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Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

ABSTRACT: To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD).A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated.A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was approximately 8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99-3.41], P = 2.42 x 10(-15)) and second-degree relatives (1.48 [95% CI 1.34-2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44-11.83], P = 4.04 x 10(-9)) and second-degree relatives (2.39 [95% CI 1.21-4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04-2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18-1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06-1.35], P = 0.004).These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives.

SUBMITTER: Frech T

PROVIDER: S-EPMC2956122 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

Frech Tracy T Khanna Dinesh D Markewitz Boaz B Mineau Geraldine G Pimentel Richard R Sawitzke Allen A

Arthritis and rheumatism 20100701 7

<h4>Objective</h4>To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD).<h4>Methods</h4>A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide disc ...[more]

PMID: 20506251

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Project description:BackgroundSystemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models.MethodsThe anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-? signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated.ResultsDZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor ?1, connective tissue growth factor, tumor necrosis factor-?, interferon-?, IL-1?, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-?1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-?/Smad signaling pathway.ConclusionsDZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.

Project description:BackgroundImmunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors.MethodsThe gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases.ResultsMicrobiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes, Bacteroides, and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism.ConclusionsThese results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.

Dataset Information

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

Publications

Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study.

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