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Sökning: L773:0012 1797 OR L773:1939 327X > (2020-2021) > Kwok William W.

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1.
  • Zhao, Lue Ping, et al. (författare)
  • Motifs of Three HLA-DQ Amino Acid Residues (alpha 44, beta 57, beta 135) Capture Full Association With the Risk of Type 1 Diabetes in DQ2 and DQ8 Children
  • 2020
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 69:7, s. 1573-1587
  • Tidskriftsartikel (refereegranskat)abstract
    • 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- to 18 year-old patients (n= 962) and control subjects (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 alpha 44Q (odds ratio [OR] 3.29,P= 2.38 * 10(-85)) and beta 57A (OR 3.44,P= 3.80 * 10(-84)) to be associated with T1D in the DQ8/9 cluster representing all ten residues (alpha 22, alpha 23, alpha 44, alpha 49, alpha 51, alpha 53, alpha 54, alpha 73, alpha 184, beta 57) due to complete linkage disequilibrium (LD) of alpha 44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found alpha 44C and beta 135D to share the risk for T1D (OR 2.10,P= 1.96 * 10(-20)). The motif "QAD" of alpha 44, beta 57, and beta 135 captured the T1D risk association of DQ8.1 (OR 3.44,P= 3.80 * 10(-84)), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10,P= 1.96 * 10(-20)). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56,P= 6.35 * 10(-8)) but negatively with IA-2A (OR 0.59,P= 6.55 * 10(-11)). QAD was negatively associated with GADA (OR 0.88;P= 3.70 * 10(-3)) but positively with IA-2A (OR 1.64;P= 2.40 * 10(-14)), despite a single difference at alpha 44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (alpha 44, beta 57, beta 135) conferring T1D risk should sharpen functional and translational studies.
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2.
  • Zhao, Lue Ping, et al. (författare)
  • 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
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:7, s. 1573-1587
  • Tidskriftsartikel (refereegranskat)abstract
    • 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- to 18 year-old patients (n = 962) and control subjects (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 (odds ratio [OR] 3.29, P = 2.38 * 10-85) and β57A (OR 3.44, P = 3.80 * 10-84) 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 * 10-20). The motif "QAD" of α44, β57, and β135 captured the T1D risk association of DQ8.1 (OR 3.44, P = 3.80 * 10-84), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10, P = 1.96 * 10-20). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56, P = 6.35 * 10-8) but negatively with IA-2A (OR 0.59, P = 6.55 * 10-11). QAD was negatively associated with GADA (OR 0.88; P = 3.70 * 10-3) but positively with IA-2A (OR 1.64; P = 2.40 * 10-14), despite a single difference at α44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodimer formation. The identification of three HLA-DQ AAs (α44, β57, β135) conferring T1D risk should sharpen functional and translational studies.
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3.
  • Zhao, Lue Ping, et al. (författare)
  • Next-Generation HLA Sequence Analysis Uncovers Seven HLA-DQ Amino Acid Residues and Six Motifs Resistant to Childhood Type 1 Diabetes
  • 2020
  • Ingår i: Diabetes. - Arlington, VA, United States : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 69:11, s. 2523-2535
  • Tidskriftsartikel (refereegranskat)abstract
    • HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow up on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (alpha a1, alpha 157, alpha 196, beta 9, beta 30, beta 57, and beta 70) that are resistant to T1D among subjects with DQ4-, 5-, 6-, and7-resistant DQ haplotypes. These 7 residues form 13 common motifs: 6 motifs are significantly resistant, 6 motifs have modest or no associations (Pvalues >0.05), and 1 motif has 7 copies observed among control subjects only. The motifs "DAAFYDG," "DAAYHDG," and "DAAYYDR" have significant resistance to T1D (odds ratios [ORs] 0.03, 0.25, and 0.18;P= 6.11 x 10(-24), 3.54 x 10(-15), and 1.03 x 10(-21), respectively). Remarkably, a change of a single residue from the motif "DAAYHDG" to "DAAYHSG" (D to S at beta 57) alters the resistance potential, from resistant motif (OR 0.15;P= 3.54 x 10(-15)) to a neutral motif (P= 0.183), the change of which was significant (FisherPvalue = 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, peptide-MHC class II complex stability, beta 167-169 RGD loop, T-cell receptor binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identification 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.
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