scholarly journals Motifs of Three HLA-DQ Amino Acid Residues (α44, β57, β135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children

Diabetes ◽  
2020 ◽  
Vol 69 (7) ◽  
pp. 1573-1587
Author(s):  
Lue Ping Zhao ◽  
George K. Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
George P. Bondinas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Amino Acid Residues ◽  
Hla Dq

scholarly journals Next-Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (11) ◽  
pp. 2523-2535
Author(s):  
Lue Ping Zhao ◽  
George K. Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
George P. Bondinas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Sequence Analysis ◽  
Amino Acid Residues ◽  
Next Generation ◽  
Hla Dq ◽  
Childhood Type 1 Diabetes ◽  
Childhood Type

scholarly journals Motifs of three HLA-DQ amino acid residues (α44, β57, β135) capture full association with the risk of type 1 diabetes in DQ2 and DQ8 children

2020 ◽  
Author(s):  
Ada Admin ◽  
Lue Ping Zhao ◽  
George K Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Amino Acid Residues ◽  
Newly Diagnosed ◽  
Old Patients ◽  
Hla Dq ◽  
Single Difference ◽  
Hla Dqa1 ◽  
Risk Association

HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1-18 year-old patients (n=962) and controls (n=636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically-organized haplotype (HOH) association analysis, allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster, included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (OR 3.29, p=2.38*10<sup>-85</sup> ) and β57A (OR 3.44, p=3.80*10<sup>-84</sup>) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage-disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, p=1.96*10<sup>-20</sup>). The motif “QAD” of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, <i>p</i>=3.80*10<sup>-84</sup>), the corresponding motif “CAD” captured the risk association of DQ2.5 (OR 2.10, <i>p</i>=1.96*10<sup>-20</sup>). Two risk associations were related to GADA and IA-2A, but in opposite directions. “CAD” was positively associated with GADA (OR 1.56; <i>p</i>=6.35*10<sup>-8</sup>) but negatively with IA-2A (OR 0.59, <i>p</i>= 6.55*10<sup>-11</sup>). “QAD” was negatively associated with GADA (OR 0.88; <i>p</i>= 3.70*10<sup>-3</sup>) but positively with IA-2A (OR 1.64; <i>p</i>= 2.40*10<sup>-14</sup>), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential TCR contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AA (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.

scholarly journals Motifs of three HLA-DQ amino acid residues (α44, β57, β135) capture full association with the risk of type 1 diabetes in DQ2 and DQ8 children

2020 ◽  
Author(s):  
Ada Admin ◽  
Lue Ping Zhao ◽  
George K Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Amino Acid Residues ◽  
Newly Diagnosed ◽  
Old Patients ◽  
Hla Dq ◽  
Single Difference ◽  
Hla Dqa1 ◽  
Risk Association

HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1-18 year-old patients (n=962) and controls (n=636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically-organized haplotype (HOH) association analysis, allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster, included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues α44Q (OR 3.29, p=2.38*10<sup>-85</sup> ) and β57A (OR 3.44, p=3.80*10<sup>-84</sup>) to be associated with T1D in the DQ8/9 cluster representing all ten residues (α22, α23, α44, α49, α51, α53, α54, α73, α184, β57) due to complete linkage-disequilibrium (LD) of α44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found α44C and β135D to share the risk for T1D (OR 2.10, p=1.96*10<sup>-20</sup>). The motif “QAD” of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, <i>p</i>=3.80*10<sup>-84</sup>), the corresponding motif “CAD” captured the risk association of DQ2.5 (OR 2.10, <i>p</i>=1.96*10<sup>-20</sup>). Two risk associations were related to GADA and IA-2A, but in opposite directions. “CAD” was positively associated with GADA (OR 1.56; <i>p</i>=6.35*10<sup>-8</sup>) but negatively with IA-2A (OR 0.59, <i>p</i>= 6.55*10<sup>-11</sup>). “QAD” was negatively associated with GADA (OR 0.88; <i>p</i>= 3.70*10<sup>-3</sup>) but positively with IA-2A (OR 1.64; <i>p</i>= 2.40*10<sup>-14</sup>), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential TCR contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AA (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.

