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.

Genome-wide association (GWA) studies revealed a number of single nucleotide polymorphisms (SNPs) significantly associated with type 1 diabetes (T1D). In an attempt to confirm some of these candidate associations, we genotyped 2046 Caucasian patients and 2417 normal controls from the United States for SNPs in five genomic regions. While no evidence was obtained for four genomic regions (rs2929366/NM_144715 on chromosome 3, rs9127/Q7Z4C4 on chromosome 5, rs1445898/CAPSL on chromosome 5 and rs2302188/NM_033543 on chromosome 19), we provide strong evidence for association between T1D and multiple SNPs in the IFIH1 linkage disequilibrium (LD) block on chromosome 2q. Among the 10 SNPs genotyped for the 2q region, four SNPs located within the IFIH1 gene or at the 5' region of IFIH1 showed significant association with T1D in the Georgia population [odds ratio (OR) = 1.7-1.9] with the best P-value found at SNP rs1990760 (P = 8 x 10(-8) and OR = 1.9). Several SNPs outside of the IFIH1 gene also showed significant but weaker associations. Furthermore, IFIH1 gene expression levels in peripheral blood mononuclear cells are significantly correlated with IFIH1 genotypes, and higher IFIH1 levels are found in individuals with the susceptible genotypes (P = 0.005). Thus, both genetic association and gene expression data suggest that IFIH1 is the most plausible candidate gene implicated in T1D in this LD block.

Risk factors for deep and superficial chest surgical-site infections after coronary artery bypass surgery differ, suggesting different mechanisms of pathogenesis. Appropriate risk stratification models specific to these important outcomes must be developed.

The present study was conducted to assess genetic associations for type 1 diabetes (T1D) reported in previous genome-wide association studies (GWAS). A total of 21 previously reported single-nucleotide polymorphisms (SNPs) were genotyped by TaqMan assays in 1434 Caucasian T1D patients and 1864 normal controls from Georgia. Analysis of the samples identified 18 SNPs (PTPN22, INS, IFIH1, SH2B3, ERBB3, CTLA4, C14orf181, CTSH, CLEC16A, CD69, ITPR3, C6orf173, SKAP2, PRKCQ, RNLS, IL27, SIRPG and CTRB2) with putative association.

T ype 1 diabetes is an autoimmune disease characterized by the T-cell-mediated destruction of the insulin-secreting -cells of the pancreatic islets (1,2). It is a complex disease involving numerous susceptibility genes and environmental factors, which may act as triggers of the autoimmune response. Much research has been focused on identifying type 1 diabetes susceptibility genes in an effort to enhance the prediction of which individuals are at high risk of developing the disease, as well as to understand the pathogenesis in order to prevent the disease. Thus far, only two susceptibility regions have been well characterized. I D D M 1 maps to the HLA region and actually contains multiple susceptibility genes (3-11). I D D M 2 h a s been identified as the variable number of tandem repeats immediately 5 to the insulin gene (12-19), which appears to play a role in the level of gene expression (13,14,(20)(21)(22). Many additional susceptibility intervals have been suggested by complete or partial genome scans conducted by multiple labs (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Several of these intervals (I D D M 4, I D D M 5, I D D M 8, and I D D M 1 2) have been confirmed in additional data sets (33-35), but the exact genes responsible for increased susceptibility to type 1 diabetes have not been i d e n t i fied. Other proposed susceptibility intervals remain to be confir m e d .One of the confirmed type 1 diabetes susceptibility loci is I D D M 1 2 , located on chromosome 2q33. Initial studies provided evidence of linkage and association of a polymorphic marker in the C T L A 4 gene with type 1 diabetes in Italian and Spanish families (35). These results were confirmed in an additional data set that included French, Spanish, MexicanAmerican, and U.S. Caucasian families (34). Case-control studies of a Belgian and German data set provided additional c o n firmation of association between C T L A 4 p o l y m o r p h i s m s and type 1 diabetes (35,36). There is also association of C T L A 4 polymorphisms with Graves' disease and Hashimoto's thyroiditis, both autoimmune thyroid diseases (36)(37)(38)(39)(40).Although these studies of I D D M 1 2 provided convincing evidence for I D D M 1 2, the precise location of the gene responsible for the disease is not well defined. Although C T L A 4 is an ideal candidate gene for autoimmune diseases, the association between type 1 diabetes and CTLA4 p o l ymorphisms could be due to linkage disequilibrium of the RESEARCH DESIGN AND METHODSS u b j e c t s . Genomic DNA was obtained from members of 178 simplex and 350 multiplex (with two or more affected children) type 1 diabetes families (Ta b l e 1). The collection includes U.S. Caucasian, Mexican-American, French, Spanish, Italian, Korean, and Chinese families. All diabetic patients participating in this study were diagnosed using the criteria of the National Diabetes Data Group. The clinical information on the patients has been described in previous publications (34,44). G e n o t y p i n g . Microsatellite repeats were ge...

Type 1 diabetes (T1D) is expected to cause significant changes in the serum proteome; however, few studies have systematically assessed the proteomic profile change associated with the disease. In this study, a semiquantitative spectral counting-based two dimensional liquid chromatography mass spectrometry platform was used to analyze serum samples from T1D patients and controls. In this discovery phase, significant differences were found for 21 serum proteins implicated in inflammation, oxidation, metabolic regulation, and autoimmunity. To assess the validity of these findings, six candidate proteins including adiponectin, insulin-like growth factor binding protein 2, serum amyloid protein A, C-reactive protein, myeloperoxidase, and transforming growth factor beta induced were selected for subsequent immune assays for 1139 T1D patients and 848 controls. A series of statistical analyses using cases and controls matched for age, sex, and genetic risk confirmed that T1D patients have significantly higher serum levels for four of the six proteins: adiponectin (odds ratio (OR) ‫؍‬ 1.95, p ‫؍‬ 10 ؊27 ), insulin-like growth factor binding protein 2 (OR ‫؍‬ 2.02, p < 10 ؊20 ), C-reactive protein (OR ‫؍‬ 1.13, p ‫؍‬ 0.007), serum amyloid protein A (OR ‫؍‬ 1.51, p < 10 ؊16 ); whereas the serum levels were significantly lower in patients than controls for the two other proteins: transforming growth factor beta induced (OR ‫؍‬ 0.74, p < 10 ؊5 ) and myeloperoxidase (OR ‫؍‬ 0.51, p < 10 ؊41 ). Compared with subjects in the bottom quartile, subjects in the top quartile for adiponectin (OR ‫؍‬ 6.29, p < 10 ؊37 ), insulin-like growth factor binding protein 2 (OR ‫؍‬ 7.95, p < 10 ؊46 ), C-reactive protein (OR ‫؍‬ 1.38, p ‫؍‬ 0.025), serum amyloid protein A (OR ‫؍‬ 3.36, p < 10 ؊16 ) had the highest risk of T1D, whereas subjects in the top quartile of transforming growth factor beta induced (OR ‫؍‬ 0.41, p < 10 ؊11 ) and myeloperoxidase (OR ‫؍‬ 0.10, p < 10 ؊43

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Aims. To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients. Methods. Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20–75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR. Results. The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR. Conclusions. The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.