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Autoantibodies and High-Risk HLA Susceptibility Markers in First-Degree Relatives of Brazilian Patients with Type 1 Diabetes Mellitus: A Progression to Disease Based Study

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Abstract

Purpose

The objective of this study was to determine the frequencies of autoantibodies to heterogeneous islet-cell cytoplasmic antigens (ICA), glutamic acid decarboxylase65 (GAD65A), insulinoma-associated antigen-2 (IA-2A) and insulin (IAA)–and human leukocyte antigen (HLA) class II markers (HLA-DR and -DQ) in first degree relatives of heterogeneous Brazilian patients with type I diabetes(T1DM). A major focus of this study was to determine the influence of age, gender, proband characteristics and ancestry on the prevalence of autoantibodies and HLA-DR and -DQ alleles on disease progression and genetic predisposition to T1DM among the first-degree relatives.

Methods

IAA, ICA, GAD65A, IA-2A and HLA- class II alleles were determined in 546 first-degree-relatives, 244 siblings, 55 offspring and 233 parents of 178 Brazilian patients with T1DM.

Results

Overall, 8.9% of the relatives were positive for one or more autoantibodies. IAA was the only antibody detected in parents. GAD65 was the most prevalent antibody in offspring and siblings as compared to parents and it was the sole antibody detected in offspring. Five siblings were positive for the IA-2 antibody. A significant number (62.1%) of siblings had 1 or 2 high risk HLA haplotypes. During a 4-year follow-up study, 5 siblings (expressing HLA-DR3 or –DR4 alleles) and 1 offspring positive for GAD65A progressed to diabetes.

Conclusions

The data indicated that the GAD65 and IA-2 antibodies were the strongest predictors of T1DM in our study population. The high risk HLA haplotypes alone were not predictive of progression to overt diabetes.

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Abbreviations

GAD65A:

Anti-glutamic acid decarboxylase 65 autoantibodies

IAA:

Anti-insulin autoantibodies

ICA:

Anti-Islet cell autoantibodies

IA-2A:

Anti-protein tyrosine phosphatase-like IA-2 (IA-2A) autoantibodies

HLA:

Human leukocyte antigen

TIDM:

Type 1 diabetes mellitus

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Acknowledgements

We wish to thank Professor Salman Azhar for the outstanding scientific suggestions and careful revision of the manuscript. We acknowledge Ms. Greci S Paula for his excellent technical assistance. We are grateful to all first-degree relatives of patients with T1DM who participated in our study. This study was supported in part by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Contribution statement

LA, ED, MC, RF, MC, RS, WV and MS all participated in designing the studies and in carrying out Clinical and Experimental Procedures. MS wrote, edited and finalized the manuscript for publication.

Duality of interest

The authors declare no duality of interest associated with this manuscript.

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Authors and Affiliations

  1. Laboratory of Medical Investigation LIM-18, Ambulatory of Endocrinology of Hospital das Clinicas of University São Paulo Medical School, São Paulo, Brazil

    L. I. Alves, E. Davini, M. R. Correia, R. T. Fukui, R. F. Santos, M. R. Cunha, D. M. Rocha & M. E. R. Silva

  2. Laboratory of Immunology, University of Campinas, Campinas, Brazil

    W. M. G. Volpini

  3. Laboratory of Medical Investigation—LIM-18, University of São Paulo Medical School, Av. Dr. Arnaldo, 455 Sala 3324, Cerqueira Cesar, São Paulo, 01246-903, Brazil

    M. E. R. Silva

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  1. L. I. Alves
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  2. E. Davini
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  3. M. R. Correia
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  4. R. T. Fukui
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  6. M. R. Cunha
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  9. M. E. R. Silva
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Correspondence to M. E. R. Silva.

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Alves, L.I., Davini, E., Correia, M.R. et al. Autoantibodies and High-Risk HLA Susceptibility Markers in First-Degree Relatives of Brazilian Patients with Type 1 Diabetes Mellitus: A Progression to Disease Based Study. J Clin Immunol 32, 778–785 (2012). https://doi.org/10.1007/s10875-012-9673-4

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  • DOI: https://doi.org/10.1007/s10875-012-9673-4

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