Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
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PMID:A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. 1567 37

Several functional genetic variants that can potentially modulate the activity of NFkappaB have been recently described. As reduced NFkappaB 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 NFkappaB was also tested.
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PMID:Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes. 1572 64

Association studies are a potentially powerful approach to identifying susceptibility variants for common multifactorial diseases such as type 1 diabetes, but the results are not always consistently reproducible. The IDDM5 locus has recently been narrowed to an approximately 200-kb interval on chromosome 6q25 by two independent groups. These studies demonstrated that alleles at markers in the mitogen-activating protein kinase 7 interacting protein 2 (MAP3K7IP2)/SUMO4 region were associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association of the SUMO4 gene with type 1 diabetes. To clarify the contribution of the M55V polymorphism of the SUMO4 gene to type 1 diabetes susceptibility, 541 type 1 diabetic patients and 768 control subjects were studied in Asian populations. The M55V polymorphism was significantly associated with type 1 diabetes in Asian populations (summary odds ratio [OR] 1.46, P = 0.00083, Mantel-Haenszel test). Meta-analysis of published studies and the present data confirmed a highly significant association in Asian populations (summary OR 1.29, P = 7.0 x 10(-6)) but indicated heterogeneity in the genetic effect of the SUMO4/MAP3K7IP2 locus on type 1 diabetes among diverse ethnic groups. These data indicate that the MAP3K7IP2/SUMO4 locus in the IDDM5 interval is associated with type 1 diabetes in Asian populations.
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PMID:Genetic heterogeneity in association of the SUMO4 M55V variant with susceptibility to type 1 diabetes. 1630 80

The evidence that there is clinical heterogeneity of type 1 diabetes is reviewed and the implications for genetic studies are discussed. In the past year, genome-wide linkage analysis of 1435 multiplex families was reported. Additionally, confirmed evidence for association of specific markers at two loci (PTPN22, OAS1) as well as failure to replicate three others (IL12B, SUMO4, PAX4) is discussed. Some common themes are identified and suggestions for improvements are made. We look forward to the results from genome-wide association studies.
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PMID:Genetic epidemiology of type 1 diabetes. 1654 25

Recent study demonstrated that M55V variant in SUMO4 at IDDM5 was associated with susceptibility to type 1 diabetes. Subsequent studies, however, showed inconsistency in the association. To clarify the population-wide effect on the association of SUMO4 with type 1 diabetes, we have performed meta-analysis including our own data in Asian populations, which confirmed a highly significant association in Asian populations (summary odds ratio [OR]: 1.29, P = 7.0 x 10(-6)), but indicated significant heterogeneity in the genetic effect of the SUMO4 gene on type 1 diabetes among diverse ethnic groups. These observations indicated the association of SUMO4 with type 1 diabetes in Asian populations.
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PMID:Association of SUMO4, as a candidate gene for IDDM5, with susceptibility to type 1 diabetes in Asian populations. 1713 May 30

Transracial studies are a powerful tool for genetic association studies of multifactorial diseases, such as type 1 diabetes. We therefore studied the association of candidate genes, HLA, INS, CTLA4, PTPN22, and SUMO4, with type 1 diabetes in Asian populations in comparison with Caucasian populations. Class II HLA was strongly associated with type 1 diabetes in both Asian and Caucasian populations, but alleles associated with type 1 diabetes are different among different ethnic groups due to difference in allele distribution in general populations. INS was associated with type 1 diabetes in both Japanese and Caucasian populations, but frequency of disease-associated haplotype was markedly higher in Japanese than in Caucasian populations. CTLA4 association was reported for both type 1 diabetes and autoimmune thyroid diseases (AITD) in Caucasian populations, but the association with type 1 diabetes was concentrated in a subset of patients with AITD in Japanese. A variant (R620W) of PTPN22 was consistently associated with type 1 diabetes in Caucasian populations, but the variant was absent in Asian populations including Japanese. M55V variant of SUMO4 was significantly associated with type 1 diabetes in Asians, but genetic heterogeneity between Asian and Caucasian populations was suggested. These data indicate the importance of transracial studies with a large number of samples in each ethnic group in genetic dissection of type 1 diabetes.
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PMID:Genetics of type 1 diabetes: similarities and differences between Asian and Caucasian populations. 1713 May 32

Genomewide linkage analyses since the early 1990s suggested over 20 genomic intervals that may contain susceptibility genes for type 1 diabetes. However, the identification of the specific genes in these intervals presents a formidable challenge due to a number of difficulties associated with genetic mapping and cloning of genes implicated in complex diseases. One of the difficulties is due to the presence of many weak and different susceptibility genes in different patients and populations, a phenomenon known as genetic heterogeneity. In 2004, we reported the cloning of a novel small ubiquitin-like modifier (SUMO) gene, SUMO4, in the IDDM5 interval on chromosome 6q25, and presented strong genetic and functional evidence suggesting that SUMO4 is a susceptibility gene for type 1 diabetes mellitus (T1DM). In this article, we will summarize genetic association data suggesting that SUMO4 is consistently associated with T1DM in the Asian populations while the association is more heterogeneous in the Caucasian populations. We will also discuss the possible molecular pathways through which sumoylation may regulate T1DM and autoimmunity.
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PMID:Genetic and functional evidence supporting SUMO4 as a type 1 diabetes susceptibility gene. 1713 May 63

