-Teh Institute, Harbin Medical University, Harbin, China
| | - Chao Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Qi Shen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongbiao Ren
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Liangshuang Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Fengmin Zhang
- Department of Microbiology, WU Lien-Teh Institute, Harbin Medical University, Harbin, China
| | - Ruijie Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| |
Collapse
|
|
34
|
Márquez A, Martín J. Genetic overlap between type 1 diabetes and other autoimmune diseases. Semin Immunopathol 2021; 44:81-97. [PMID: 34595540 DOI: 10.1007/s00281-021-00885-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a chronic disease caused by the destruction of pancreatic β cells, which is driven by autoreactive T lymphocytes. It has been described that a high proportion of T1D patients develop other autoimmune diseases (AIDs), such as autoimmune thyroid disease, celiac disease, or vitiligo, which suggests the existence of common etiological factors among these disorders. In this regard, genetic studies have identified a high number of loci consistently associated with T1D that also represent established genetic risk factors for other AIDs. In addition, studies focused on identifying the shared genetic component in autoimmunity have described several common susceptibility loci with a potential role in T1D. Elucidation of this genetic overlap has been useful in identifying key molecular pathways with a pathogenic role in multiple disorders. In this review, we summarize recent advances in understanding the shared genetic component between T1D and other AIDs and discuss how the identification of common pathogenic mechanisms can help in the development of new therapeutic approaches as well as in improving the use of existing drugs.
Collapse
Affiliation(s)
- Ana Márquez
- Institute of Parasitology and Biomedicine López-Neyra. Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.,Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain
| | - Javier Martín
- Institute of Parasitology and Biomedicine López-Neyra. Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.
| |
Collapse
|
|
35
|
Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases. Nat Commun 2021; 12:5641. [PMID: 34561436 PMCID: PMC8463615 DOI: 10.1038/s41467-021-25768-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 08/31/2021] [Indexed: 12/15/2022] Open
Abstract
An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well established, but whether this reflects a shared genetic aetiology, and whether consistent genetic relationships exist between MS and the two predominant IBD subtypes, ulcerative colitis (UC) and Crohn’s disease (CD), remains unclear. Here, we use large-scale genome-wide association study summary data to investigate the shared genetic architecture between MS and IBD overall and UC and CD independently. We find a significantly greater genetic correlation between MS and UC than between MS and CD, and identify three SNPs shared between MS and IBD (rs13428812), UC (rs116555563) and CD (rs13428812, rs9977672) in cross-trait meta-analyses. We find suggestive evidence for a causal effect of MS on UC and IBD using Mendelian randomization, but no or weak and inconsistent evidence for a causal effect of IBD or UC on MS. We observe largely consistent patterns of tissue-specific heritability enrichment for MS and IBDs in lung, spleen, whole blood and small intestine, and identify cell-type-specific enrichment for MS and IBDs in CD4+ T cells in lung and CD8+ cytotoxic T cells in lung and spleen. Our study sheds light on the biological basis of comorbidity between MS and IBD. An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.
Collapse
|
|
36
|
Fang Q, Li T, Chen P, Wu Y, Wang T, Mo L, Ou J, Nandakumar KS. Comparative Analysis on Abnormal Methylome of Differentially Expressed Genes and Disease Pathways in the Immune Cells of RA and SLE. Front Immunol 2021; 12:668007. [PMID: 34079550 PMCID: PMC8165287 DOI: 10.3389/fimmu.2021.668007] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/26/2021] [Indexed: 12/13/2022] Open
Abstract
We identified abnormally methylated, differentially expressed genes (DEGs) and pathogenic mechanisms in different immune cells of RA and SLE by comprehensive bioinformatics analysis. Six microarray data sets of each immune cell (CD19+ B cells, CD4+ T cells and CD14+ monocytes) were integrated to screen DEGs and differentially methylated genes by using R package “limma.” Gene ontology annotations and KEGG analysis of aberrant methylome of DEGs were done using DAVID online database. Protein-protein interaction (PPI) network was generated to detect the hub genes and their methylation levels were compared using DiseaseMeth 2.0 database. Aberrantly methylated DEGs in CD19+ B cells (173 and 180), CD4+ T cells (184 and 417) and CD14+ monocytes (193 and 392) of RA and SLE patients were identified. We detected 30 hub genes in different immune cells of RA and SLE and confirmed their expression using FACS sorted immune cells by qPCR. Among them, 12 genes (BPTF, PHC2, JUN, KRAS, PTEN, FGFR2, ALB, SERB-1, SKP2, TUBA1A, IMP3, and SMAD4) of RA and 12 genes (OAS1, RSAD2, OASL, IFIT3, OAS2, IFIH1, CENPE, TOP2A, PBK, KIF11, IFIT1, and ISG15) of SLE are proposed as potential biomarker genes based on receiver operating curve analysis. Our study suggests that MAPK signaling pathway could potentially differentiate the mechanisms affecting T- and B- cells in RA, whereas PI3K pathway may be used for exploring common disease pathways between RA and SLE. Compared to individual data analyses, more dependable and precise filtering of results can be achieved by integrating several relevant data sets.
Collapse
Affiliation(s)
- Qinghua Fang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tingyue Li
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Peiya Chen
- Department of Science and Education, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yuzhe Wu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tingting Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Lixia Mo
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jiaxin Ou
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | | |
Collapse
|
|
37
|
Pinto-Sanchez MI, Seiler CL, Verdu EF. Reply. Gastroenterology 2021; 160:2207-2208. [PMID: 33484688 DOI: 10.1053/j.gastro.2021.01.205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 01/17/2021] [Indexed: 12/02/2022]
Affiliation(s)
- María Ines Pinto-Sanchez
- Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Canada
| | - Caroline L Seiler
- Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Canada
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, McMaster University Medical Center, Hamilton Health Sciences, Hamilton, Canada
| |
Collapse
|
|
38
|
Posttraumatic Stress Disorder and the Associated Risk of Autoimmune Skin Diseases: A Nationwide Population-Based Cohort Study. Psychosom Med 2021; 83:212-217. [PMID: 33587564 DOI: 10.1097/psy.0000000000000920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Posttraumatic stress disorder (PTSD) is known as a risk factor for various immune-related disorders; however, the association between PTSD and related autoimmune skin diseases (ASDs) remains unclear. This study aimed to investigate the association of PTSD with the risk of related ASDs. METHODS Participants were recruited from the National Health Insurance Research Database in Taiwan. We included 9801 patients with PTSD and 39,204 matched controls to assess the risk of developing ASDs. Cox regression model was used for analyses. RESULTS After adjusting for confounders, we found an increased risk of ASDs among the patients with PTSD (adjusted hazard ratio [aHR] = 3.00, 95% confidence interval [CI] = 2.21-4.07) compared with that among matched controls. Statistically significant associations were found between PTSD and five individual ASDs, including psoriasis (aHR = 3.81, 95% CI = 1.90-7.67), lichen planus (aHR = 31.63, 95% CI = 4.00-249.91), alopecia areata (aHR = 4.77, 95% CI = 2.47-9.20), autoimmune bullous diseases (aHR = 9.55, 95% CI = 1.98-45.99), and vitiligo (aHR = 16.06, 95% CI = 4.48-57.54). CONCLUSIONS Patients with PTSD had an increased risk of developing ASDs compared with the matched controls. Further studies are needed for better understanding of the underlying mechanisms.
Collapse
|
|
39
|
Caliskan M, Brown CD, Maranville JC. A catalog of GWAS fine-mapping efforts in autoimmune disease. Am J Hum Genet 2021; 108:549-563. [PMID: 33798443 PMCID: PMC8059376 DOI: 10.1016/j.ajhg.2021.03.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/05/2021] [Indexed: 12/11/2022] Open
Abstract
Genome-wide association studies (GWASs) have enabled unbiased identification of genetic loci contributing to common complex diseases. Because GWAS loci often harbor many variants and genes, it remains a major challenge to move from GWASs' statistical associations to the identification of causal variants and genes that underlie these association signals. Researchers have applied many statistical and functional fine-mapping strategies to prioritize genetic variants and genes as potential candidates. There is no gold standard in fine-mapping approaches, but consistent results across different approaches can improve confidence in the fine-mapping findings. Here, we combined text mining with a systematic review and formed a catalog of 85 studies with evidence of fine mapping for at least one autoimmune GWAS locus. Across all fine-mapping studies, we compiled 230 GWAS loci with allelic heterogeneity estimates and predictions of causal variants and trait-relevant genes. These 230 loci included 455 combinations of locus-by-disease association signals with 15 autoimmune diseases. Using these estimates, we assessed the probability of mediating disease risk associations across genes in GWAS loci and identified robust signals of causal disease biology. We predict that this comprehensive catalog of GWAS fine-mapping efforts in autoimmune disease will greatly help distill the plethora of information in the field and inform therapeutic strategies.
Collapse
Affiliation(s)
- Minal Caliskan
- Department of Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, NJ 08540, USA.
| | - Christopher D Brown
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joseph C Maranville
- Department of Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, NJ 08540, USA
| |
Collapse
|
|
40
|
Yazdanpanah M, Jalilian N, Abdollah Zadeh R, Sahraian MA, Noori-Daloii MR. Investigating the association of polymorphisms of ANKRD55 and MMEL1 with susceptibility to multiple sclerosis in Iranian population. Int J Neurosci 2021; 132:1037-1042. [PMID: 33491520 DOI: 10.1080/00207454.2020.1860964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Multiple sclerosis (MS) is an autoimmune neurological disability in which immune cells attack the myelin sheaths that protect nerve fibers. The pathogenesis of the disease involves both complex genetic effects as well as multifaceted gene-environment interactions. In the present study, we examined the association of two Single nucleotide polymorphisms (SNPs) in ANKRD55 (rs6859219) and MMEL (rs3748816) with MS in the Iranian population. ANKRD55 is specifically expressed in human peripheral blood mononuclear cells and CD4 + T cells, while MMEL1is involved in the degradation of both neuropeptides and β-amyloid. METHODS In this case-control study, 110 patients with MS and 110 matched healthy controls were enrolled. The Participants were genotyped for ANKRD55 and MMEL1 SNPs using PCR-RFLP and Real-Time TaqMan SNP Genotyping respectively. The results were finally analyzed using SPSS software version 22. RESULTS Our results did not show significant differences in allelic frequencies of two SNPs among cases and controls (P-Value >0.05). However, for ANKRD55 (rs6859219), CA genotype was shown to have a protective effect (p = 0.035 and OR = 0.55), while CC genotype was a susceptive genotype to MS (p = 0.036 and OR = 1.8). There was no significant difference in genotypic frequencies of SNP rs3748816 in MMEL1. CONCLUSION We could successfully replicate the association of ANKRD55 (rs6859219) with susceptibility to MS in the Iranian population. Our result can provide an insight into better understanding the pathogenesis of MS and also improve the genetic counseling for patients affected with multiple sclerosis in Iran.
Collapse
Affiliation(s)
- Mahboobeh Yazdanpanah
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nazanin Jalilian
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rasoul Abdollah Zadeh
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Sahraian
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | |
Collapse
|
|
41
|
Gill T, Rosenbaum JT. Putative Pathobionts in HLA-B27-Associated Spondyloarthropathy. Front Immunol 2021; 11:586494. [PMID: 33537028 PMCID: PMC7848169 DOI: 10.3389/fimmu.2020.586494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases with a strong association to the major histocompatibility (MHC) class I molecule, HLA-B27. Although the association between HLA-B27 and AS has been known for almost 50 years, the mechanisms underlying disease pathogenesis are elusive. Over the years, three hypotheses have been proposed to explain HLA-B27 and disease association: 1) HLA B27 presents arthritogenic peptides and thus creates a pathological immune response; 2) HLA-B27 misfolding causes endoplasmic reticulum (ER) stress which activates the unfolded protein response (UPR); 3) HLA-B27 dimerizes on the cell surface and acts as a target for natural killer (NK) cells. None of these hypotheses explains SpA pathogenesis completely. Evidence supports the hypothesis that HLA-B27-related diseases have a microbial pathogenesis. In animal models of various SpAs, a germ-free environment abrogates disease development and colonizing these animals with gut commensal microbes can restore disease manifestations. The depth of microbial influence on SpA development has been realized due to our ability to characterize microbial communities in the gut using next-generation sequencing approaches. In this review, we will discuss various putative pathobionts in the pathogenesis of HLA-B27-associated diseases. We pursue whether a single pathobiont or a disruption of microbial community and function is associated with HLA-B27-related diseases. Furthermore, rather than a specific pathobiont, metabolic functions of various disease-associated microbes might be key. While the use of germ-free models of SpA have facilitated understanding the role of microbes in disease development, future studies with animal models that mimic diverse microbial communities instead of mono-colonization are indispensable. We discuss the causal mechanisms underlying disease pathogenesis including the role of these pathobionts on mucin degradation, mucosal adherence, and gut epithelial barrier disruption and inflammation. Finally, we review the various uses of microbes as therapeutic modalities including pre/probiotics, diet, microbial metabolites and fecal microbiota transplant. Unravelling these complex host-microbe interactions will lead to the development of new targets/therapies for alleviation of SpA and other HLA-B27 associated diseases.
Collapse
Affiliation(s)
- Tejpal Gill
- Division of Arthritis and Rheumatic Diseases, Department of Medicine, Oregon Health & Science University, Portland, OR, United States
| | - James T Rosenbaum
- Departments of Ophthalmology, Medicine, and Cell Biology, Oregon Health & Science University, Portland, OR, United States.,Legacy Devers Eye Institute, Portland, OR, United States
| |
Collapse
|
|
42
|
Räisänen L, Viljakainen H, Sarkkola C, Kolho KL. Perinatal risk factors for pediatric onset type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases. Eur J Pediatr 2021; 180:2115-2123. [PMID: 33624160 PMCID: PMC8195774 DOI: 10.1007/s00431-021-03987-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/11/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes mellitus (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases with unknown risk factors. Using nationwide registers, we searched for their perinatal risk factors. Our study followed up 11,407 children (born 2000-2005) for a median of 16.6 years (from birth to 2018). Of them, 2.15% received primary diagnosis and 0.08% also secondary: 0.89% had DM, 0.60% had AIT, 0.48% had JIA, and 0.25% had IBD. The incidences per 100,000 children/year were 106.1 for DM, 46.0 for AIT, 55.0 for JIA, and 23.7 for IBD. There were more preterm births (< 37 weeks) among children with studied autoimmune diseases compared with the rest of the cohort (8.6% vs. 5.3%, p = 0.035). Among those born preterm, children with studied autoimmune diseases received more postnatal antibiotics compared with other preterm children in the cohort (47.6% vs. 27.7%, p = 0.046). Children with IBD were born to older mothers compared with those without studied diagnoses (33.0 vs 30.2, p = 0.004).Conclusion: Preterm birth was a shared risk factor for autoimmune diseases in our study, especially when combined with postnatal antibiotic treatments. High maternal age was associated with IBD. What is Known: • Type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases • It is unclear whether these diseases have shared risk factors, since there are no previous simultaneous epidemiological nor follow-up studies on them in one cohort What is New: • Preterm births were more common in children with DM, AIT, JIA, or IBD compared with other children in the cohort, and preterm children who developed these diseases recieved more postnatal antibiotics compared with other preterm children • High maternal age was associated with IBD.
Collapse
Affiliation(s)
- Laura Räisänen
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland. .,Folkhälsan Research Center, Helsinki, Finland.
| | - Heli Viljakainen
- grid.428673.c0000 0004 0409 6302Folkhälsan Research Center, Helsinki, Finland ,grid.7737.40000 0004 0410 2071Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Catharina Sarkkola
- grid.428673.c0000 0004 0409 6302Folkhälsan Research Center, Helsinki, Finland
| | - Kaija-Leena Kolho
- grid.502801.e0000 0001 2314 6254Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland ,grid.7737.40000 0004 0410 2071Faculty of Medicine and Children´s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| |
Collapse
|
|
43
|
Ferrè L, Filippi M, Esposito F. Involvement of Genetic Factors in Multiple Sclerosis. Front Cell Neurosci 2020; 14:612953. [PMID: 33335478 PMCID: PMC7735985 DOI: 10.3389/fncel.2020.612953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/09/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Laura Ferrè
- Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Neurorehabilitation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Filippi
- Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Neurorehabilitation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Neurophysiology Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
| | - Federica Esposito
- Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Neurorehabilitation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
44
|
Vastarella M, Megna M, Lupoli GA, Napolitano M, Gallo L, Balato A, Tasso M, Costa L, Fabbrocini G, Peluso R. Is there any association between psoriasis, psoriatic arthritis and thyroid autoimmunity? Australas J Dermatol 2020; 62:e207-e211. [PMID: 33070319 DOI: 10.1111/ajd.13484] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 09/04/2020] [Accepted: 09/06/2020] [Indexed: 01/12/2023]
Abstract
BACKGROUND Autoimmune diseases share a significant part of their genetic background and tend to coexist in the same patient. Some studies have investigated the possible association between autoimmune thyroiditis and psoriasis or psoriatic arthritis (PsA), with conflicting results. This study aimed to investigate the prevalence of autoimmune thyroiditis in psoriatic patients with (PsA) or without (PsC) joint involvement. METHODS 208 patients with psoriasis and/or PsA were recruited. These patients were divided into two groups: psoriasis patients (without PsA) (PsC group: 100 patients; mean age of 50.1 ± 11.7 years) and subjects with psoriasis and psoriatic arthritis (PsA group: 108 subjects: mean age of 39.8 ± 10.8 years). Assessment of psoriasis severity was conducted using the Psoriasis Area and Severity Index (PASI) score. The diagnosis of psoriatic arthritis was made according to CASPAR criteria. All patients had thyroid evaluation through evaluation of thyroid function, thyroperoxidase antibodies and thyroid ultrasound examination. RESULTS A statistically significant difference was found between the prevalence of autoimmune thyroiditis in the PsA group than the PsC group (25.9 vs 9.0 %; P = 0.018) with higher trends to hypothyroidism in the PsA group compared to the PsC group (13.9% vs 2.0%, P = 0.0018). CONCLUSIONS The higher prevalence of autoimmune thyroiditis in the PsA group may be due to an immune dysfunction pathway in patients with psoriatic arthritis with a higher risk to develop other autoimmune diseases. This evidence confirms that psoriatic arthritis is an autoimmune disease with an overactive immune system that can involve multiple organs. Thyroid function evaluation should be part of the clinical and laboratory examination of patients with psoriatic arthritis.
Collapse
Affiliation(s)
- Maria Vastarella
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Matteo Megna
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Gelsy Arianna Lupoli
- Endocrinology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Maddalena Napolitano
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Lucia Gallo
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Anna Balato
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Marco Tasso
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Luisa Costa
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Gabriella Fabbrocini
- Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Rosario Peluso
- Rheumatology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| |
Collapse
|
|
45
|
Hsieh WC, Svensson MN, Zoccheddu M, Tremblay ML, Sakaguchi S, Stanford SM, Bottini N. PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis. JCI Insight 2020; 5:141868. [PMID: 33055428 PMCID: PMC7605542 DOI: 10.1172/jci.insight.141868] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/09/2020] [Indexed: 12/28/2022] Open
Abstract
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice — modeling human carriers of disease-associated variants of PTPN2 — displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor γT (RORγt) — a gut-enriched Treg subset that can undergo conversion into FoxP3–IL-17+ arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of RORγt-expressing Tregs expressing the colonic marker G protein–coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15+ Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15+ exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs. Loss of protein tyrosine phosphatase non-receptor type 2 amplifies the link between gut and joint inflammation through conversion of colonic Tregs into arthritogenic exTregs.
Collapse
Affiliation(s)
- Wan-Chen Hsieh
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| | - Mattias Nd Svensson
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA.,Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martina Zoccheddu
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| | - Michael L Tremblay
- Rosalind and Morris Goodman Cancer Research Centre.,Department of Biochemistry, and.,Division of Experimental Medicine, Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.,Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
| | | | - Nunzio Bottini
- Department of Medicine, UCSD School of Medicine, La Jolla, California, USA
| |
Collapse
|
|
46
|
Singh R, Chandel S, Dey D, Ghosh A, Roy S, Ravichandiran V, Ghosh D. Epigenetic modification and therapeutic targets of diabetes mellitus. Biosci Rep 2020; 40:BSR20202160. [PMID: 32815547 PMCID: PMC7494983 DOI: 10.1042/bsr20202160] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/07/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
The prevalence of diabetes and its related complications are increasing significantly globally. Collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. Associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. Epigenetic factors include deoxyribonucleic acid (DNA) methylation and histone post-translational modifications. These factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. These result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a DNA sequence. Environmental factors and malnutrition are equally responsible for epigenetic states. Accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. Recent studies proposed that epigenetics may include the occurrence of 'metabolic memory' found in animal studies. Further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. In this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. We highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications.
Collapse
Affiliation(s)
- Rajveer Singh
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Shivani Chandel
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Dhritiman Dey
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Arijit Ghosh
- Department of Chemistry, University of Calcutta, Kolkata 700009, India
| | - Syamal Roy
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Velayutham Ravichandiran
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| | - Dipanjan Ghosh
- National Institute of Pharmaceutical Education and Research, Kolkata 164, Manicktala Main Road, Kolkata 700054, India
| |
Collapse
|
|
47
|
Dibble JJ, McGrath SJ, Ponting CP. Genetic risk factors of ME/CFS: a critical review. Hum Mol Genet 2020; 29:R117-R124. [PMID: 32744306 PMCID: PMC7530519 DOI: 10.1093/hmg/ddaa169] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of ∼0.2-0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases. Here we critically review existing evidence that genetic factors alter ME/CFS risk before concluding that most ME/CFS candidate gene associations are not replicated by the larger CFS cohort within the UK Biobank. Multiple genome-wide association studies of this cohort also have not yielded consistently significant associations. Ahead of upcoming larger genome-wide association studies, we discuss how these could generate new lines of enquiry into the DNA variants, genes and cell types that are causally involved in ME/CFS disease.
Collapse
Affiliation(s)
- Joshua J Dibble
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
| | | | - Chris P Ponting
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
| |
Collapse
|
|
48
|
Dai YX, Tai YH, Chang YT, Chen TJ, Chen MH. Association between major depressive disorder and subsequent autoimmune skin diseases: A nationwide population-based cohort study. J Affect Disord 2020; 274:334-338. [PMID: 32469824 DOI: 10.1016/j.jad.2020.05.070] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) has been implicated as a risk factor for various immune-related disorders; however, the association between MDD and subsequent autoimmune skin diseases (ASDs) remains unclear. This study aimed to investigate the association of MDD with risk of subsequent ASDs. METHODS Subjects were recruited from the National Health Insurance Research Database in Taiwan. We included 222,522 patients with MDD and 890,088 matched controls to assess the risk of developing ASDs. RESULTS After controlling for confounders, we found an increased risk of ASDs among the patients with MDD (adjusted hazard ratio [aHR], 10.41; 95% CI, 9.62-11.42) compared to matched controls. Subgroup analyses showed that MDD patients had a significantly increased risk of developing psoriasis (aHR, 12.01; 95% CI, 10.37-13.91), lichen planus (aHR, 11.84; 95% CI, 8.90-15.75), alopecia areata (aHR, 11.61; 95% CI, 9.92-13.59), morphea (aHR, 6.03; 95% CI, 2.47-14.73), autoimmune bullous diseases (aHR, 7.67; 95% CI, 5.94-9.90), hidradenitis suppurativa (aHR, 8.45; 95% CI, 3.61-19.74), vitiligo (aHR, 7.24; 95% CI, 5.65-9.28), lupus erythematosus (aHR, 11.30; 95% CI, 9.21-13.86), systemic sclerosis (aHR, 8.07; 95% CI, 4.30-15.14), Sjogren's syndrome (aHR, 6.71; 95% CI, 5.29-8.50), and dermatomyositis (aHR, 14.44; 95% CI, 5.55-37.55). CONCLUSIONS Patients with MDD had an increased risk of developing ASDs as compared to the controls. Further studies are needed to better understand the underlying mechanisms.
