The Immunogenetics of Systemic Sclerosis

Ünlü, Begüm; Türsen, Ümit; Rajabi, Zeynab; Jabalameli, Navid; Rajabi, Fateme

doi:10.1007/978-3-030-92616-8_10

Cited by 7 publications

(5 citation statements)

References 352 publications

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“…Historically, IRF5 was the first gene identified through candidate gene studies across diverse ethnic populations to potentially contribute to SSc pathogenesis. Single-nucleotide polymorphisms (SNPs) located in the IRF5-TNPO3 region exhibited the strongest associations beyond the human leukocyte antigen (HLA) region, a finding corroborated by numerous SSc Genome-Wide Association (GWA) and Immunochip studies [59]. Interestingly, SNPs identified through candidate gene studies, including rs2004640, rs2280714, rs10488631, and rs10954213, were found to be associated with an increased risk of SSc development.…”

Section: The Interferon Regulatory Factor Genesmentioning

confidence: 84%

“…STAT4 activity seems to be essential for driving the inflammatory response, since different combinations of STAT4 are activated by a variety of cytokines, including interleukin (IL)12. The role of STAT4 polymorphisms in the development of SSc was first suggested by several candidate genes studies and then confirmed by GWAS immunochip and meta-analyses [59]. These studies addressed the role of SNP in the development of the disease.…”

Section: Stat Genes and Jak-stat Pathwaymentioning

confidence: 93%

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Immunogenetics of Systemic Sclerosis

Gumkowska-Sroka,

Kotyla,

Kotyla

2024

Genes

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Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by massive fibrosis, vascular damage, and immune imbalance. Advances in rheumatology and immunology over the past two decades have led to a redefinition of systemic sclerosis, shifting from its initial perception as primarily a “hyperfibrotic” state towards a recognition of systemic sclerosis as an immune-mediated disease. Consequently, the search for genetic markers has transitioned from focusing on fibrotic mechanisms to exploring immune regulatory pathways. Immunogenetics, an emerging field at the intersection of immunology, molecular biology, and genetics has provided valuable insights into inherited factors that influence immunity. Data from genetic studies conducted thus far indicate that alterations in genetic messages can significantly impact disease risk and progression. While certain genetic variations may confer protective effects, others may exacerbate disease susceptibility. This paper presents a comprehensive review of the most relevant genetic changes that influence both the risk and course of systemic sclerosis. Special emphasis is placed on factors regulating the immune response, recognizing their pivotal role in the pathogenesis of the disease.

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Section: The Interferon Regulatory Factor Genesmentioning

confidence: 84%

Section: Stat Genes and Jak-stat Pathwaymentioning

confidence: 93%

Immunogenetics of Systemic Sclerosis

Gumkowska-Sroka,

Kotyla,

Kotyla

2024

Genes

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“…They showed that incidence of SSc development was higher in the close relatives of those affected by SSc [6]. Since inheritance seems to be the strongest risk factor for developing SSc [7,8], several studies (gene association studies and genome wide analyses) were conducted to try to identify the genes responsible for this inheritance [9]. Currently, several susceptibility genes for SSc are known, such as STAT3, STAT4, IRF5, IRF8, TNFSF4, CD226, CD247, MIF, IL23R, IL2RA, IL-21, TLR2, CD226, BANK1, IRAK1, NFk, CCN2, TIMP1, AIF, and ACE [6][7][8][9].…”

Section: Genetics Of Sscmentioning

confidence: 99%

“…Since inheritance seems to be the strongest risk factor for developing SSc [7,8], several studies (gene association studies and genome wide analyses) were conducted to try to identify the genes responsible for this inheritance [9]. Currently, several susceptibility genes for SSc are known, such as STAT3, STAT4, IRF5, IRF8, TNFSF4, CD226, CD247, MIF, IL23R, IL2RA, IL-21, TLR2, CD226, BANK1, IRAK1, NFk, CCN2, TIMP1, AIF, and ACE [6][7][8][9]. All are involved in the regulation of the immune functions or have effects on fibroblasts and endothelial cells activity.…”

Section: Genetics Of Sscmentioning

confidence: 99%

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

Mennella,

Ocone,

Stefanantoni

et al. 2024

JMP

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Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8 (IRF8), a factor involved in the type I interferon (IFN-I) signature, which is present in about half of SSc patients. Variants of this factor may play a role in autoimmunity, but little is known regarding the role of IRF8 in SSc pathogenesis. We carried out a literature search to address the association between the IRF8 factor and SSc susceptibility and clinical manifestations. The current studies appear to confirm a possible association between the alteration of the gene for IRF8 and SSc susceptibility. A link between IRF8 mutations and expression of a pro-fibrotic phenotype at the cellular level also emerges. Additional investigations are needed to confirm the role of IRF8 in SSc. However, IRF8 is worth consideration as a possible new disease marker of fibrosis in SSc patients.

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“…In 2017, Chairta et al conducted a Meta-analysis which revealed frequent associations between specific alleles in the HLA-DRB1, HLA-DQB1, HLA-DQA1, and HLA-DPB1 genes as well as variants in STAT4, IRF5 and CD247 with SSc. NFKB1, CSF3R, STAT4, IFNG, PRL and ILs are key components of the interaction network involving non-HLA genes associated with SSc 10 . The candidate gene approach (CGA) and genome-wide association study (GWAS) are fundamental methods employed for genetic association studies.…”

Section: Introductionmentioning

confidence: 99%

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

Han,

Wang

et al. 2024

Sci Rep

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Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-related connective tissue disease with a complex and unknown pathophysiological mechanism with genes association. Several articles have reported a high prevalence of thyroid disease in SSc patients, while one study suggested a potential contribution of appendicitis to the development of SSc. To investigate this causal association, we conducted Mendelian randomization (MR) analysis using instrumental variables (IVs) to assess exposure and outcome. In the MR study involving two cohorts, all analyses were conducted using the TwoSampleMR package in R (version 4.3.0). Single nucleotide polymorphisms (SNPs) meeting a statistically significant threshold of 5E−08 were included in the analysis. Multiple complementary approaches including MR-IVW, MR-Egger, weighted median, simple mode, and weighted mode were employed to estimated the relationship between the exposure and outcome. Leave-one-out analysis and scatter plots were utilized for further investigation. Based on the locus-wide significance level, all of the MR analysis consequences manifested no causal association between the risk of appendicitis with SSc (IVW OR 0.319, 95% CI 0.063–14.055, P = 0.966). Negative causal effects of autoimmune thyroiditis (AT) on SSc (IVW OR 0.131, 95% CI 0.816–1.362, P = 0.686), Graves’ disease (GD) on SSc (IVW OR 0.097, 95% CI 0.837–1.222, P = 0.908), and hypothyroidism on SSc (IVW OR 1.136, 95% CI 0.977–1.321, P = 0.096) were derived. The reverse MR revealed no significant causal effect of SSc on thyroid disease. According to the sensitivity analysis, horizontal pleiotropy was unlikely to distort the causal estimates. The consequences indicated no significant association between AT, GD, and hypothyroidism with SSc. Similarly, there was no observed relationship with appendicitis.

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The Immunogenetics of Systemic Sclerosis

Cited by 7 publications

References 352 publications

Immunogenetics of Systemic Sclerosis

Immunogenetics of Systemic Sclerosis

The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis

Negative causal exploration of systemic sclerosis: a Mendelian randomization analysis

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