4.7 Article

Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes

期刊

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 107, 期 4, 页码 E1510-E1517

出版社

ENDOCRINE SOC
DOI: 10.1210/clinem/dgab853

关键词

type 1 diabetes; epidemiology; electrochemiluminescence assay; prediction; genetics; HLA genotyping; autoantibody

资金

  1. NIDDK K12 training grant [K12DK094712]
  2. Type 1 Diabetes TrialNet Pathway to Prevention Study Group [NCT00097292]
  3. National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases
  4. National Institute of Allergy and Infectious Diseases
  5. Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK103180, U01-DK103153, U01-DK085476, U01-DK103266]
  6. Juvenile Diabetes Research Foundation International (JDRF)

向作者/读者索取更多资源

Objective Electrochemiluminescence (ECL) assays are high-affinity autoantibody tests used for risk screening and prediction of type 1 diabetes progression. This study analyzed the association of high-risk HLA haplotypes and genotypes with ECL positivity in relatives of individuals with type 1 diabetes, showing that ECL-GADA and ECL-IAA positivity are associated with HLA-DR3 and HLA-DR4 haplotypes, respectively.
Objective Electrochemiluminescence (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 human leukocyte antigen (HLA) haplotypes and genotypes with 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 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (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 Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 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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