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In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

ABSTRACT: 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 ? 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 ? 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 ? 3 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.

SUBMITTER: Mbunwe E

PROVIDER: S-EPMC3918938 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Mbunwe E E Van der Auwera B J BJ Weets I I Van Crombrugge P P Crenier L L Coeckelberghs M M Seret N N Decochez K K Vandemeulebroucke E E Gillard P P Keymeulen B B van Schravendijk C C Wenzlau J M JM Hutton J C JC Pipeleers D G DG Gorus F K FK

Diabetologia 20130528 9

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>A registry-based group of 288 persistentl ...[more]

PMID: 23712485

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Project description:BACKGROUND AND OBJECTIVES:Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection. RESULTS:A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P<0.01), but not in deceased kidney donor recipients (HR, 1.05; 95% CI, 0.98 to 1.12; P=0.18) (P value for interaction <0.01). When taking cold ischemic time into account, HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P=0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P=0.49) (P value for interaction <0.01). Recipients with one or two HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P<0.01) in deceased donor and 1.14 (95% CI, 1.03 to 1.27; P=0.02) in living donor kidney transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not. CONCLUSIONS:HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants.

Dataset Information

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Publications

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Publications

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.

In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A24 and HLA-B18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions.