Genetics of systemic sclerosis

Ramos, Paula S.; Silver, Richard M.; Feghali‐Bostwick, Carol

doi:10.1097/bor.0000000000000214

Cited by 32 publications

(27 citation statements)

References 87 publications

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“…It appears that indigenous peoples of the Americas may have the highest reported prevalence of SSc. While it is not clear what exactly contributes to the difference, genetic factors may have an important impact, as genetic association studies continue to identify multiple genetic risk loci associated with SSc and other autoimmune diseases …”

Section: Discussionsupporting

confidence: 86%

Prevalence and incidence of systemic sclerosis: A systematic review and meta‐analysis

et al. 2019

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Objective Systemic sclerosis (SSc) is a rare debilitating autoimmune disease of the connective tissue. This study aimed to assess the recent prevalence and incidence of SSc across the world. Methods Using a systematic search strategy, PubMed/MEDLINE and EMBASE were searched to identify relevant studies published between 2006 and 2016. Two reviewers independently evaluated studies for inclusion based on inclusion/exclusion criteria and performed data extraction. The review was conducted and reported following the Preferred Reporting Items for Systematic Review and Meta‐analysis (PRISMA) statement. The pooled prevalence of SSc was calculated by meta‐analysis using a random‐effects model. Results There were 1364 references retrieved using the initial searching strategy, and 20 epidemiological publications were selected for data extraction. The identified studies reported prevalence ranging from 3.8 per 100 000 in Taiwan to 50 per 100 000 in the USA. The prevalence was 23 per 100 000 (95% CI: 16‐29 per 100 000; 18 studies) in a pooled sample of 11 574 individuals. Incidence rate of SSc ranges from 0.77 per 100 000 person‐years in the Netherlands to 5.6 per 100 000 person‐years in the USA. SSc predominates in females with higher prevalence and incidence rates. It is important to note that different methodologies were used to derive these numbers so comparisons were made with caution. Conclusion This review provides an assessment of the current estimates of disease prevalence and incidence of SSc. The epidemiological burdens of SSc vary among different regions of the world. The epidemiological data need to be interpreted with caution considering the methodological differences in deriving these estimates.

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Section: Discussionsupporting

confidence: 86%

Prevalence and incidence of systemic sclerosis: A systematic review and meta‐analysis

et al. 2019

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“…Inter-relationships between genetic susceptibility, potential drug targets and hub positions on the network were shown schematically in supplementary figure S4. Of these, 14 DEGs overlapped with SSc genetic susceptibility loci previously discovered10–13 and five genes ( CTGF , HCK , LYN , PDGFRB and PPARG ) were the potential target molecules for therapy 14 15. A total of 89 genes were ranked as hub molecules based on centrality analysis, and four target molecules, except PPARG , have the hub position.…”

Section: Resultsmentioning

confidence: 99%

Compendium of skin molecular signatures identifies key pathological features associated with fibrosis in systemic sclerosis

et al. 2019

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ObjectivesTreatment of patients with systemic sclerosis (SSc) can be challenging because of clinical heterogeneity. Integration of genome-scale transcriptomic profiling for patients with SSc can provide insights on patient categorisation and novel drug targets.MethodsA normalised compendium was created from 344 skin samples of 173 patients with SSc, covering an intersection of 17 424 genes from eight data sets. Differentially expressed genes (DEGs) identified by three independent methods were subjected to functional network analysis, where samples were grouped using non-negative matrix factorisation. Finally, we investigated the pathways and biomarkers associated with skin fibrosis using gene-set enrichment analysis.ResultsWe identified 1089 upregulated DEGs, including 14 known genetic risk factors and five potential drug targets. Pathway-based subgrouping revealed four distinct clusters of patients with SSc with distinct activity signatures for SSc-relevant pathways. The inflammatory subtype was related to significant improvement in skin fibrosis at follow-up. The phosphoinositide-3-kinase-protein kinase B (PI3K-Akt) signalling pathway showed both the closest correlation and temporal pattern to skin fibrosis score. COMP, THBS1, THBS4, FN1, and TNC were leading-edge genes of the PI3K-Akt pathway in skin fibrogenesis.ConclusionsConstruction and analysis of normalised skin transcriptomic compendia can provide useful insights on pathway involvement by SSc subsets and discovering viable biomarkers for a skin fibrosis index. Particularly, the PI3K-Akt pathway and its leading players are promising therapeutic targets.

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“…Pathology develops from an interplay between altered vasculature and immune‐mediated inflammatory events . Genes associated with SSc are involved in TCR and cytokine receptor signalling (Table ) . A major feature of autoimmunity in SSc is high levels of autoantibodies to cellular proteins including topoisomerase I enzyme (Scl‐70) .…”

Section: Do Th17 Cells Contribute To the Pathogenesis Of Systemic Sclmentioning

confidence: 99%

Functional and phenotypic heterogeneity of Th17 cells in health and disease

Byström

Clanchy

Taher

et al. 2018

Eur J Clin Investigation

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Background Th17 cells have nonredundant roles in maintaining immunity, particularly at mucosal surfaces. These roles are achieved principally through the production of cytokines and the recruitment of other immune cells to maintain the integrity of mucosal barriers and prevent the dissemination of microorganisms. Th17 cells are heterogeneous and exhibit a considerable degree of plasticity. This allows these cells to respond to changing environmental challenges. However, Th17 cells also play pro‐inflammatory roles in chronic autoimmune diseases. The trigger(s) that initiate these Th17 responses in chronic autoimmune diseases remain unclear. Design In this report, we provide an overview of studies involving animal models, patient data, genome wide association studies and clinical trials targeting IL‐17 for treatment of patients to gain a better understanding of the pathogenic roles of Th17 cells play in a range of autoimmune diseases. Results The report sheds light on likely triggers that initiate or perpetuate Th17 responses that promote chronic inflammation and autoimmunity. The divergent effects of tumour necrosis factor alpha blockade on Th17 cells in patients, is explored. Furthermore, we highlight the role of Th17 cells in inducing autoreactive B cells, leading to autoantibody production. Pathogenic bacterial species can change Th17 cell phenotype and responses. These findings provide insights into how Th17 cells could be induced to promoting autoimmune disease pathogenesis. Conclusion This article provides an overview of the distinct roles Th17 cells play in maintaining immunity at mucosal surfaces and in skin mucosa and how their functional flexibility could be linked with chronic inflammation in autoimmune rheumatic diseases.

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Genetics of systemic sclerosis

Cited by 32 publications

References 87 publications

Prevalence and incidence of systemic sclerosis: A systematic review and meta‐analysis

Prevalence and incidence of systemic sclerosis: A systematic review and meta‐analysis

Compendium of skin molecular signatures identifies key pathological features associated with fibrosis in systemic sclerosis

Functional and phenotypic heterogeneity of Th17 cells in health and disease

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