Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Diabetes 2005 Dec
PMID:Genetic heterogeneity in association of the SUMO4 M55V variant with susceptibility to type 1 diabetes. 1630 80

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

OBJECTIVE-SUMO4 mRNA was recently found to be mainly expressed in the kidney, and the methionine-to-valine substitution at codon 55 (M55V) variant of SUMO4 may induce higher nuclear factor-kappaB (NF-kappaB) activity. Because NF-kappaB is known to mediate the development of diabetic nephropathy, we examined the association between the SUMO4 M55V variant and the severity of diabetic nephropathy. RESEARCH DESIGN AND METHODS-We recruited a total of 430 patients with type 2 diabetes. The M55V (rs237025, 163A-->G) polymorphism of SUMO4 was genotyped by real-time PCR, and urine albumin concentration was measured by radioimmunoassay. RESULTS-The frequencies of SUMO4 AA, GA, and GG were 52.6, 40.7, and 6.7%, respectively, in the normoalbuminuric group; 45.5, 47.3, and 7.1% in the microalbuminuric group; and 36.9, 46.2, and 16.9% in the macroalbuminuric group. We detected a significant linear trend for SUMO4 genotype between the macroalbuminuric and normoalbuminuric groups. The mean urine albumin-to-creatinine ratio (42.3 +/- 108.82 mg/mmol) in the GG group was significantly higher than in the AA (14.9 +/- 51.49 mg/mmol) and GA (17.0 +/- 43.74 mg/mmol) groups. Multivariate logistic regression analysis showed the SUMO4 M55V variant to be independently associated with the severity of diabetic nephropathy. CONCLUSIONS-This study indicates that the SUMO4 gene M55V variant is associated with severity of diabetic nephropathy in patients with type 2 diabetes.
Diabetes 2007 Apr
PMID:SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes. 1766 Feb 69

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.
Diabetes Res Clin Pract 2007 Sep
PMID:Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. 1744 64

Among candidate genes for type 1 diabetes, HLA, INS, CTLA4, PTPN22 and SUMO4 have been shown to be associated with the disease in Caucasian populations. To clarify the similarities and differences in the contribution of these genes to type 1 diabetes between Asian and Caucasian populations, association of these genes with type 1 diabetes was studied in a large number of samples in Japanese and Korean populations. Class II HLA was strongly associated with type 1 diabetes in both Asian and Caucasian populations, but haplotypes associated with type 1 diabetes were markedly different due to difference in the presence and absence of haplotypes in each population. INS was consistently associated with type 1 diabetes in both Japanese and Caucasian populations, but frequency of disease-associated haplotype was markedly high in Japanese general population. CTLA4 was associated with type 1 diabetes only in a subset of patients with type 1 diabetes complicated with AITD in Japanese. A variant (R620W) of PTPN22 was associated with type 1 diabetes and other autoimmune diseases in Caucasians, but the variant was absent in Asians. SUMO4 was associated with type 1 diabetes in Asians, but not in Caucasian, suggesting a genetic heterogeneity among diverse ethnic groups. Trans-racial study with a large number of samples in both Asian and Caucasian populations will contribute to genetic dissection of type 1 diabetes and identification of causative variants.
Diabetes Res Clin Pract 2007 Sep
PMID:Genetics of type 1 diabetes in Asian and Caucasian populations. 1745 59

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.
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PMID:SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients. 1755 41

Autoimmune diabetes is an organ specific and multifactorial disorder including insulin dependent diabetes mellitus (Type 1 Diabetes) and latent autoimmune diabetes in adults (LADA), which progresses to insulin dependency because of the beta cells destruction. Several polymorphisms in different genes have been associated with diabetes. The CTLA4 gene is considered a down regulator of T cell function, and the SUMO4 gene encodes a small ubiquitin-like modifier implicated in the intensity and duration of the immune response. We selected 62 LADA patients, 123 patients with Type 1 diabetes patients and 136 unrelated volunteers to study CTLA4 -318 C/T, 159 C/T, 3' STR and SUMO4 163 A/G polymorphisms by PCR. There was a statistical difference significant in the frequency of the allele 209pb for the 3'STR between LADA and Type 1 diabetes patients but not with respect the normal group, the frequencies were found to be 6.9%, 1.0% and 1.9%, respectively. However, no association with either of the polymorphisms has been found in the studied population. The knowledge of the several susceptibility loci in autoimmune diabetes will enhanced the prediction of individuals at high risk of developing the disease in order to establish the best treatment and the prevention of autoimmune diabetes.
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PMID:No evidence of association of CTLA-4 -318 C/T, 159 C/T, 3' STR and SUMO4 163 AG polymorphism with autoimmune diabetes. 1755 9

Susceptibility to type 1 diabetes (T1D) is determined by interactions of multiple genes with unknown environmental factors. Despite the characterization of over 20 susceptibility regions for T1D, identification of specific genes in these regions is still a formidable challenge. In 2004, we first 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 T1D susceptibility gene. Subsequent studies have consistently confirmed this association in multiple Asian populations despite controversial observations in Caucasians. In this review, we will update the genetic evidence supporting SUMO4 as a T1D susceptibility gene and discuss the possible explanations for the discrepant associations observed in Caucasians. We will then discuss the mechanisms through which SUMO4 contributes to the pathogenesis of T1D.
Diabetes Metab Res Rev 2008 Feb
PMID:SUMO4 and its role in type 1 diabetes pathogenesis. 1799 Feb 97


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