Small ubiquitin-related modifier (SUMO4), located in IDDM5, has been identified as a potential susceptibility gene for type 1 diabetes mellitus (T1DM). The novel polymorphism M55V, causing an amino acid change in the evolutionarily conserved met55 residue has been shown to activate the nuclear factor kappaB (NF-kappaB), hence the suspected role of SUMO4 in the pathogenicity of T1DM. The M55V polymorphism has been shown to be associated with susceptibility to T1DM in Asians, but not in Caucasians. Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of T1DM and SUMO4 M55V has not been studied in LADA to date. The current study aims to test whether Latvians are similar to Caucasians in susceptibility to autoimmune diabetes (T1DM and LADA), with respect to SUMO4 M55V. We studied, age- and sex-matched, Latvian T1DM patients (n = 100) and healthy controls (n = 90) and LADA patients (n = 45) and healthy controls (n = 95). SUMO4 M55V polymorphism was analyzed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). The allelic frequencies of the A and G alleles were compared with HLA DR3-DR4-positive and HLA DR3-DR4-negative patients to identify any potential relation between HLA DR3-DR4 and SUMO4 M55V. We found no significant association between SUMO4 M55V and T1DM susceptibility in Latvians, the results being in concurrence with the previous studies in Caucasians of British and Canadian origin. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P values. No significant association was found between SUMO4 M55V and LADA. SUMO4 M55V is not associated with susceptibility to T1DM and LADA in Latvians, and Latvians exhibit similarity to other Caucasians with respect to association of SUMO4 M55V with autoimmune diabetes.
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PMID:Association of SUMO4 M55V polymorphism with autoimmune diabetes in Latvian patients. 1713 May 65

Autoimmune diabetes [type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and part of malnutrition-related diabetes] has been shown to have genetic predisposition. Studies in IDDM 5 have lead to the discovery of a novel polymorphism 163 A-->G, of SUMO4 (small ubiquitin-related modifier) gene, associated with risk to T1DM in Asians, but not in Caucasians. We studied patients with T1DM (n = 134), patients with LADA (n = 101), patients with malnutrition-modulated diabetes mellitus (n = 66) and patients with fibrocalculous pancreatic diabetes (n = 43) and healthy controls subjects (n = 114) from Cuttack, India. Polymerase chain reaction-sequence-specific primer (PCR-SSP) was used to amplify the 163 A-->G sequences. Restriction fragment length polymorphism (RFLP) was performed using restriction enzyme Taq I (PCR-RFLP). Differences in the allelic frequencies of the A and the G alleles were tested statistically using Fisher's exact test or chi-squared test wherever appropriate. P-values were considered significant when equal to or less than 0.05. No significant association was detected between SUMO4 M55V and T1DM susceptibility in Asian-Indians. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P-values. No significant association was found between SUMO4 M55V and LADA or malnutrition-related diabetes mellitus (MRDM). Our results show that Asian-Indians with T1DM are different from other Asian populations. Asian-Indians show more similarity to Caucasians with respect to the association of SUMO4 M55V variant in T1DM. Association studies on Asian-Indian patients with LADA and MRDM showed no significant difference in the presence of the A and the G alleles when compared to healthy controls.
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PMID:No association of SUMO4 M55V with autoimmune diabetes in Asian-Indian patients. 1737 40

Progress has been made in investigating the genetic factors involved in type 1 diabetes (T1D) development for the past few years. While Linkage disequilibrium (LD) mapping has been useful for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations, identification of specific disease genes has been a challenge and limited to known candidate genes. The overall risk for T1D from the HLA DR and DQ molecules (IDDM1) is determined by combinations of polymorphic alleles. Functional studies indicate that the susceptible and protective HLA-DR and -DQ bind and present non-overlapping peptides. Although consistent linkage evidence was reported for the susceptibility intervals IDDM2, IDDM5 and IDDM12, evidence for most other intervals varies in different data sets. The variable number of tandem repeats at the 5' end of the insulin gene (IDDM2) regulates insulin expression in the thymus. Studies on IDDM5 have led to the discovery of a novel polymorphism 163 A-->G (M55V) in SUMO4 gene, which was found to be associated with T1D patients with Asian origin. Functionally SUMO4 conjugates to IkBalpha and negatively regulates NFkB transcriptional pathway. The M55V substitution reduces the sumoylation activity of the V55 variant, which resulted in higher NFkB dependent transcriptional activity. The polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4, IDDM12) encoding a regulatory molecule in the immune system associate with T1D and autoimmune thyroid diseases (ATD). The 3' untranslated region of this gene determines the level of soluble CTLA-4. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as evidenced by quantitative alterations of candidate genes contributing to autoimmune tissue destruction. Moreover, the identification of two transcription factors that, when mutated, are responsible for severe autoimmune disease is leading to a better understanding of T cell tolerance. Both AIRE and Foxp3, identified initially via their association with genetically manipulated mice, are involved in tolerance induction in humans. Although mutations in these genes may cause rare but serious diseases, it is likely that other transcription factors will contribute to the genetic load that predisposes certain individuals to disease.
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PMID:Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. 1744 64


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