Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population

Zhong, Hua; Li, Xiaolan; Li, Ming; Hao, Li-Xia; Chen, Rong-wei; Xiang, Kun; Qi, Xuebin; Runlin, Z.; Su, Bing

doi:10.1186/ar3514

Cited by 44 publications

(41 citation statements)

References 53 publications

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“…46 A replicate study of rs7708392 and rs10036748 in a southwest Chinese SLE population found a weak association, but as for the Japanese population, a significant association for rs7708392 with LN in their SLE population was apparent. 48 Consistent with those previous reports, the current study found association (OR, 1.22; P=3.66310 24 ) for rs7708392 when United States patients of European ancestry with SLE and LN versus those without LN, but this association was not significant in African, Asian, or Hispanic American cohorts. The discord for the finding in our Asian cohort and the reported finding in southwest Chinese and Japanese populations with regards to LN association may be explained by the composition of our Asian population of 1012 total patients, which was 90% Korean.…”

Section: Discussionsupporting

confidence: 81%

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Caster¹,

Korte²,

Nanda

et al. 2013

Journal of the American Society of Nephrology

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The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-kB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-kB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-kB and mitogen-activated protein kinase activity. 24: 174324: -175424: , 201324: . doi: 10.1681 Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an abnormal immune response leading to autoantibody production, immune complex formation, T cell activation, and inflammatory cytokine release. 1 Multiple factors contribute to the immune response in SLE, including genetic, epigenetic, immunoregulatory, environmental, and hormonal factors. 1 Lupus nephritis (LN) occurs in about 50% of patients with SLE and is a major cause of morbidity and mortality. 2 The incidence of LN varies among different ethnic groups, suggesting that genetic factors play an important role in the pathogenesis. Patients with African ancestry are at Received February 11, 2013. Accepted May 7, 2013 D.J.C. and E.A.K. contributed equally to this work. J Am Soc NephrolPublished online ahead of print. Publication date available at www.jasn.org. LN,4 and that therapy is associated with undesirable short-and long-term adverse effects. Thus, identifying the molecular mechanisms responsible for the pathogenesis of LN is necessary to define more specific diagnostic and therapeutic targets. However, the complex interactions of genetic risks, environmental factors, and molecular events that contribute to the development of LN are only beginning to be defined. The transcription factor nuclear factor-kB (NF-kB) regulates the expression of hundreds of genes that control cell proliferation and survival, the cellular stress r...

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Section: Discussionsupporting

confidence: 81%

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Caster¹,

Korte²,

Nanda

et al. 2013

Journal of the American Society of Nephrology

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“…The ets-1 rs6590330 sNp is in high linkage disequilibrium with the rs1128334 sNp (r 2 = 0.97) (ref. 70 ) and has been associated with earlier onset of the disease and certain sle manifestations, including malar rash, photosensivity, arthritis, serositis and renal involvement 72 . The clinical diversity of sle should probably be considered in further studies to elucidate genetic interactions, at least between ets-1 and mir-146a.…”

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confidence: 99%

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

Hušáková¹

2016

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Small non-coding RNA molecules (miRs) are involved in immune cell maturation and function and might influence immunopathological processes of systemic lupus erythematosus (SLE) pathogenesis. Methods and Results. This paper presents the results of a literature search for publications dealing with the relationship between miRs and pathological factors related to SLE such as genetic background, immune dysregulation and gender-associated differences participating in SLE development. In SLE, distinct miRs are differentially expressed in SLE cells of innate and adaptive immunity. The miR-146a and miR-155 genes, among others, interfere with intracellular signalling pathways downstream of toll-like receptors 7 and 9 (TLR-7, TLR-9) and influences interferon (IFN)-type I synthesis in plasmacytoid dendritic cells. In T and B cells, miR-126, miR-21, miR-146a, miR-155, miR-1246 and others might influence gene expression by epigenetic modifications, support abnormal cytosine release, differentiation of cell subsets, B cell hyperactivity and autoantibody production. Besides, estrogen might up-and downregulate immunologically active miRs, which are potential mediators of hormonal influences in SLE development. Moreover, SLE genetic basis included some polymorphisms of the miR-146a gene, which varies across populations. Conclusion. Distinct miRs are differentially expressed in both SLE mice models and human patients and promote autoimmune features of immune processes. MiRs are important molecules modulating susceptibility to SLE as well as its onset, clinical diversity and progression.

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“…In recent years, several studies have drawn a connection between Ets-1 and autoimmune diseases. In particular, ETS-1 is a common susceptibility gene for SLE in Chinese populations [31], and the level of ETS-1 mRNA is downregulated in the PBMCs of SLE patients [32]. Whether Ets-1 is important for CD1d function in B cells in the context of SLE remains unclear.…”

Section: Introductionmentioning

confidence: 99%

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

et al. 2015

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B cells present lipid antigens to CD1d-restricted invariant natural killer T (iNKT) cells to maintain autoimmune tolerance, and this process is disrupted in systemic lupus erythematosus (SLE). Inflammation may inhibit CD1d expression to exacerbate the pathology of lupus. However, how inflammation regulates CD1d expression on B cells is unclear in SLE.In the present study, we showed that the surface expression of CD1d on B cells from SLE mice was decreased and that stimulation of inflammatory responses through TLR9 decreased the membrane and total CD1d levels of CD1d on B cells. Moreover, inflammation-related microRNA-155 (miR-155) negatively correlated with the expression of CD1d in B cells. miR-155 directly targeted the 3 -untranslated region (3 -UTR) of CD1d upon TLR9 activation in both humans and mice. The inhibitory effects of miR-155 on CD1d expression in B cells impaired their antigen-presenting capacity to iNKT cells. In addition, Ets-1, a susceptibility gene of SLE, also directly regulated the expression of the CD1d gene at the transcriptional level. These findings provide new insight into the mechanism underlying decreased CD1d expression on B cells in SLE, suggesting that inhibition of inflammation may increase CD1d expression in B cells to ameliorate SLE via modulating iNKT cells.Keywords: B cells r CD1d r Ets-1 r miR-155 r SLE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is a complex and chronic autoimmune disease with an unclear etiology [1]. B cells play a central role in the pathogenesis of SLE [2], and patients with SLE exhibit abnormal B-cell activation and increased sensitivity and proliferation of B cells [3]. Moreover, the Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn clinical success of B-cell depletion therapy further proves the important role of B cells in SLE pathogenesis [4,5]. B cells not only produce antibodies and release cytokines and chemokines but also present both peptide and lipid antigens [6].CD1 family molecules are nonclassical MHC proteins related to the class I MHC proteins and are involved in the presentation of lipid antigens to T cells. Several studies have suggested that CD1d may play an immunoregulatory role in the development of lupus, and CD1d deficiency exacerbates lupus nephritis in the pristineinduced model [7] and inflammatory dermatitis in MRL-lpr/lpr C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1934-1945 Cellular immune response 1935 mice [8]. Importantly, endogenous DNA stimulates inflammatory responses through TLR9 and exacerbates lupus disease pathology [9,10]. Viral infection could downregulate the expression of CD1d in APCs, such as B cells [11,12], DCs, and macrophages [13]. A number of exogenous viruses, especially Epstein-Barr virus (EBV) [14,15], also have been linked to the pathogenesis of SLE [16]. Our previous studies have indicated that ligands for both TLR9 and TLR7 lead to B...

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Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population

Cited by 44 publications

References 53 publications

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

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