The GTF2I rs117026326 polymorphism is associated with anti-SSA-positive primary Sjögren’s syndrome

Zheng, Jiangjun; Huang, Renliang; Huang, Qiaoniang; Deng, Fengyuan; Chen, Yanchun; Ju, Youlun; Chen, Juan; Wang, Ying; Shi, Guixiu; Gao, Xing; Liu, Zuguo; Petersen, Frank; Yu, Xinhua

doi:10.1093/rheumatology/keu466

Cited by 17 publications

(16 citation statements)

References 8 publications

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“…An interesting finding from a large study (GWAS) in Han-Chinese [ 46 ] but not in European population revealed that a polymorphism in the GTF2I gene (namely, rs117026326) (encodes a transcription factor involved in both T-cell signaling [ 99 ] and activation of immunoglobulin heavy-chain transcription upon B-lymphocyte activation [ 100 ]) is strongly associated with SS development with overall risk (OR) scores higher than other SS-associated identified genes including MHC-II genes, STAT4, and TNFAIP3 [ 46 ]. This finding was also confirmed in another study in Chinese population and was linked to the presence of anti-Ro/SSA autoantibodies [ 70 ].…”

Section: Genetic Factors Associated With Sjögren's Syndromesupporting

confidence: 79%

“…HLA class II SS-related phenotype has been associated with the presence of autoantibodies in various studies [ 33 , 35 , 40 ]. SNPs in the 5′ untranslated region of the BAFF [ 61 ] gene as well as in GTF2I [ 70 ] and genes implicated in the NF- κ B pathway [ 45 ] have been also associated with the presence of autoantibodies. Finally, the third one contains apoptotic and inflammatory genes, which participate in the NF- κ B signaling pathway.…”

Section: Genetic Factors Associated With Sjögren's Syndromementioning

confidence: 99%

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Contribution of Genetic Factors to Sjögren’s Syndrome and Sjögren’s Syndrome Related Lymphomagenesis

Nezos

Mavragani

2015

Journal of Immunology Research

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We aimed to summarize the current evidence related to the contributory role of genetic factors in the pathogenesis of Sjögren's syndrome (SS) and SS-related lymphoma. Genes within the major histocompatibility complex (MHC) locus previously considered conferring increased susceptibility to SS development have been also revealed as important contributors in recent genome wide association studies. Moreover, genetic variations outside the MHC locus involving genes in type I interferon pathway, NF-κB signaling, B- and T-cell function and methylation processes have been shown to be associated with both SS and SS-related lymphoma development. Appreciating the functional implications of SS-related genetic variants could provide further insights into our understanding of SS heterogeneity, allowing the design of tailored therapeutic interventions.

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Section: Genetic Factors Associated With Sjögren's Syndromesupporting

confidence: 79%

Section: Genetic Factors Associated With Sjögren's Syndromementioning

confidence: 99%

Contribution of Genetic Factors to Sjögren’s Syndrome and Sjögren’s Syndrome Related Lymphomagenesis

Nezos

Mavragani

2015

Journal of Immunology Research

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“…Data mining based on peer reviewed literature information (PubMed) and publicly available databases (centralgwas.org) served in the compilation of a list of 43 gene risk factors and their reported variants ( n = 72) in SS (Table S1 in Supplementary Material) ( 19 – 49 ). The number of SS patients and controls were also reported as well as the OR average (95%), when available.…”

Section: Methodsmentioning

confidence: 99%

An in silico Approach Reveals Associations between Genetic and Epigenetic Factors within Regulatory Elements in B Cells from Primary Sjögren’s Syndrome Patients

Konsta¹,

Dantec²,

Charras³

et al. 2015

Front. Immunol.

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Recent advances in genetics have highlighted several regions and candidate genes associated with primary Sjögren’s syndrome (SS), a systemic autoimmune epithelitis that combines exocrine gland dysfunctions, and focal lymphocytic infiltrations. In addition to genetic factors, it is now clear that epigenetic deregulations are present during SS and restricted to specific cell type subsets, such as lymphocytes and salivary gland epithelial cells. In this study, 72 single nucleotide polymorphisms (SNPs) associated with 43 SS gene risk factors were selected from publicly available and peer reviewed literature for further in silico analysis. SS risk variant location was tested revealing a broad distribution in coding sequences (5.6%), intronic sequences (55.6%), upstream/downstream genic regions (30.5%), and intergenic regions (8.3%). Moreover, a significant enrichment of regulatory motifs (promoter, enhancer, insulator, DNAse peak, and expression quantitative trait loci) characterizes SS risk variants (94.4%). Next, screening SNPs in high linkage disequilibrium (r2 ≥ 0.8 in Caucasians) revealed 645 new variants including 5 SNPs with missense mutations, and indicated an enrichment of transcriptionally active motifs according to the cell type (B cells > monocytes > T cells ≫ A549). Finally, we looked at SS risk variants for histone markers in B cells (GM12878), monocytes (CD14+) and epithelial cells (A548). Active histone markers were associated with SS risk variants at both promoters and enhancers in B cells, and within enhancers in monocytes. In conclusion and based on the obtained in silico results that need further confirmation, associations were observed between SS genetic risk factors and epigenetic factors and these associations predominate in B cells, such as those observed at the FAM167A–BLK locus.

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“…Specific HLA-DR allele subtypes and gene polymorphisms in STAT-4, IL-12A, TNIP1, IRF5, BLK and CXCR5 are reported to be associated with SjS [28]. A recent publication reported the first genome-wide association study in Han Chinease population for primary SjS [29, 30]. In the study, three non-HLA susceptibility loci, GTF2I , STAT4 and TNFAIP3, were identified in addition to the HLA locus.…”

Section: Sjogren’s Syndromementioning

confidence: 99%

“…In the study, three non-HLA susceptibility loci, GTF2I , STAT4 and TNFAIP3, were identified in addition to the HLA locus. Interestingly, the locus indicating the strongest susceptibility was not the HLA locus but the GTF2I rs117026326 C/T polymorphism, with the T allele as the risk allele for primary SjS, which was also associated with anti-Ro/SSA autoantibody in primary SjS [29, 30]. Of note, most autoimmune susceptibility loci are located outside of protein-coding regions, which may alter expression levels of the affected genes [31] and underscores the importance of epigenetic gene regulation in SjS predisposition[3].…”

Section: Sjogren’s Syndromementioning

confidence: 99%

Mouse Models of Primary Sjogren’s Syndrome

Park¹,

Gauna²,

Cha

2015

CPD

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Sjögren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS and describe them under three categories of spontaneous, genetically engineered, and experimentally induced development of SjS-like disease. In addition, we discuss future perspectives of SjS mouse models highlighting pros and cons of utilizing mouse models and demands for improved models.

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The GTF2I rs117026326 polymorphism is associated with anti-SSA-positive primary Sjögren’s syndrome

Cited by 17 publications

References 8 publications

Contribution of Genetic Factors to Sjögren’s Syndrome and Sjögren’s Syndrome Related Lymphomagenesis

Contribution of Genetic Factors to Sjögren’s Syndrome and Sjögren’s Syndrome Related Lymphomagenesis

An in silico Approach Reveals Associations between Genetic and Epigenetic Factors within Regulatory Elements in B Cells from Primary Sjögren’s Syndrome Patients

Mouse Models of Primary Sjogren’s Syndrome

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