Effects of Non-HLA Gene Polymorphisms on Development of Islet Autoimmunity and Type 1 Diabetes in a Population With High-Risk HLA-DR,DQ Genotypes

Abstract Objective ECL assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk HLA haplotypes and genotypes with electrochemiluminescence (ECL) positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab (GADA or IAA) and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (Z-scores) for analyses. Results Mean age at initial visit was 19.4+13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA- DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all p<0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both p<0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (p<0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

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Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02040 ◽

2017 ◽

Vol 103 (8) ◽

pp. 2870-2878 ◽

Cited By ~ 3

Author(s):

Maarit K Koskinen ◽

Johanna Lempainen ◽

Eliisa Löyttyniemi ◽

Olli Helminen ◽

Anne Hekkala ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Response ◽

Class Ii ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Intravenous Glucose ◽

Hla Dr ◽

Hla Genotype ◽

First Phase Insulin Response

Abstract Context A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

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rs11203203 is associated with type 1 diabetes risk in population pre-screened for high-risk HLA-DR,DQ genotypes

Pediatric Diabetes ◽

10.1111/j.1399-5448.2012.00888.x ◽

2012 ◽

Vol 13 (8) ◽

pp. 611-615 ◽

Cited By ~ 9

Author(s):

Kelly Johnson ◽

Randall Wong ◽

Katherine J Barriga ◽

Georgeanna Klingensmith ◽

Anette-G Ziegler ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Diabetes Risk ◽

Hla Dr

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The effect of childhood cow's milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: The Diabetes Autoimmunity Study in the Young

Pediatric Diabetes ◽

10.1111/pedi.12115 ◽

2014 ◽

Vol 16 (1) ◽

pp. 31-38 ◽

Cited By ~ 34

Author(s):

Molly M Lamb ◽

Melissa Miller ◽

Jennifer A Seifert ◽

Brittni Frederiksen ◽

Miranda Kroehl ◽

...

Keyword(s):

Type 1 Diabetes ◽

Milk Intake ◽

Islet Autoimmunity ◽

Cow’S Milk ◽

Cow's Milk ◽

Hla Dr

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Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

10.2337/figshare.14384324 ◽

2021 ◽

Author(s):

Vibha Anand ◽

Ying Li ◽

Bin Liu ◽

Mohamed Ghalwash ◽

Eileen Koski ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cohort Studies ◽

Prospective Cohort ◽

Diabetes Risk ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Diabetes Incidence ◽

Prospective Cohort Studies ◽

Hla Dr

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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Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Islet Autoimmunity and Progression to Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young (DAISY)

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2256 ◽

2013 ◽

Vol 98 (11) ◽

pp. E1845-E1851 ◽

Cited By ~ 35

Author(s):

Brittni N. Frederiksen ◽

Miranda Kroehl ◽

Tasha E. Fingerlin ◽

Randall Wong ◽

Andrea K. Steck ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Gene Polymorphisms ◽

Islet Autoimmunity ◽

Vitamin D Metabolism ◽

Metabolism Gene

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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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