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

Lue Ping Zhao; George K. Papadopoulos; William W. Kwok; Antonis K. Moustakas; George P. Bondinas; Annelie Carlsson; Helena Elding Larsson; Johnny Ludvigsson; Claude Marcus; Ulf Samuelsson; Ruihan Wang; Chul-Woo Pyo; Wyatt C. Nelson; Daniel E. Geraghty; Åke Lernmark

doi:10.2337/db20-0374

Next-Generation Sequencing Reveals ThatHLA-DRB3,-DRB4, and-DRB5May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes

Diabetes ◽

10.2337/db15-1115 ◽

2016 ◽

Vol 65 (3) ◽

pp. 710-718 ◽

Cited By ~ 32

Author(s):

Lue Ping Zhao ◽

Shehab Alshiekh ◽

Michael Zhao ◽

Annelie Carlsson ◽

Helena Elding Larsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Next Generation Sequencing ◽

Islet Autoantibodies ◽

Next Generation ◽

Childhood Type 1 Diabetes ◽

Childhood Type ◽

Generation Sequencing

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

10.2337/figshare.12860438.v1 ◽

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

HLA-DQA1 and -DQB1 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*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif “DAAYHDG” to “DAAYHSG” (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) 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.

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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 ◽

10.2337/db20-0075 ◽

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

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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

10.2337/db20-4567/suppl.12053640 ◽

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*10-85 ) 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), 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 GADA and 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 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.

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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

10.2337/db20-4567/suppl.12053640.v1 ◽

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*10-85 ) 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), 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 GADA and 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 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.

Download Full-text

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

10.2337/figshare.12860438 ◽

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

HLA-DQA1 and -DQB1 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*10-24, 3.54*10-15 and 1.03*10-21, respectively). Remarkably, a change of a single residue from the motif “DAAYHDG” to “DAAYHSG” (D to S at β57) alters the resistance potential, from resistant motif (OR = 0.15, p-value = 3.54*10-15) 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.

Download Full-text

Abstract #288 Dyslipidemia in Childhood Type 1 Diabetes in India: Prevalence Correlates and Management Challenges in a Resource Limited Setting

Endocrine Practice ◽

10.1016/s1530-891x(20)46632-7 ◽

2019 ◽

Vol 25 ◽

pp. 117

Author(s):

S Chandraprabha ◽

T Jayalakshmi ◽

Reshma Vijay ◽

Kavitha Muniraj ◽

Muralidhara Krishna ◽

...

Keyword(s):

Type 1 Diabetes ◽

Resource Limited Setting ◽

Resource Limited ◽

Childhood Type 1 Diabetes ◽

Childhood Type ◽

Limited Setting

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Clinical Pattern of Childhood Type 1 Diabetes Mellitus in Karbala, Iraq

International Journal of Pharmaceutical Research ◽

10.31838/ijpr/2020.sp1.201 ◽

2020 ◽

Vol 12 (sp1) ◽

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Clinical Pattern ◽

Childhood Type 1 Diabetes ◽

Childhood Type

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Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

Current Diabetes Reviews ◽

10.2174/1573399814666180730105351 ◽

2019 ◽

Vol 15 (3) ◽

pp. 199-204 ◽

Cited By ~ 7

Author(s):

Elin Pettersen Sørgjerd

Keyword(s):

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Autoimmune Diabetes ◽

Acid Decarboxylase ◽

Adult Onset ◽

Latent Autoimmune Diabetes ◽

Childhood Type 1 Diabetes ◽

Childhood Type

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

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