Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families

Kuo, Chang‐Fu; Luo, Shue‐Fen; Yu, Kuang‐Hui; See, Lai‐Chu; Zhang, Weiya; Doherty, Michael

doi:10.1186/s13075-016-1127-6

Cited by 24 publications

(13 citation statements)

References 31 publications

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“…In comparison with healthy individuals, higher prevalences of autoimmune disease, such as systemic lupus erythematosus, autoimmune thyroid disease, or type 1 diabetes, have been reported concurrently in patients with IIM, as well as in first-degree relatives of both adult and juvenile patients with IIM, on the basis of data from a relatively small number of patients 5,6 . Conversely, a nationwide study in Taiwan that investigated co-aggregation of autoimmune disease in families with systemic lupus erythematosus and systemic sclerosis, identified higher relative risk of IIM than that of the general population 7,8 , and a national study in China suggested an increased risk of IIM and certain other autoimmune diseases in relatives of patients with systemic sclerosis 8 . These findings of aggregation of autoimmune diseases within families of patients with IIM suggest that shared genetic and/or environmental factors might contribute to disease risk.…”

Section: Genetic Risk Factorsmentioning

confidence: 95%

Risk factors and disease mechanisms in myositis

et al. 2018

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Autoimmune diseases develop as a result of chronic inflammation owing to interactions between genes and the environment. However, the mechanisms by which autoimmune diseases evolve remain poorly understood. Newly discovered risk factors and pathogenic processes in the various idiopathic inflammatory myopathy (IIM) phenotypes (known collectively as myositis) have illuminated innovative approaches for understanding these diseases. The HLA 8.1 ancestral haplotype is a key risk factor for major IIM phenotypes in some populations, and several genetic variants associated with other autoimmune diseases have been identified as IIM risk factors. Environmental risk factors are less well studied than genetic factors but might include viruses, bacteria, ultraviolet radiation, smoking, occupational and perinatal exposures and a growing list of drugs (including biologic agents) and dietary supplements. Disease mechanisms vary by phenotype, with evidence of shared innate and adaptive immune and metabolic pathways in some phenotypes but unique pathways in others. The heterogeneity and rarity of the IIMs make advancements in diagnosis and treatment cumbersome. Novel approaches, better-defined phenotypes, and international, multidisciplinary consensus have contributed to progress, and it is hoped that these methods will eventually enable therapeutic intervention before the onset or major progression of disease. In the future, preemptive strategies for IIM management might be possible.

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Section: Genetic Risk Factorsmentioning

confidence: 95%

Risk factors and disease mechanisms in myositis

et al. 2018

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“…This is supported by the higher familial relative risk of the disease itself or autoimmune diseases [4, 8], low disease concordance but high concordance of autoantibodies produced in monozygotic twins [5], and multi-case SSc families that are concordant for SSc-specific autoantibodies as well as human leukocyte antigen (HLA) haplotypes [9]. Twin studies have been performed in several autoimmune diseases.…”

Section: Genetic Involvementmentioning

confidence: 99%

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Tsou

Sawalha

2017

Journal of Autoimmunity

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With unknown etiology, scleroderma (SSc) is a multifaceted disease that comprises of immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated miRNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that were affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomincs and epigenomics research in SSc.

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“…Although the exact aetiology of SLE is still unknown, both environmental and genetic factors could be involved in the development and propagation of SLE (Lo & Tsokos, ). However, the higher concordance rate in monozygotic twins and increased risk of SLE in relatives highlight the genetic factors in SLE pathogenesis (Kuo et al, ). Various genes have been suggested as SLE predisposing factors which are commonly known as “ SLE susceptibility genes” such as human leucocyte antigen (HLA) (Armstrong et al, ), mannose‐binding lectin (MBL) (Tanha et al, ), Fc gamma receptor (FcγR) (Tsang‐A‐Sjoe et al, ) and programmed cell death‐1 (PD‐1) (Gianchecchi, Delfino, & Fierabracci, ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

Mohammadi

Jazi

Ebrahimabad

et al. 2018

Int J Immunogenetics

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown aetiology. According to the role of interleukin 10 (IL10) in SLE pathogenesis, the genetic alterations in its promoter region could be associated with elevated IL10 levels and exacerbated disease. Here, we investigated the association of genotype and haplotype frequencies of three IL10 gene promoter polymorphisms with susceptibility to SLE, IL10 plasma levels and disease activity of patients in an Iranian population. A total of 116 SLE patients and 131 healthy subjects were enrolled. The PCR-RFLP technique was used to detect IL10 promoter genotypes at the positions of −1082 (G/A), −819 (C/T) and −592 (C/A) in association with IL10 plasma levels and SLEDAI scores. The GG genotype of −1082 polymorphism was associated with the increased risk of SLE [OR = 2.65, 95% CI (1.21-5.82), p-value = 0.046]. The CC genotype in −819 region was associated with SLE susceptibility [OR = 3.38, 95% CI (1.26-9.07), p-value = 0.034] and C allele was introduced as risk allele [OR = 1.86, 95% CI (1.15-3.01), p-value = 0.009] in this region. IL10 plasma levels were overexpressed in CC genotype carriers of −592 SNP and decreased in AA genotype carriers of −1082. IL10 was also increased in SLE patients with CGT (−592/−1082/−819) haplotype. The SLEDAI score was higher among CC genotype carriers at the position of −592 and TT genotype carriers at the region of −819. SLEDAI was also elevated among patients with CGC (−592/−1082/−819) and CAC (p = 0.011) haplotypes. The present study suggests that the IL10 -819(C/T), −1082(G/A) and −592(C/A) polymorphisms and the haplotypes are associated with SLE susceptibility, increased disease activity and elevated IL10 levels. While this is the first time to report such an association in an Iranian population, further studies are needed to confirm these findings. K E Y W O R D S haplotype, interleukin 10, polymorphism, promoter, systemic lupus erythematosus | 21 MOHAMMADI et Al.

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Familial risk of systemic sclerosis and co-aggregation of autoimmune diseases in affected families

Cited by 24 publications

References 31 publications

Risk factors and disease mechanisms in myositis

Risk factors and disease mechanisms in myositis

Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Interleukin10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

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