期刊
DIABETOLOGIA
卷 56, 期 9, 页码 1964-1970出版社
SPRINGER
DOI: 10.1007/s00125-013-2951-8
关键词
Autoantibodies; HLA-A; HLA-B; HLA class I; HLA class II; HLA-DQ; Prediction; Prevention; Risk assessment; Type 1 diabetes
资金
- JDRF [4-2005-1327]
- European Union [241833]
- Belgian Fund for Scientific Research (FWO Vlaanderen projects) [G.0319.01, G.0514.04, G.0311.07, G.0374.08, G.0868.11]
- Research Council of the Brussels Free University
- Willy Gepts Fund (University Hospital Brussels-UZ Brussel) [3-2005, 3/22-2007]
- DERC [NIH P30 DK57516]
- NIH [R01 DK052068]
- Belgian National Lottery
- ministry of Public Health of the Flemish Community of Belgium
- ministry of Public Health of the French Community of Belgium
- Hippo Friends
- WeightWatchers
- Ortho-Clinical Diagnostics
- Novo Nordisk Pharma
- Lifescan
- Roche Diagnostics
- Bayer
- Eli Lilly
Secondary type 1 diabetes prevention trials require selection of participants with impending diabetes. HLA-A and -B alleles have been reported to promote disease progression. We investigated whether typing for HLA-B*18 and -B*39 may complement screening for HLA-DQ8, -DQ2 and -A*24 and autoantibodies (Abs) against islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8) for predicting rapid progression to hyperglycaemia. A registry-based group of 288 persistently autoantibody-positive (Ab(+)) offspring/siblings (aged 0-39 years) of known patients (Ab(+) against insulin, GAD, IA-2 and/or ZnT8) were typed for HLA-DQ, -A and -B and monitored from the first Ab(+) sample for development of diabetes within 5 years. Unlike HLA-B*39, HLA-B*18 was associated with accelerated disease progression, but only in HLA-DQ2 carriers (p < 0.006). In contrast, HLA-A*24 promoted progression preferentially in the presence of HLA-DQ8 (p < 0.002). In HLA-DQ2- and/or HLA-DQ8-positive relatives (n = 246), HLA-B*18 predicted impending diabetes (p = 0.015) in addition to HLA-A*24, HLA-DQ2/DQ8 and positivity for IA-2A or ZnT8A (p a parts per thousand currency signaEuro parts per thousand 0.004). HLA-B*18 interacted significantly with HLA-DQ2/DQ8 and HLA-A*24 in the presence of IA-2 and/or ZnT8 autoantibodies (p a parts per thousand currency signaEuro parts per thousand 0.009). Additional testing for HLA-B*18 and -A*24 significantly improved screening sensitivity for rapid progressors, from 38% to 53%, among relatives at high Ab-inferred risk carrying at least one genetic risk factor. Screening for HLA-B*18 increased sensitivity for progressors, from 17% to 28%, among individuals carrying a parts per thousand yen3 risk markers conferring > 85% 5 year risk. These results reinforce the importance of HLA class I alleles in disease progression and quantify their added value for preparing prevention trials.
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