Collapse
Affiliation(s)
- Ying-Xiu Dai
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Hsuan Tai
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yun-Ting Chang
- Department of Dermatology, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Tzeng-Ji Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mu-Hong Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
| |
Collapse
|
|
49
|
Pinto-Sanchez MI, Seiler CL, Santesso N, Alaedini A, Semrad C, Lee AR, Bercik P, Lebwohl B, Leffler DA, Kelly CP, Moayyedi P, Green PH, Verdu EF. Association Between Inflammatory Bowel Diseases and Celiac Disease: A Systematic Review and Meta-Analysis. Gastroenterology 2020; 159:884-903.e31. [PMID: 32416141 DOI: 10.1053/j.gastro.2020.05.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/23/2020] [Accepted: 05/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS There is controversy over the association between celiac disease (CeD) and inflammatory bowel diseases (IBD). We performed a systematic review and meta-analysis to assess evidence for an association between CeD and IBD. METHODS We searched databases including MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL, DARE, and SIGLE through June 25, 2019 for studies assessing the risk of CeD in patients with IBD, and IBD in patients with CeD, compared with controls of any type. We used the Newcastle-Ottawa Scale to evaluate the risk of bias and GRADE to assess the certainty of the evidence. RESULTS We identified 9791 studies and included 65 studies in our analysis. Moderate certainty evidence found an increased risk of CeD in patients with IBD vs controls (risk ratio [RR] 3.96; 95% confidence interval [CI] 2.23-7.02) and increased risk of IBD in patients with CeD vs controls (RR 9.88; 95% CI 4.03-24.21). There was low-certainty evidence for the risk of anti-Saccharomyces antibodies, a serologic marker of IBD, in patients with CeD vs controls (RR 6.22; 95% CI 2.44-15.84). There was low-certainty evidence for no difference in risk of HLA-DQ2 or DQ8 in patients with IBD vs controls (RR 1.04; 95% CI 0.42-2.56), and very low-certainty evidence for an increased risk of anti-tissue transglutaminase in patients with IBD vs controls (RR 1.52; 95% CI 0.52-4.40). Patients with IBD had a slight decrease in risk of anti-endomysial antibodies vs controls (RR 0.70; 95% CI 0.18-2.74), but these results are uncertain. CONCLUSIONS In a systematic review and meta-analysis, we found an increased risk of IBD in patients with CeD and increased risk of CeD in patients with IBD, compared with other patient populations. High-quality prospective cohort studies are needed to assess the risk of CeD-specific and IBD-specific biomarkers in patients with IBD and CeD.
Collapse
Affiliation(s)
- Maria Ines Pinto-Sanchez
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Caroline L Seiler
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Nancy Santesso
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada
| | - Armin Alaedini
- Celiac Disease Center at Columbia University, New York, New York
| | - Carol Semrad
- Celiac Disease Center at University of Chicago Medicine, Chicago, Illinois
| | - Anne R Lee
- Celiac Disease Center at Columbia University, New York, New York
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Benjamin Lebwohl
- Celiac Disease Center at Columbia University, New York, New York
| | - Daniel A Leffler
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ciaran P Kelly
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Paul Moayyedi
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Peter H Green
- Celiac Disease Center at Columbia University, New York, New York
| | - Elena F Verdu
- Department of Medicine, Farncombe Family Digestive Research Institute, McMaster University, Hamilton, Ontario, Canada.
| |
Collapse
|
|
50
|
Laufer VA, Tiwari HK, Reynolds RJ, Danila MI, Wang J, Edberg JC, Kimberly RP, Kottyan LC, Harley JB, Mikuls TR, Gregersen PK, Absher DM, Langefeld CD, Arnett DK, Bridges SL. Genetic influences on susceptibility to rheumatoid arthritis in African-Americans. Hum Mol Genet 2020; 28:858-874. [PMID: 30423114 DOI: 10.1093/hmg/ddy395] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 11/05/2018] [Accepted: 11/09/2018] [Indexed: 12/29/2022] Open
Abstract
Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA < 5 × 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.
Collapse
Affiliation(s)
- Vincent A Laufer
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hemant K Tiwari
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Richard J Reynolds
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Maria I Danila
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jelai Wang
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jeffrey C Edberg
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Robert P Kimberly
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Leah C Kottyan
- Center for Autoimmune Genetics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - John B Harley
- Center for Autoimmune Genetics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,United States Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - Ted R Mikuls
- VA Nebraska-Western Iowa Health Care System and the Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Peter K Gregersen
- Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY, USA
| | - Devin M Absher
- Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA
| | - Carl D Langefeld
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Donna K Arnett
- University of Kentucky College of Public Health, Lexington, KY, USA
| | - S Louis Bridges
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| |
Collapse
|