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Roswell, GA, United States

Reddy M.P.L.,Georgia Regents University | Wang H.,Georgia Regents University | Liu S.,Georgia Regents University | Bode B.,Georgia Regents University | And 6 more authors.
Genes and Immunity | Year: 2011

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. © 2011 Macmillan Publishers Limited All rights reserved. Source

Zhi W.,University of Georgia | Sharma A.,University of Georgia | Purohit S.,University of Georgia | Miller E.,University of Georgia | And 7 more authors.
Molecular and Cellular Proteomics | Year: 2011

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) had the lowest risk of T1D. These findings provided valuable information on the proteomic changes in the sera of T1D patients. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Wang H.,Georgia Regents University | Jin Y.,Georgia Regents University | Reddy M.V.P.L.,Georgia Regents University | Podolsky R.,Georgia Regents University | And 10 more authors.
PLoS ONE | Year: 2010

Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4×10-11), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p<10-10). Furthermore, ERBB3 protein is expressed on the surface of CD11c+ cells (dendritic cells and monocytes) in peripheral blood after stimulation with LPS, polyI:C or CpG. Subjects with protective genotypes have significantly higher percentages of ERBB3+ monocytes and dendritic cells (p = 1.1×10-9); and the percentages of ERBB++cells positively correlate with the ability of APC to stimulate T cell proliferation (R2 = 0.90, p<0.0001). Our results indicate that ERBB+ plays a critical role in determining APC function and potentially T1D pathogenesis. © 2010 Wang et al. Source

Guan R.,Nanjing University of Technology | Guan R.,China Agricultural University | Guan R.,Georgia Regents University | Purohit S.,Georgia Regents University | And 10 more authors.
PLoS ONE | Year: 2011

Background: Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), has been implicated in the pathogenesis of many diseases characterized by monocytic infiltration. However, limited data have been reported on MCP-1 in type 1 diabetes (T1D) and the findings are inconclusive and inconsistent. Methods: In this study, MCP-1 was measured in the sera from 2,472 T1D patients and 2,654 healthy controls using a Luminex assay. The rs1024611 SNP in the promoter region of MCP-1 was genotyped for a subset of subjects (1764 T1D patients and 1323 controls) using the TaqMan-assay. Results: Subject age, sex or genotypes of MCP-1 rs1024611SNP did not have a major impact on serum MCP-1 levels in either healthy controls or patients. While hemoglobin A1c levels did not have a major influence on serum MCP-1 levels, the mean serum MCP-1 levels are significantly higher in patients with multiple complications (mean = 242 ng/ml) compared to patients without any complications (mean = 201 ng/ml) (p = 3.5×10-6). Furthermore, mean serum MCP-1 is higher in controls (mean = 261 ng/ml) than T1D patients (mean = 208 ng/ml) (p<10-23). More importantly, the frequency of subjects with extremely high levels (>99th percentile of patients or 955 ng/ml) of serum MCP-1 is significantly lower in the T1D group compared to the control group (odds ratio = 0.11, p<10-33). Conclusion: MCP-1 may have a dual role in T1D and its complications. While very high levels of serum MCP-1 may be protective against the development of T1D, complications are associated with higher serum MCP-1 levels within the T1D group. © 2011 Guan et al. Source

Purohit S.,Georgia Regents University | Sharma A.,Georgia Regents University | Hopkins D.,Georgia Regents University | Steed L.,Georgia Regents University | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D. Participants: The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study. Main Outcome Measures: Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays. Results: Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients withT1Dthan controls (IL8:oddsratio [OR] =0.40;P=5.7×10-19; IL-1Ra:OR=0.42;P=1.1× 10-13; MCP-1: OR = 0.60; P = 6.7 × 10-9; and MIP-1β: OR = 0.63; P = 4.2 × 10-7). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10-32; IL-1Ra: OR = 0.56, P = 3.7 × 10-27; MCP-1: OR = 0.61, P = 4.3 × 10-17; and MIP-1β: OR = 0.69, P = 2.4 × 10-13). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups. Conclusions: IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls. Copyright © 2015 by the Endocrine Society. Source

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