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

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

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The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study

Diabetes Care ◽

10.2337/dc20-2820 ◽

2021 ◽

pp. dc202820

Author(s):

Antigoni Eleftheriou ◽

Clive J. Petry ◽

Ieuan A. Hughes ◽

Ken K. Ong ◽

David B. Dunger

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Growth Study ◽

Hla Dr ◽

Hla Dq ◽

Igf I ◽

High Risk Type

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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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Newborn HLA-DR,DQ genotype screening: age- and ethnicity-specific type 1 diabetes risk estimates

Pediatric Diabetes ◽

10.1111/j.1399-543x.2005.00117.x ◽

2005 ◽

Vol 6 (3) ◽

pp. 136-144 ◽

Cited By ~ 31

Author(s):

Lisa M Emery ◽

Sunanda Babu ◽

Teodorica L Bugawan ◽

Jill M Norris ◽

Henry A Erlich ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Risk ◽

Risk Estimates ◽

Hla Dr ◽

Genotype Screening

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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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HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families

Diabetes ◽

10.2337/db07-1331 ◽

2008 ◽

Vol 57 (4) ◽

pp. 1084-1092 ◽

Cited By ~ 424

Author(s):

H. Erlich ◽

A. M. Valdes ◽

J. Noble ◽

J. A. Carlson ◽

M. Varney ◽

...

Keyword(s):

Type 1 Diabetes ◽

Risk Analysis ◽

Diabetes Risk ◽

Hla Dr ◽

Diabetes Genetics

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Estimation of Diabetes Risk in Brazilian Population by Typing for Polymorphisms in HLA-DR-DQ, INS and CTLA-4 Genes

Disease Markers ◽

10.1155/2005/684123 ◽

2005 ◽

Vol 21 (3) ◽

pp. 139-145 ◽

Cited By ~ 11

Author(s):

Omar M. Hauache ◽

André F. Reis ◽

Carolina S.V. Oliveira ◽

José Gilberto H. Vieira ◽

Minna Sjüroos ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Gene Polymorphisms ◽

Diabetes Risk ◽

Brazilian Population ◽

Healthy Controls ◽

Typing Method ◽

Hla Dr ◽

Screening Sensitivity

The study aimed to further characterise HLA encoded risk factors of type 1 diabetes (T1D) in Brazilian population and test the capability of a low resolution full-house DR-DQ typing method to find subjects at diabetes risk. Insulin and CTLA-4 gene polymorphisms were also analysed. The method is based on an initial DQB1 typing supplemented by DQA1 and DR4 subtyping when informative. Increased frequencies of both (DR3)-DQA1*05-DQB1*02 and DRB1*04-DQA1*03-DQB1*0302 haplotypes were detected among patients. DRB1*0401, *0402, *0404 and *0405 alleles were all common in DQB1*0302 haplotypes and associated with T1D. (DRB1*11/12/1303)-DQA1*05-DQB1*0301, (DRB1*01/10)-DQB1*0501, (DRB1*15)-DQB1*0602 and (DRB1*1301)-*0603 haplotypes were significantly decreased among patients. Genotypes with two risk haplotypes or a combination of a susceptibility associated and a neutral haplotype were found in 78 of 126 (61.9%) T1D patients compared to 8 of 75 (10.7%) control subjects (P< 0.0001). Insulin gene −2221 C/T polymorphism was also associated with diabetes risk: CC genotype was found among 83.1% of patients compared to 69.3% of healthy controls (P= 0.0369, OR 1.98) but CTLA-4 gene +49 A/G polymorphism did not significantly differ between patients and controls. Despite the diversity of the Brazilian population the screening sensitivity and specificity of the used method for T1D risk was similar to that obtained in Europe.

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