A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes

Guo, Dadong; Li, Manyu; Zhang, Yan; Yang, Ping; Eckenrode, Sarah; Hopkins, Diane; Zheng, Weipeng; Purohit, Sharad; Podolsky, Robert H.; Muir, Andrew; Wang, Jinzhao; Dong, Zheng; Brusko, Todd M.; Atkinson, Mark A.; Pozzilli, Paolo; Zeidler, Adina; Raffel, Leslie J.; Jacob, Chaim O.; Park, Yong Soo; Serrano-Rı́os, Manuel; Larrad, Maria Teresa Martínez; Zhang, Zixin; Garchon, Henri Jean; Bach, Jean François; Rotter, Jerome I.; She, Jin‐Xiong; Wang, Cong Yi

doi:10.1038/ng1391

Cited by 366 publications

(374 citation statements)

References 26 publications

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“…The question remains whether the very same genes are involved in both diseases or whether in the case of genes within the MHC region, the two diseases are due to different genes in linkage disequilibrium. Recently, a number of non-MHC susceptibility genes have been identified in various autoimmune disorders, including interferon regulatory factor 5 (IRF5), protein tyrosine phosphatase nonreceptor-type 22 (PTPN22), small ubiquitin-like modifier 4 (SUMO4) and MHC class II transactivator (MHC2TA) [35][36][37][38]. This has prompted a search for an association in PID patients not only for genes involved in B cell development or immune regulation, but also genes primarily thought to be involved in the development of autoimmunity.…”

Section: Negative Association Studies In Igad/cvidmentioning

confidence: 99%

Antibody deficiency diseases

Pan‐Hammarström

Hammarström

2008

Eur J Immunol

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Primary immunodeficiency diseases are rare disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of disorders have been described. In this review, we will focus on novel findings in antibody deficiency syndromes. IntroductionPrimary immunodeficiency diseases (PID) are disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of diseases have been described and the genetic basis for most of these defects is known (see [1,2] for recent reviews).Principally, PID can be subdivided into T cell, B cell, combined (T+B), phagocyte and complement defects. The combined immunodeficiencies (SCID) are clinically the most severe and will, if undiagnosed, lead to death of the affected child, usually within the first year of life. Other defects, numerically more prevalent and including common variable immunodeficiency (CVID) and IgA deficiency (IgAD), will result in considerable morbidity, but are rarely associated with mortality.The above defects are all "global", i.e. associated with susceptibility to a variety of different pathogens. However, recently, several PID have been described that are characterized by an increased frequency of infections caused by selected pathogens such as mycobacteria, pneumococci [3] and herpes simplex virus [4,5]. Such "holes-in-the-repertoire" defects (for recent review see [6]) are likely to be common in the population and may, taken together, account for a substantial number of, hitherto largely undiagnosed, patients with PID. Furthermore, a recent observation [7] shows that novel mutations in "classical" genes, i.e. those known to be involved in a given PID, may give rise to a different phenotype, suggesting that the field is getting more complex than previously recognized. In addition, the etiology of several phenotypically similar, albeit in some cases not entirely identical, PID have recently been shown to be caused by mutations in other genes than those originally implicated (examples include hyper-IgM (HIGM, see below), X-linked lymphoproliferative syndrome [8], hyper-IgE [9, 10], Omenn syndrome [11] and X-linked susceptibility to mycobacterial infections [12]. Differences in glycosylation pattern may also account for selected disease phenotypes [13] and...

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Section: Negative Association Studies In Igad/cvidmentioning

confidence: 99%

Antibody deficiency diseases

Pan‐Hammarström

Hammarström

2008

Eur J Immunol

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“…SUMO4 encodes a protein involved in the ubiquitination of IkBa, and a single nucleotide polymorphism (SNP) causing methionine to valine substitution (rs237025, A163G, M55V) results in greater NF-kB transcriptional activity. 4 This polymorphism has been associated with susceptibility to AITD, type 1 diabetes (T1D) and rheumatoid arthritis in Asian populations. 5,6 However, the association of M55V with Graves' disease (GD) and T1D could not be replicated in Caucasian populations, suggesting heterogeneity in the genetic effect of the SUMO4 locus among diverse ethnic groups.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10] MAP3K7IP2 (also known as TAB2) encodes a different inhibitor of the NF-kB signaling pathway and a SNP (001Msp) has been shown to be associated with AITD. 4,9 Recently, a functional NFKB1 promoter polymorphism (À94ins/del ATTG) has been identified and associated with the development of ulcerative colitis. 11 In this study, we analyzed the association of this polymorphism with GD.…”

Section: Introductionmentioning

confidence: 99%

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

et al. 2007

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Recently, a functional polymorphism in the NFKB1 gene promoter (À94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and JapaneseKurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the À94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P ¼ 0.00005; OR ¼ 1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P ¼ 0.009; OR ¼ 1.49 (1.10-2.01)), and the age of disease onset (P ¼ 0.009; OR ¼ 1.45 (1.09-1.91)). Our results suggest that NFKB1 À94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.

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“…17,18 SUMO4 is a novel gene located entirely within the 6th intron of the TAB2 gene. IkBa, a negative regulator of NFkB, is a substrate for SUMO4.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23] The TAB2/SUMO4 locus maps within the region that has been designated as IDDM5 based on prior linkage studies in ASP families. 18 Two independent studies genotyped overlapping 300 and 320 kb intervals in the IDDM5 region with 18 and 15 SNP markers, respectively. 18,24 Both studies identified markers that displayed strong evidence of association with T1D in either family-based transmission/disequilibrium tests (TDT) or case-control tests.…”

Section: Introductionmentioning

confidence: 99%

Functional variants in SUMO4, TAB2, and NFκB and the risk of type 1 diabetes

Kosoy

Concannon

2005

Genes Immun

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Several functional genetic variants that can potentially modulate the activity of NFkB have been recently described. As reduced NFkB activity has been implicated in risk for autoimmune diabetes in the NOD mouse, these variants were tested for allelic association with type 1 diabetes (T1D) in a family based study. Alleles at markers in the TAB2/SUMO4 locus on chromosome 6q had been previously reported to be associated with T1D in two separate studies, but these studies disagreed on the identity of the risk allele. The current study failed to confirm either of these results. No significant evidence of association with T1D was obtained for three SNP markers in the TAB2/SUMO4 region. An additional functional variant in the promoter of the NFKB1 gene that has been shown to directly affect the expression of NFkB was also tested.

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A functional variant of SUMO4, a new IκBα modifier, is associated with type 1 diabetes

Cited by 366 publications

References 26 publications

Antibody deficiency diseases

Antibody deficiency diseases

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

Functional variants in SUMO4, TAB2, and NFκB and the risk of type 1 diabetes

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