scholarly journals Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk

2015 ◽  
Vol 47 (8) ◽  
pp. 898-905 ◽  
Author(s):  
Xinli Hu ◽  
Aaron J Deutsch ◽  
Tobias L Lenz ◽  
Suna Onengut-Gumuscu ◽  
Buhm Han ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Interaction Effects ◽  
Diabetes Risk ◽  
Hla Dr ◽  
Hla Dq

scholarly journals Next generation HLA sequence analysis uncovers seven HLA-DQ amino acid residues and six motifs resistant to childhood type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Lue Ping Zhao ◽  
George K Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
P Value ◽  
Amino Acid Residues ◽  
Molecular Approaches ◽  
Hla Dq ◽  
Immunological Mechanisms ◽  
Control Disease ◽  
Hla Dqa1 ◽  
Childhood Type 1 Diabetes

<i>HLA-DQA1</i> and <i>-DQB1</i> genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif “DAAFYDG”, “DAAYHDG” and “DAAYYDR” have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10<sup>-24</sup>, 3.54*10<sup>-15</sup> and 1.03*10<sup>-21</sup>, respectively). Remarkably, a change of a single residue from the motif “DAAYH<b><u>D</u></b>G” to “DAAYH<b><u>S</u></b>G” (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10<sup>-15</sup>) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher’s p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, b167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

scholarly journals Next generation HLA sequence analysis uncovers seven HLA-DQ amino acid residues and six motifs resistant to childhood type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Lue Ping Zhao ◽  
George K Papadopoulos ◽  
William W. Kwok ◽  
Antonis K. Moustakas ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
P Value ◽  
Amino Acid Residues ◽  
Molecular Approaches ◽  
Hla Dq ◽  
Immunological Mechanisms ◽  
Control Disease ◽  
Hla Dqa1 ◽  
Childhood Type 1 Diabetes

<i>HLA-DQA1</i> and <i>-DQB1</i> genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (αa1, α157, α196, β9, β30, β57, β70) that are resistant to T1D among subjects with DQ4, 5, 6 and 7 resistant DQ haplotypes. These seven residues form 13 common motifs; six motifs are significantly resistant, six motifs have modest or no associations (p-values>0.05), and one motif has 7 copies observed among controls only. The motif “DAAFYDG”, “DAAYHDG” and “DAAYYDR” have significant resistance to T1D (OR = 0.03, 0.25 and 0.18, p-value = 6.11*10<sup>-24</sup>, 3.54*10<sup>-15</sup> and 1.03*10<sup>-21</sup>, respectively). Remarkably, a change of a single residue from the motif “DAAYH<b><u>D</u></b>G” to “DAAYH<b><u>S</u></b>G” (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10<sup>-15</sup>) to a neutral motif (p-value = 0.183), the change of which was significant (Fisher’s p-value = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, pMHCII complex stability, b167-169 RGD loop, TCR binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identifications of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies.

scholarly journals A C-peptide complex with albumin and Zn2+ increases measurable GLUT1 levels in membranes of human red blood cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
M. Geiger ◽  
T. Janes ◽  
H. Keshavarz ◽  
S. Summers ◽  
C. Pinger ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Blood Cells ◽  
Glucose Transporter ◽  
Peptide Binding ◽  
C Peptide ◽  
Amino Acid Peptide ◽  
Human Red Blood Cells

Abstract People with type 1 diabetes (T1D) require exogenous administration of insulin, which stimulates the translocation of the GLUT4 glucose transporter to cell membranes. However, most bloodstream cells contain GLUT1 and are not directly affected by insulin. Here, we report that C-peptide, the 31-amino acid peptide secreted in equal amounts with insulin in vivo, is part of a 3-component complex that affects red blood cell (RBC) membranes. Multiple techniques were used to demonstrate saturable and specific C-peptide binding to RBCs when delivered as part of a complex with albumin. Importantly, when the complex also included Zn2+, a significant increase in cell membrane GLUT1 was measured, thus providing a cellular effect similar to insulin, but on a transporter on which insulin has no effect.

scholarly journals Effect of Insulin with Concurrent Amino Acid Infusion on Protein Metabolism in Rapidly Growing Pubertal Children with Type 1 Diabetes

2005 ◽  
Vol 58 (2) ◽  
pp. 229-234 ◽  
Author(s):  
Mushtaq A Godil ◽  
Thomas A Wilson ◽  
Peter J Garlick ◽  
Margaret A McNurlan
Keyword(s):  
Type 1 Diabetes ◽  
Amino Acid ◽  
Protein Metabolism ◽  
Acid Infusion ◽  
Amino Acid Infusion
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